A misshapen calf, born in  Freiberg, Saxony , on 8 December 1522, quickly became important in the German Reformation. It was born with oddly shaped legs (its hind legs straight as a human's) and with a fold of skin over its head shaped like a  cowl —hence its comparison to a  monk . An illustration made its way to a Prague astrologer, who "discovered that the monster did indeed signify something terrible, indeed the most awful thing possible-- Martin Luther ." [ 10 ]  Luther himself responded quickly with a pamphlet containing a mock  exegesis  of the creature,  Monk Calf , in which the "Monk Calf" stands, in all its monstrosity, for the Catholic church. [ 12 ]  Luther's anti-papist pamphlet appeared together with a tract by  Philipp Melanchthon [ 13 ]  which discussed a fictional monster, the Pope-Ass, a hybrid between a man and a donkey supposedly found near Rome after the 1496 flood. [ 14 ]  Circulated in 1523, Martin Luther and Philipp Melanchthon's pamphlet was titled  The Meaning of Two Horrific Figures, the Papal Ass at Rome and the Monk Calf Found at Freyberg in Meissen . [ 15 ]   Lucas Cranach the Elder  and his workshop provided the illustrations of the Papal Ass and the Monk Calf for the pamphlet. Variations of Luther and Melanchthon's pamphlet eventually were circulated, including one that depicted the Papal Ass and the Monk Calf in "an encounter between the two creatures. This opening page adds a new phrase to the title of the book: 'with signs of the Day of Judgement.'" [ 16 ]


Especially monstrous births among humans were, from the early Middle Ages on, seen as signifying God's interaction with the world: "a monstrous birth  is  the shape of wickedness, not only the result of original sin but of more local and immediate forms as well." [ 17 ]  One of the best known examples of such births was the  Monster of Ravenna .


Although the connections between a monstrous birth and improper maternal behavior were eventually dismissed by reliable authorities, a particularly late incident involving such allegations took place in the  Massachusetts Bay Colony .  Mary Dyer , later to become a Quaker martyr, gave birth to a deformed child in October 1637. Noted religious dissenter  Anne Hutchinson , who was acquainted with the Dyer family and was present at that birth, was herself delivered of a "monster" in the next year. Both cases were publicized by  John Winthrop , who was at the time bringing legal proceedings against both women for heresy. [ 18 ]


MORM syndrome  is an  autosomal   recessive   congenital disorder [ 1 ]  characterized by  mental retardation , truncal obesity,  retinal dystrophy , and  micropenis ". [ 1 ]  The disorder shares similar characteristics with  Bardet–Biedl syndrome  and  Cohen syndrome , both of which are autosomal recessive genetic disorders. [ 1 ] [ 2 ]  MORM syndrome can be distinguished from the above disorders because symptoms appear at a young age. [ 1 ]  The disorder is not dependent on sex of the offspring, both male and female offspring are equally likely to inherit the disorder.


The syndrome is caused by a mutation in the  INPP5E  gene which can be located on chromosome 9 in humans. [ 3 ]   Further mapping resulted in the identification of a MORM syndrome locus on chromosome 9q34.3 between the genetic markers D9S158 and D9S905. [ 4 ]


For individuals with MORM syndrome, symptoms do not appear until about one year of age. [ 1 ]  From conception to birth, individuals with MORM syndrome appear asymptotic, with no abnormal characteristics. [ 1 ]  Vision is negatively affected within the first year of life, particularly night vision. [ 1 ]  Individuals with MORM syndrome experience decreased  visual acuity , meaning their ability to see distinct sharp lines decreases. [ 1 ] [ 5 ]  Vision quality continues to deteriorate until age three. [ 1 ]  Any further reduction in vision acuity is not observed until the individual is between the ages thirty to forty. [ 1 ]  Delayed  sentence processing  and  intellectual disability  is associated with individuals with MORM syndrome, primarily observed at age four. [ 1 ]  Individuals continue to develop and grow until they are five to twelve years old. During this age bracket, truncal obesity can develop, [ 1 ]  characterized by the buildup of fat around one's trunk or torso as opposed to the person's extremities. [ 6 ]  Males enter puberty at around age twelve and develop normally, except for their penis, which will remain at the prepubescent size, resulting in a  micropenis . [ 1 ]  Both the life span and fertility of individuals with MORM syndrome is unclear . [ 1 ]


MORM syndrome is associated with the gene INPP5E. [ 4 ]  INPP5E is a gene whose function is not well understood. [ 7 ]  It is hypothesized to play a role in primary cilia stability. [ 7 ]  A  homozygous   mutation  in the INPP5E gene, on chromosome 9q34, is the cause for MORM syndrome. [ 4 ]  The mutation causes a homozygous  transition  in the last  exon  of the INPP5E gene. [ 8 ]  This transition results in the  DNA bases  changing from a cytosine residue to a thymine residue. [ 8 ]
The resulting protein will then have an altered amino acid sequence. In unaffected individuals this specific  codon  (region of DNA bases) is supposed to code for the amino acid glutamine. [ 8 ]  In cases of MORM syndrome this codon codes for a termination sequence, which prematurely stops the production of the protein. [ 8 ]  In unaffected individuals the protein is evenly disbursed throughout the  cilia   axoneme , which stabilizes the cilia, which are antenna like structures which protrude from the extracellular surface of the cell. [ 7 ] [ 3 ]  They play an important role in extracellular signalling/communication between cells and their environment. [ 3 ]  When the INPP5E gene is mutated, the protein is damaged and is unable to spread out along the cilia axoneme or interact with other stabilizing proteins. [ 8 ]  This inability to stabilize one's cilia axoneme results in MORM syndrome. [ 8 ]  The exact mechanism as to how the mutation in the INPP5E gene causes cilia instability is still not well understood. [ 3 ]


MORM syndrome is a  genetic disorder  obtained through  inheritance . [ 4 ]  The main method for testing individuals showing symptoms of MORM syndrome is  sequence analysis  of the entire  coding region . [ 9 ]  When performing a sequence analysis of the entire coding region the gene INPP5E is targeted. [ 9 ]  Sequence analysis is the  biotechnological  process in which the structure and sequence of  DNA ,  RNA , or  protein sequence  is determined through the use of technology. This sequence can be analyzed to determine  mutations  or abnormalities in that particular region. When testing for MORM syndrome, sequence analysis of the region of the genome which contains the gene INPP5E is targeted and examined to look for mutations. [ 9 ]


Muenke syndrome , also known as  FGFR3-related craniosynostosis , [ 1 ]  is a human specific condition characterized by the premature closure of certain  bones  of the  skull  during  development , which affects the shape of the  head  and  face . First described by Maximilian Muenke, the syndrome occurs in about 1 in 30,000  newborns . This condition accounts for an estimated 8 percent of all cases of  craniosynostosis .


Many people with this disorder have a premature fusion of skull bones along the  coronal suture . Not every case has had craniosynostosis however. Other parts of the skull may be malformed as well. This will usually cause an abnormally shaped head, wide-set eyes, low set ears and flattened cheekbones in these patients. About 5 percent of affected individuals have an enlarged head ( macrocephaly ). There may also be associated  hearing loss  in 10–33% of cases and it is important for affected individuals to have hearing tests to check on the possibility of a problem. They can lose about 33-100% of hearing. [ citation needed ]


Most people with this condition have normal intellect, but developmental delay and  learning disabilities  are possible. The signs and symptoms of Muenke syndrome vary among affected people, and some findings overlap with those seen in other craniosynostosis syndromes. Between 6 percent and 7 percent of people with the  gene mutation  associated with Muenke syndrome do not have any of the characteristic features of the disorder. [ citation needed ]


Apart from craniosynostosis, it has been suggested [ by whom? ]  that hearing loss, and learning difficulties are common in Muenke syndrome.  According to Ulster Medical Journal, most individuals with Muenke syndrome may have limb findings.  The most common ocular finding in Muenke syndrome is strabismus as studied by Dr. Agochukwu-Nwubah and her researching team.
Approximately 20% of people with Muenke Syndrome will also be affected by epilepsy. [ citation needed ]


Muenke syndrome is caused by a specific gene mutation in the FGFR3 gene. The mutation arises randomly; there is no full understanding for what causes this mutation.  This mutation causes the FGFR3 protein to be overly active; it interferes with normal bone growth, and allows skull bones to fuse prematurely. There is no connection between anything mother did (or did not do) to activate the syndrome. If neither of the parents have Muenke syndrome, chances of having another child with the syndrome are minimal.
This condition is inherited in an autosomal dominant pattern. This means if a parent has Muenke syndrome, every newborn has a 50% chance of inheriting the syndrome. [ citation needed ]


Muenke syndrome is inherited in an  autosomal dominant  pattern. In some cases, an affected person inherits the mutation from one affected parent. If a patient is shown to have Muenke, they have a 50/50 chance of passing it on to their children. Not all cases of Muenke however is obvious. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.


A single mutation in the  FGFR3  gene cause this syndrome. The FGFR3 gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue. This mutation causes the FGFR3 protein to be overly active, which interferes with normal bone growth and allows the bones of the skull to fuse before they should. [ citation needed ]


As stated by researchers at the University of Washington, Muenke syndrome is inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity."  Prenatal diagnosis for pregnancies at increased risk is possible if the defining mutation has been identified in the family (Agochukwu et.al. 2006).  According to the article  Craniosynostosis: Molecular Genetics,  penetrance is higher in females (87%) than in males (76%).  Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis according to the Journal of Anatomy. [ citation needed ]


The diagnosis of Muenke syndrome is suspected bases on abnormal skull shape and a diagnosis of coronal craniosynostosis.  In 2006, Agochukwu and her colleagues concluded that "A distinct Muenke syndrome phenotype includes: uni or bilateral coronal synostosis, midface hypoplasia, broad toes, and brachydactyly."  Due to phenotypic overlap and/or mild phenotypes, clinical differentiation of this syndrome may be difficult.  The suspected diagnosis is confirmed by a blood test to check for gene mutation.  To establish the extent of disease in an individual diagnosed with Muenke syndrome, various evaluations are recommended. [ citation needed ]


The treatment of Muenke syndrome is focused on the correction of the abnormal skull shape and mirrors the treatment of coronal craniosynostosis.  The abnormal growth patterns continue throughout the growing years; therefore, intervention, accurate diagnosis, and a customized, expertly carried-out treatment plan should be a primary concern.  Although the timing of surgery can be highly individualized, surgical correction of the bicoronal craniosynostosis is most often done between 6 and 12 months of age.  Surgery is usually performed through a scalp incision that lies concealed within the hair of the head.  A craniofacial surgeon will work in concert with a pediatric neurosurgeon in order to safely remove the bones of the skull.  Then, the craniofacial surgeon reshapes and repositions those bones to give a more normal skull shape. [ citation needed ]


Mulibrey nanism  (" MU scle- LI ver- BR ain- EY e nanism")  is a rare  autosomal   recessive   congenital disorder . It causes severe growth failure along with abnormalities of the  heart ,  muscle ,  liver ,  brain  and eye.  TRIM37  is responsible for various cellular functions including developmental patterning. [ 5 ] [ 6 ] [ 7 ]


An individual with Mulibrey nanism has growth retardation, a short broad neck, misshapen  sternum , small  thorax , square  shoulders , enlarged  liver , and yellowish dots in the  ocular  fundi. [ 1 ] [ 7 ] [ 8 ]  Individuals with Mulibrey nanism have also been reported to have  intellectual disability ,  tumors , and  infertility . [ 1 ]


Mulibrey nanism is caused by mutations of the TRIM37  gene , [ 2 ]  located at human  chromosome   17q22-23 . [ 9 ]  The disorder is inherited in an  autosomal   recessive  manner. [ 7 ]  This means the defective gene responsible for the disorder is located on an  autosome  (chromosome 17 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both  carry  one copy of the defective gene, but usually do not experience any symptoms of the disorder. [ medical citation needed ]


The diagnosis of Mulibrey nanism can be done via  genetic testing , [ 3 ]  as well as by the physical characteristics (signs/symptoms) displayed by the individual. [ 10 ]


In terms of treatment/management for those with Mulibrey nanism should have routine medical follow-ups, additionally the following can be done: [ 4 ]


Worldwide, it has been documented in 110 persons, 85 of them  Finnish .  It is a  recessive  genetic disease. Many people with Mulibrey nanism have parents who are closely related,  consanguine .  Signs and symptoms are variable: siblings who suffer this disease sometimes do not share the same symptoms. [ 1 ]


When a patient has  multiple abnormalities  ( multiple anomaly ,  multiple deformity ), they have a  congenital abnormality  that cannot be primarily identified with a single  system of the body  or single  disease  process. [ 1 ]  Most  medical conditions  can have systemic  sequelae , but multiple abnormalities occur when the effects on multiple systems is immediately obvious. [ 1 ]


Abnormalities can have a range of multifactorial causes including; genetic causes, maternal conditions during pregnancy, combination of environment and genetic causes or unknown etiologies. [ 2 ]


MURCS association  (a variant of  Mayer-Rokitansky-Küster-Hauser syndrome ) is a very rare developmental disorder [ 2 ]  that primarily affects the reproductive and urinary systems involving  MU llerian agenesis ,  R enal agenesis ,  C ervicothoracic  S omite abnormalities. [ 3 ]  It affects only females.


Genetic heterogeneity is observed in MURCS association. [ 4 ]


Normal external genitalia.
Short blind-ending vagina (0–3 cm) with no cervix at the apex.
No uterus detected by manual palpation.


Two functional ovaries.


Determines the presence of rudimentary uterine buds or complete uterovaginal agenesis


Management of vaginal agenesis:  correction of vaginal agenesis in MRKH syndrome with creation of a functional neovagina has been a hallmark in the treatment. Various different surgical and non-surgical methods have been suggested for vaginal construction. [ 6 ]


Infertility and uterus transplantation (UTx):  Uterus transplantation (UTx) has now emerged as the first true infertility treatment for women with MRKH syndrome and giving them full (gestational, genetic, legal) motherhood from start. [ 7 ]


Muscle–eye–brain  ( MEB )  disease , also known as  muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A3  ( MDDGA3 ), [ 2 ]  is a kind of rare  congenital muscular dystrophy  (CMD), largely characterized by  hypotonia  at birth. Patients have muscular dystrophy, central nervous system abnormalities and ocular abnormalities. The condition is degenerative.


MEB is caused by mutations in the POMGnT1 gene, it is congenital and inherited as an  autosomal recessive disorder . There is no cure for MEB. Supportive care mainly focuses on symptoms alleviation which varies in different clinical settings. Symptomatic treatment may include physiological therapies, occupational therapies, medications, and surgeries. The life expectancy of patients with MEB is 10-30 years old, although there have been cases with longer lifespans.


The main signs and symptoms of MEB includes: [ 3 ]


The most prevalent signs of MEB is infants being born floppy. [ 4 ]  It refers to the condition of  hypotonia . The types of hypotonia found on patients include generalized hypotonia, diffuse hypotonia, congenital hypotonia and the other subtypes. [ 5 ]  Its cause behind is mainly the severe muscular dystrophy and partly brain abnormalities. [ 6 ]


80% - 99% individuals display various  myopathy . [ 2 ]  In general, they manifest severe muscle weakness and retarded motor development. Hence, gait disturbance (abnormal walking) is found in 80% - 99% of the diseased individuals. [ 2 ]  A significant portion of them have limited mobility that fail to walk or even rotate the head. [ 4 ]  The muscle weakness affects facial muscles apart from skeletal muscles. It gives rise to speech impairment in most of the cases. [ citation needed ]


The other signs include joint and/or spinal rigidity, reduced muscle mass,  hyporeflexia , muscular  contracture ,  spasticity , muscle atrophy and spinal deformities. [ 4 ]


Visual problems are often found in people with MEB. Patients have low visual acuity and fail to fixate to the visual stimuli. Depends on the severity, some display no visual response, some can response to light and some to object. [ 7 ]


More than 80% of the patients reported visual impairment. [ 2 ]  Common problems include  glaucoma ,  myopia ,  strabismus  ("crossed-eye") and optic atrophy which all occurs in 80-99%. [ 2 ]  Optic atrophy contains poor pigmentation of  ocular fundi , thin blood vessels of retina, small optic discs and scleral border and optic coloboma (degeneration of the inferior optic nerve). [ 3 ] [ 8 ]   Cataract  affects 30% - 79% of individuals. [ 2 ]   Buphthalmos  (enlargement of the eyeball),  megalocornea  (enlargement of cornea) and  nystagmus  (uncontrollable eyeball movement) are present in some rare case. [ 2 ] [ 8 ]


Although ocular abnormalities account for the poor vision to a large extent, some of the visual problems is associated with the brain abnormalities. [ 7 ]


MEB impairs the cognition gravely. This is reflected by the abnormal  EEG  and  EMG  reading in 80% - 99% individuals. [ 2 ]  At the same frequency,  hydrocephalus  present in many cases. [ 2 ]  The severe form of it is associated with the compression of other nerves and results in more complications. [ 9 ]


Clinical features include severe mental retardation in all aspects. Most individuals have intellectual disabilities of a range of severity. [ 2 ] [ 10 ]  Progressive deterioration in behavioral development has been recorded. [ 8 ]   Epilepsy  and  seizures  are found in 30% - 79% of the affected individuals. [ 2 ]


Manifestations in structural malformation are common as well.  Hypoplasia  of  mesencephalon ,  pons ,  cerebellum  and  medulla  are often. [ 11 ] [ 12 ]   Aplasia  may occur on top of  hypoplasia . Flattened brainstem,  ventriculomegaly ,  pachygyria , Type II  lissencephaly  have been reported. [ 10 ] [ 12 ]  At the rate between 5% and 29%  holoprosencephaly  and  meningocele  occurs in patients too. [ 2 ]


Distinctive facial features for MEB found are high prominent forehead, bulging eye and narrow temporal regions. [ 13 ]


MEB is caused by mutations of the protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) gene. Pathogenic variants mutate the gene and lead to dysfunction of the POMGnT1 enzyme.  Currently, there are 14 clinically identified mutations, the locations are dispersed and scattered throughout the POMGnT1 gene. [ 10 ] [ 6 ]  Different mutations were observed in MEB patients from different countries, namely Finland, Sweden, Norway, Estonia, USA, Israel, Spain and Italy. [ 6 ]  From 14 non-Finnish patients, 9 different types of mutation were identified. [ 6 ]


The location of the mutation is slightly correlated with the severity of the symptoms in terms of brain structural abnormalities. [ 10 ]  Mutations close to the 5′ terminus of the POMGnT1 coding region lead to relatively more severe phenotype such as hydrocephalus. Mutations that occurred close to the 3′ terminus shows weaker symptoms. [ 10 ]


MEB is an autosomal recessive disease inherited from parents. Patients with MEB have two copies of a pathogenic variant in their gene. There will be a risk of having a child with MEB given that both parents are carriers of a pathogenic variant in their gene. The affected child inherits a mutated copy of the gene from each carrier parent. The chance of inheritance is 1 in 4  when both parents carry the pathogenic variant. [ 15 ]


The pathogenesis of MEB is related to an abnormal level of α‐dystroglycan glycosylation. Genetic mutations of the POMGnT1 gene reduced the O-mannosyl glycosylation of α-dystroglycan. The POMGnT1 gene encodes the enzyme POMGnT1, a type II transmembrane protein residing in the Golgi Apparatus. [ 14 ]  The role of the enzyme POMGnT1 is to catalyse glycosylation specific for alpha-linked terminal mannose, the process where  N -acetylglucosamine is added to O-linked mannose of α-dystroglycan. [ 14 ]  In humans, O-mannosylation is a rare type of glycosylation, occurring in skeletal muscle, brain and nerve glycoproteins. [ 10 ]  O-mannosylation is used to increase the stability of the interaction between the extracellular basement membrane and α-dystroglycan. Without stabilization, the glycoprotein cannot anchor to the cell, leading to  congenital muscular dystrophy  (CMD), characterised by severe brain malformations. [ 16 ]


Medical diagnosis for the MEB usually involves the study of family history, measurement of serum CPK level, molecular testing, muscle biopsy and imaging study. [ 17 ]


People with MEB have distinctive facial dysmorphisms. [ 18 ]  Rounded forehead, thin and drooping lip, micrognathia, midface retrusion, short nasal bridge are the possible indicative evidence for diagnosis. [ 2 ] [ 18 ]  Assessment of motor and mental development, visual ability also provide clues. [ citation needed ]


Genetic test can analyze the genome of infants for confirmation of the specific genetic mutation. Mutation in the POMGNT1 is the determinant in the diagnosis of MEB. [ 19 ]  Several mutations like [c.1539+1G→A], [c.879+5G→T] are the prevalent nucleotide change found in affected people. [ 18 ] [ 19 ]  The commonly used practices collect fetal DNA by chronic villus sampling, followed by linkage analysis and direct sequencing to conclude the POMGNT1 gene sequence. [ 20 ]


The genome determination helps to distinguish other congenital muscular dystrophies before and after birth. However, only some laboratories provide prenatal genetic test to screen for MEB. [ 2 ]


MEB can be diagnosed with medical imaging by the shared patterns of brain structural abnormalities. Common practice includes  magnetic resonance imaging  (MRI) and  computerized tomography  (CT). They can show the enlargement of ventricle, absence or degeneration of septum pellucidum, pachygyric symptoms, abnormalities in corpus collosum, lissencephaly. [ 21 ]  Fetal MRI and ultrasound are used as a prenatal diagnostic tool if needed to screen for the disease. Observation like general structural malformation in the third trimester suggests congenital muscular dystrophy. [ 22 ]  Further diagnostic test is required to make confirmation. [ citation needed ]


Clinically, MRI is preferred over CT scan for its ability to reveal the neuron migration more precisely. [ 21 ]  The result obtained from CT scan is limited to the size of ventricles and location of white matter whereas only MRI can provide information on cortical problems.


Muscle biopsy  is a means to investigate the muscle tissue. Morphology of muscle cells and other chemical parameters can be used to diagnoses muscle–eye–brian disease. [ citation needed ]


Direct examination of muscular tissues can proof muscle dystrophy, which can support the potential diagnosis of MEB. Patients are found to have myofibrils round in shape and in markedly various diameters, later nuclei, regenerating fibers and angulated fibers as a result from atrophy. [ 17 ] [ 23 ]


The mutation of MEB involves the malfunction of  O -mannosyl ß-1,2- N -acetylgucosaminyltransfersase 1. By measuring the enzymatic activity of this protein, the presence of MEB can be affirmed. [ 17 ]  Fibroblast and lymphoblasts are chosen to be the assayed participants. [ 24 ]


Western-blot  (immunoblot) can be used to detect the  O -mannosyl ß-1,2- N -acetylgucosaminyltransfersase 1 for diagnosis. [ 23 ] [ 25 ]  It helps to evaluate the glycosylation state of the protein which it supposed to do. [ citation needed ]


As a subtype of muscular dystrophy-dystroglycanopathy, MEB is often confused with other sub-type including  Walker–Warburg syndrome  and  Fukuyama congenital muscular dystrophy . [ 17 ] [ 26 ]  All these 3 diseases share similar clinical presentation and are classified as the Type A(severe). [ 26 ]  Overlapped findings contain clinical presentation and immunochemistry result. [ 27 ]  The diagnosis has to make distinction among them. The decisive evidences for MEB are:


MEB: muscle–eye–brain disease


WWS: Walker–Warburg syndrome


FCMD: Fukuyama congenital muscular dystrophy


There is no current curative treatment for any form of muscle dystrophies and only symptomatic care is available for the patients. [ 17 ]


The corresponding supportive care to symptoms is: [ 33 ] [ 34 ]


MEB has a wide range in severity. Most children with MEB has a life expectancy of 10-30 years. But in some patients with milder type of congenital muscle dystrophies, might have a survival up to more than 70 years being possible. [ 34 ]  The severity of MEB determines its prognosis. Though the prognosis is associated with the progression of symptoms, supportive care enhances the quality of life and also the life expectancy. [ 29 ]


The majority of MEB occurrence is reported in the Finnish population. It is estimated to affect 1 in 50,000 newborns in Finland. [ 15 ]  MEB is also identified outside of Finland, there were cases of suspected MEB in Japan and Korea. [ 10 ]  However, worldwide distribution is unclear. [ 10 ]  According to the European Union, the estimated prevalence of MEB in Europe is 0.12 per 100000. [41]


The frequency of being a carrier of MEB is 1 in 50 in Finland, carriers for MEB commonly shows no signs or symptoms. However, their offsprings will have a higher chance to be affected by MEB. [ 15 ]


MEB was first discovered in Finland. In 1978, a patient from Finland showed symptoms including congenital muscular weakness, severe myopia, glaucoma, optical malformation, intellectual disability, retinal hypoplasia, etc. [ 36 ]  In 1980, 14 more people with similar symptoms were identified in Finland. [ 37 ]  Similar cases were also published in 1989. [ 38 ]  The disease was found in Dutch in 1992, 6 people were affected coming from 4 families. [ 39 ]  After that, more cases were reported outside the Finnish population. [ citation needed ]


MEB is phenotypically similar to the Walker–Warburg syndrome (WWS), both disorders are congenital muscular dystrophy.  In 1990, Santavuori argued to distinct MEB from WWS, since MEB is specifically involving muscle weakness and there is a relatively long survival for MEB patients. [ 40 ]  In the same year, Dobyns further examined the relation of WWS and MEB. [ 41 ]


In 2001, the cause of MEB was first demonstrated as the mutations in the POMGNT1 gene, causing loss of its function. [ 42 ]


Myelokathexis  is a  congenital disorder  of the  white blood cells  that causes severe, chronic  leukopenia  (a reduction of circulating white blood cells) and  neutropenia  (a reduction of  neutrophil granulocytes ). [ 1 ]  The disorder is believed to be inherited in an  autosomal   dominant  manner. [ 1 ] [ 2 ]  Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). The disorder shows prominent neutrophil morphologic abnormalities.  [ citation needed ]


Myelokathexis is amongst the diseases treated with  bone marrow transplantation  and  cord blood   stem cells . [ citation needed ]
WHIM syndrome is a very rare variant of severe congenital neutropenia that presents with warts, hypogammaglobunemia, infections, and myelokathexis. A gain-of-function mutation resulting in a truncated form of CXCR4 is believed to be its cause. The truncated form of the receptor has a 2-fold increase in G-protein coupled intracellular signalling, and this mutation of the receptor can be identified by DNA sequencing.  [ 3 ]


Nager acrofacial dysostosis , also known as  Nager syndrome , is a  genetic disorder  which displays several or all of the following characteristics:  underdevelopment of the cheek and jaw area , down-sloping of the opening of the  eyes , lack or absence of the lower  eyelashes , kidney or stomach  reflux ,  hammer toes , shortened  soft palate , lack of development of the  internal  and external  ear , possible  cleft palate , underdevelopment or absence of the  thumb ,  hearing loss  (see  hearing loss with craniofacial syndromes ) and shortened  forearms , as well as poor movement in the  elbow , and may be characterized by accessory  tragi . [ 3 ]  Occasionally, affected individuals develop vertebral anomalies such as  scoliosis .


The inheritance pattern is  autosomal , but there are arguments as to whether it is  autosomal dominant  or  autosomal recessive . Most cases tend to be sporadic. Nager syndrome shares many characteristics with other craniofacial syndromes:  Miller ,  Treacher Collins  and  Pierre Robin .


While Nager syndrome is thought to be most often caused by  haploinsufficiency  of the  spliceosomal  factor  SF3B4 , [ 4 ]  in over one third of patients tested, the SF3B4 mutation is not found. [ 5 ]  Genetic sequencing shows that the syndrome can be caused by either autosomal recessive or autosomal dominant inheritance. [ 6 ]


Due to craniofacial development, it is recommended that families work closely with craniofacial specialists as soon as Nager is recognized or suspected. Children born with Nager may need intubation immediately after birth, requiring tube feeding and a tracheotomy tube to help with breathing. Surgical intervention is commonly necessary to increase mandibular mobility. As the child grows and develops, further surgery is usually required on the lower jaw and is often done in tandem with orthodontic treatments. [ 7 ]  Further treatment depends upon the symptoms of the individual patient and may include oral surgery, plastic surgery, audiological intervention to manage hearing loss, speech therapy, and surgery on the limbs to aid with mobility limitations. [ 8 ]


Nakajo syndrome , also called  nodular erythema with digital changes , [ 1 ]  is a rare  autosomal   recessive   congenital disorder  first reported in 1939 by A. Nakajo in the offspring of  consanguineous  (blood relative) parents. [ 2 ] [ 3 ]  The syndrome can be characterized by  erythema  (reddened skin), loss of  body fat  in the upper part of the body, and disproportionately large eyes, ears, nose, lips, and fingers. [ 1 ]


Signs of the disease begin during early childhood with individuals developing red, swollen lumps (nodular erythema) on the skin especially during colder weather, frequent fevers, and elongated fingers and toes with widened and rounded tips ( clubbing ). [ 4 ]


Later in childhood, individuals with the disease develop join pain, and joint deformities ( contractures ) that limit movement predominantly in the hands, wrists, and elbows. They additional have weakness and wasting of muscle and fat loss that worsens over time. This leads to an extremely thin ( emaciated ) appearance in the face, chest, and arms. [ 4 ]


Other symptoms of Nakajo-Nishimura syndrome are enlarged liver and spleen ( hepatosplenomegaly ), shortage of red blood cells ( anemia ), reduced levels of platelet blood cells ( thrombocytopenia ), and calcification in the basal ganglia area of the brain. There have been cases of intellectual disability in affected individuals. [ 4 ]


Nakajo-Nishimura syndrome has overlapping symptoms with joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP) syndrome and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature ( CANDLE ) syndrome. These conditions are all caused by mutations in  PSMB8  and characterized by skin abnormalities and  lipodystrophy . Although these conditions are considered different diseases, some researchers believe they represent different forms of a single condition. [ 4 ]


Nakajo syndrome is inherited in an  autosomal recessive  manner. [ 3 ]  This means the defective gene responsible for the disorder is located on an  autosome , and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. This gene is called  PSMB8  and is located on chromosome 6 at 6p21.32. [ 5 ]  This gene codes for a subunit called immunoproteasomes that are found immune system cells. These cells are crucial for identifying viral proteins. It has been noted that malfunctions in PSMB8 cause the destruction of proteins which leads to muscle degradation and fat loss. The parents of an individual with an autosomal recessive disorder both  carry  one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. [ 4 ]  Although variations in severity has little clinical support, onset of Nakajo syndrome can vary from ages 1–18. [ 6 ]


Typical diagnosis looks for at least five out of eight proposed criteria for Nakajo syndrome: an autosomal recessive inheritance pattern, pernio-like purplish lesions (on hands and feet), ''haunting'' nodular erythema, repetitive spiking fever, long clubbed fingers and toes with joint contractures, progressive upper body lipomuscular atrophy/emaciation, hepatosplenomegaly and basal ganglion calcification on computed tomography (CT) scans. These features are not always apparent until childhood.  Histopathologic  examination shows focal mononuclear cell infiltration with  vasculopathy . Laboratory results include continually elevated C-reactive protein (CRP) levels and  hyper-gamma-globulinemia . Autoantibody titers rise as the disease progresses in some but remain negative in others. Molecular  genetic testing  can detect a disease causing mutation, verifying diagnosis. [ 7 ]


Currently, there are no treatments for Nakajo syndrome. However, available treatment options may help alleviate some of the symptoms. Existing steroids may help reduce inflammatory responses. Various  immunosuppressive  and  anti-rheumatic  have shown to have little or no temporal response in PRAAS patients. Ultimately, the progressive  lipodystrophy  caused by Nakajo syndrome continues despite treatment. [ 8 ]


Two affected siblings reported by Tanaka were born from a  consanguineous  marriage. [ 9 ]  Though a majority of cases originate in Japan, however two siblings reported by Garg were Portuguese and also born from a consanguineous marriage. [ 6 ]


Nasodigitoacoustic syndrome , also called  Keipert syndrome , is a  rare   congenital   syndrome  first described by J.A. Keipert and colleagues in 1973. The syndrome is characterized by a misshaped nose, broad thumbs and  halluces  (the big toes),  brachydactyly ,   sensorineural hearing loss , facial features such as  hypertelorism  (unusually wide-set eyes), and  developmental delay .


It is believed to be inherited in an  X-linked recessive  manner, which means a  genetic   mutation  causing the disorder is located on the  X chromosome , and while two copies of the mutated gene must be inherited for a female to be born with the disorder, just one copy is sufficient to cause a male to be born with the disorder. Nasodigitoacoustic syndrome is likely caused by a mutated gene  located  on the X chromosome between positions Xq22.2–q28.


The incidence of the syndrome has not been determined, but it is considered to affect less than 200,000 people in the United States, and no greater than 1 per 2,000 in Europe. It is  similar  to  Keutel ,  Muenke ,  Rubinstein  and  Teunissen–Cremers syndrome . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]


Nasodigitoacoustic syndrome is congenital and is characterized by a number of nasal, facial and cranial features. These include a broad and high, sometimes depressed  nasal  bridge (top of the nose, between the eyes) and a flattened nasal tip. [ 2 ] [ 6 ] [ 7 ]  This can give the nose a shortened, arch-like appearance. [ 8 ]   Hypertelorism  (unusually wide-set eyes), [ 4 ]  prominent frontal bones and  supraorbital ridge  (the eyebrow ridge), bilateral  epicanthic folds  (an extra flap of skin over the eyelids), a broad forehead and an overall enlarged head circumference have also been observed. A bulging of the upper lip with an exaggerated  cupid's bow  shape, [ 9 ]  and  maxillary hypoplasia  (underdevelopment of the  upper jaw ) with  retraction  have also been reported. [ 2 ] [ 7 ] [ 10 ]


Several anomalies affecting the  digits  (fingers and toes) have been observed with the syndrome. A broadening of the thumbs and big toes ( halluces ) was reported in two brothers. The broadening was apparent in all  distal phalanges  of the fingers, although the pinkies were unaffected yet appeared to be  clinodactylic  (warped, or bent toward the other fingers). [ 2 ]  Additional reports described this broadness of the thumbs and big toes, with  brachydactyly  (shortness) in the distal phalanges of the other digits except the pinkies in affected individuals. On  X-rays  of a two-year-old boy with the disorder, the brachydactyly was shown to be caused by shortening of  epiphyses  ( joint -ends) of the distal phalanges. [ 7 ] [ 11 ]  The broadness and brachydactyly of the big toes in particular may give them a stunted, rounded and stub-like appearance. [ 8 ]


The  auditory , or "acoustic" abnormalities observed with the syndrome include  sensorineural hearing loss  and hoarseness. Two affected Turkish brothers with a mild form of this hearing loss, and a hoarse voice were reported. A  laryngoscopic  examination of both brothers revealed  swelling  of the  vocal cords , and a malformed  epiglottis . [ 6 ]  Sensorineural-associated  hearing impairment  and hoarseness was also observed in a 10-year-old girl and her father, [ 10 ]  and in a number of other cases. [ 3 ] [ 7 ]


Other characteristics seen with the syndrome include  developmental delay ,  growth retardation ,  pulmonary stenosis  (an obstruction of blood-flow from the  right ventricle  of the  heart  to the  pulmonary artery ) with associated  dyspnea  (shortness of breath), and  renal agenesis  (failure of the  kidneys  to develop during the  fetal  period).  Undescended testes ,  hyperactivity  and  aggressive behavior  have also been noted. [ 2 ] [ 3 ] [ 4 ]


Nasodigitoacoustic syndrome is thought to be caused by a  mutation  in a gene on the  X chromosome . A 2007 study concluded, based on analysis of  microsatellite  markers (small gene sequences found in common among individuals having the same ethnicity, ancestry or genetic disease) of the family described by Keipert, that this gene was likely  located  on the long arm of the X chromosome between positions Xq22.2–q28. This is not definitive, however, and no specific gene has been named. [ 3 ]


The syndrome is strongly believed to be inherited in an  X-linked recessive  manner. [ 3 ]  When a female  carries  a mutated gene on one of her two copies of the X chromosome, there is a 50% chance of passing the mutation on to her children. Much like her, a daughter inheriting this mutation will be a carrier, but will not herself have the associated disease. However, a son who inherits the mutation will have the disease; this is because males have only  one copy  of the X chromosome and therefore could only express the disease mutation.


This form of inheritance for Nasodigitoacoustic syndrome is not yet absolute, though, as a girl has been reported with the disorder. It is suggested that further analysis is needed for the inheritance to be formally established. [ 7 ] [ 10 ]


The mutations causing this syndrome have been mapped to the glypican 4 ( GPC4 ) gene. [ 12 ]  This gene is located on the long arm of  chromosome X  (Xq26.2).


The constellation of anomalies seen with nasodigitoacoustic syndrome result in a distinct diagnosis. The diagnostic criteria for the disorder are broad distal phalanges of the thumbs and big toes, accompanied by a broad and shortened nose, sensorineural hearing loss and developmental delay, with predominant occurrence in males. [ 4 ] [ 9 ]


Nasodigitoacoustic syndrome is  similar  to several syndromes that share its features. [ 4 ] [ 7 ]  Brachydactyly of the distal phalanges, sensorineural deafness and pulmonary stenosis are common with  Keutel syndrome . [ 13 ]  In  Muenke syndrome , developmental delay, distal brachydactyly and sensorineural hearing loss are reported; features of  Teunissen-Cremers syndrome  include nasal aberrations and broadness of the thumbs and big toes, also with brachydactyly. [ 14 ] [ 15 ]  Broad thumbs and big toes are primary characteristics of  Rubinstein syndrome . [ 16 ]


A number of features found with nasodigitoacoustic syndrome can be managed or treated. Sensorineural hearing loss in humans may be caused by a loss of  hair cells  (sensory receptors in the inner ear that are associated with hearing). This can be hereditary and/or within a syndrome, as is the case with nasodigitoacoustic syndrome, [ 4 ]  or attributed to infections such as viruses. For the management of sensorineural hearing loss,  hearing aids  have been used. Treatments, depending upon the cause and severity, may include a  pharmacological  approach (i.e., the use of certain  steroids ), or  surgical intervention , like a  cochlear implant . [ 17 ] [ 18 ] [ 19 ]


Pulmonary, or pulmonic stenosis is an often congenital  narrowing  of the pulmonary valve; it can be present in nasodigitoacoustic-affected infants. [ 4 ]  Treatment of this cardiac abnormality can require surgery, or non-surgical procedures like  balloon valvuloplasty  (widening the valve with a  balloon catheter ). [ 20 ]


The syndrome was initially described in 1973 by James A. Keipert and associates. They reported of two brothers with broad distal phalanges, sensorineural hearing loss, and facial features consistent with what would become known as Keipert or "nasodigitoacoustic" syndrome. [ 2 ] [ 4 ]


Although no specific rate of incidence has been determined, the syndrome is considered a  rare disease  by both the Office of Rare Diseases (ORDR) at the  National Institutes of Health , and  Orphanet . This suggests, respectively, that nasodigitoacoustic syndrome affects less than 200,000 people in the U.S., or affects no greater than 1 per 2,000 people in Europe. [ 5 ]


Natal teeth  are  teeth  that are present above the gumline (have already  erupted ) at  birth , and  neonatal teeth  are teeth that emerge through the  gingiva  during the first month of life (the  neonatal  period). [ 1 ] [ 2 ]


The incidence of neonatal teeth varies considerably, between 1:700 and 1:30,000 depending on the type of study; the highest prevalence is found in the only study that relies on personal examination of patients. [ 3 ]


Natal teeth, and neonatal teeth, can be the baby's normal deciduous teeth, sprouting prematurely. [ 4 ]  These should be preserved, if possible.  Alternately, they could be  supernumerary teeth , extra teeth, not part of the normal allotment of teeth. [ 5 ]


Most often natal teeth are mandibular central incisors. [ 6 ]  They have little root structure and are attached to the end of the gum by soft tissue and are often mobile. [ 7 ]


Most of the time, natal teeth are not related to a medical condition. However, sometimes they may be associated with: [ 7 ]


No intervention is usually recommended unless they are causing difficulty to the infant or mother. [ 3 ]


However some recommend that they be removed as the tooth can cut or amputate the tip of the tongue.


They should be left in the mouth as long as possible to decrease the likelihood of removing permanent tooth buds with the natal tooth. [ 9 ]  They should also not be removed if the infant has  hypoprothrombinemia . [ 9 ]  In case of complications when the natal teeth need to be removed, dental radiographs should be obtained whenever possible, and evaluated and followed up with  pediatric dentists . [ 9 ]


Neu–Laxova syndrome  (NLS, also known as  Neu syndrome ;  Neu-Povysilová syndrome ; or  3-phosphoglycerate dehydrogenase deficiency , neonate form) [ 2 ]
is a rare  autosomal recessive  disorder characterized by severe  intrauterine growth restriction  and multiple  congenital malformations . Neu–Laxova syndrome is a very severe disorder, leading to  stillbirth  or death shortly after birth. It was first described by Dr. Richard Neu in 1971 [ 3 ]  and Dr.  Renata Laxova  in 1972 [ 4 ]  as a lethal disorder in siblings with multiple malformations. Neu–Laxova syndrome is an extremely rare disorder with fewer than 100 cases reported in medical literature.


Neu-Laxova syndrome presents with severe malformations leading to prenatal or neonatal death. Typically, NLS involves characteristic facial features, decreased fetal movements and skin abnormalities. [ 5 ]
Fetuses or newborns with Neu–Laxova syndrome have typical facial characteristics which include  proptosis  (bulging eyes) with eyelid malformations, nose malformations, round and gaping mouth,  micrognathia  (small jaw) and low set or malformed ears. Additional facial malformations may be present, such as  cleft lip  or  cleft palate . Limb malformations are common and involve the fingers ( syndactyly ), hands, or feet. Additionally,  edema  and flexion deformities are often present. Other features of NLS are severe  intrauterine growth restriction , skin abnormalities ( ichthyosis  and  hyperkeratosis ) and decreased movement.
Malformations in the  central nervous system  are frequent and may include  microcephaly ,  lissencephaly  or  microgyria ,  hypoplasia of the cerebellum  and  agenesis of the corpus callosum . Other malformations may also be present, such as  neural tube defects . [ citation needed ]


Neu-Laxova syndrome is a heterogeneous  metabolic disorder  caused by  homozygous  or  compound heterozygous  mutations in one of three genes:  PHGDH ,  PSAT1  and  PSPH [ 6 ] [ 7 ]  These genes are involved in the  serine biosynthesis pathway  and are essential for  cell proliferation .
Mutations in all three genes had been previously identified as the cause of serine-deficiency syndromes. Although there is some clinical overlap between NLS and these neurometabolic disorders, the phenotype in other serine-deficiency disorders is milder.


The diagnosis is usually based on clinical features present at birth.
Ultrasound in the second trimester may show abnormalities associated with NLS, including  polyhydramnios ,  intrauterine growth restriction ,  microcephaly ,  proptosis  and decreased fetal motility. [ citation needed ]


Serine  and  glycine  supplementation has shown tentative benefits in those with related serine biosynthesis defects and milder forms of NLS. [ 8 ]


The prognosis is poor; affected individuals are either  stillborn  or die shortly after birth. The longest survival reported in the literature is 134 days. [ citation needed ]  This syndrome is transmitted as an  autosomal recessive  disorder and there is a  risk for recurrence  of 25% in future pregnancies.


Neurocristopathy  is a diverse class of pathologies that may arise from defects in the development of tissues containing cells commonly derived from the embryonic  neural crest  cell lineage. [ 1 ] [ 2 ]  The term was coined by Robert P. Bolande in 1974. [ 3 ]


After the induction of the  neural crest , the newly formed neural crest cells (NCC) delaminate from their tissue of origin and migrate from the entire neural axis of the vertebrate embryo to specific locations where they will give rise to different cell derivatives. The formation of this cell population therefore requires a timely and spatially controlled interplay of inter- and intra-cellular signals. An alteration in the occurrence and timing of these signals leads to a set of syndromes called Neurocristopathies (NCP), which comprises a broad spectrum of congenital malformations affecting an appreciable percentage of newborns. [ 4 ]  Moreover, since NCC migrate along the embryo, they are susceptible to subtle changes in the environment both during their migration and upon arrival at their destination. This means that even little modifications, either genetically or environmentally caused, [ 5 ]  in the external cues that modulate NCC migration have a deep effect on the normal migration and differentiation of these cells, thus becoming a causative factor for the development of NCP.


Recently, a new classification for this group of diseases has been proposed. [ 6 ]  This new criteria takes into account the axial origin of the NC population that contributes to the derived tissue affected in a particular NCP. According to this, some diseases have a single axial origin, i.e., they arise from an alteration in the development of only one NC population (e.g. cranial NCP, such as Auriculo Condylar Syndrome). However, other NCP arise from a defect in two or more NC populations (such as the  CHARGE syndrome ).


Accepted examples of NCP are  piebaldism ,  Waardenburg syndrome ,  Hirschsprung disease ,  Ondine's curse  (congenital central hypoventilation syndrome),  pheochromocytoma ,  paraganglioma ,  Merkel cell carcinoma ,  multiple endocrine neoplasia ,  neurofibromatosis type I ,  CHARGE syndrome ,  familial dysautonomia ,  DiGeorge syndrome ,  Axenfeld-Rieger syndrome ,  Goldenhar syndrome  (a.k.a.  hemifacial microsomia ),  craniofrontonasal syndrome ,  congenital melanocytic nevus ,  melanoma , and certain  congenital heart defects  of the outflow tract. Recently, many diseases have been incorporated as NCP, mainly based on the finding of new NC derivatives. In particular,  Multiple sclerosis  has been suggested as being neurocristopathic in origin. [ 7 ]


The usefulness of the definition resides in its ability to refer to a potentially common  etiological  factor for certain neoplasms and/or congenital malformation associations that are otherwise difficult to group with other means of  nosology . Moreover, the classification of NCP is intended to help physicians understand the causal mechanism that drives the formation of a certain NCP, and therefore the selection of the correct diagnostic test and therapies.


Neurocutaneous melanosis  is a congenital disorder characterized by the presence of  congenital melanocytic nevi  on the skin and  melanocytic tumors  in the  leptomeninges  of the  central nervous system . [ 2 ]  These  lesions  may occur in the  amygdala ,  cerebellum ,  cerebrum ,  pons  and  spinal cord  of patients. Although typically asymptomatic,  malignancy  occurs in the form of leptomeningeal  melanoma  in over half of patients. [ 3 ]  Regardless of the presence of malignancy, patients with symptomatic neurocutaneous melanosis generally have a poor prognosis with few treatment options. [ 4 ]  The pathogenesis of neurocutaneous melanosis is believed to be related to the abnormal  postzygotic  development of  melanoblasts  and mutations of the  NRAS  gene. [ 5 ]


Neurocutaneous melanosis is associated with the presence of either giant congenital melanocytic nevi or non-giant nevi of the skin. It is estimated that neurocutaneous melanosis is present in 2% to 45% of patients with giant congenital melanocytic nevi. Patients with non-giant congenital melanocytic nevi seem to have a much lower, but undefined risk. Of these patients, only a small number are symptomatic, usually displaying symptoms before the age of 2. [ 6 ]  These symptoms are the result of melanocytic lesions being present in the leptomeninges of the central nervous system. [ 3 ]  Symptoms can include:


Others symptoms may also exist that are related to an increase in  intracranial pressure . These symptoms seem to be present regardless of the malignancy of the melanin deposits within the central nervous system. [ 7 ]


Approximately 10% of patient with neurocutaneous melanosis also present the  Dandy–Walker syndrome  and associated Dandy-Walker malformation. This malformation involves an enlargement of the  posterior fossae  and  fourth ventricle  along with agenesis of the  cerebellar vermis . The abnormalities of the leptomeninges during fetal development due to neurocutaneous melanosis may be the cause of this increased incidence of the Dandy-Walker malformation.  The development of  hydrocephalus  is the most common symptom associated with a combination of neurocutaneous melanosis and a Dandy-Walker malformation, occurring in about two out of three patients. [ 8 ]


The exact pathogenesis of neurocutaneous melanosis is not entirely clear. [ citation needed ]


One factor that may contribute to the development of neurocutaneous melanosis is the abnormal postzygotic development of melanoblasts. This mutation would possibly occur within the  neural crest  of the  ectoderm . After the mutation occurs, these cells would then migrate to the  meninges  as the precursors to the malignant or benign melanocytes.
This mutation may be due to abnormal expression of  hepatocyte growth factor/scatter factor  by the mesenchymal cells within the neural crest. [ 2 ]


Another proposed cause of neurocutaneous melanosis is a mutation of the  NRAS gene  at codon 61. This mutation has been detected in patients with congenital melanocytic nevi, as well as those with melanocytic tumors of the central nervous system. The mutation would also likely occur within the neural crest. [ 5 ]


If a patient displays congenital melanocytic nevi or giant congenital melanocytic nevi, the criteria for diagnosis of neurocutaneous melanosis are as follows: [ citation needed ]


These criteria are typically validated through  biopsy  of the cutaneous lesions and imaging of the central nervous system. It is important to establish that the cutaneous lesions are benign. If not, then the melanocytic deposits in the central nervous system may be the result of metastasis of cutaneous melanoma and not neurocutaneous melanosis. [ 3 ]


Imaging has been shown to be the only reliable detection method for the presence of neurocutaneous melanosis that can be performed in living patients. Currently, the preferred imaging modality for diagnosis of neurocutaneous melanosis is  magnetic resonance imaging , although ultrasound is another viable option. [ 9 ]  The signal due melanin deposits in the leptomeninges typical of neurocutaneous melanosis can be easily detected in MRI scans of patients under four months old. In patients above this age, there is some suggestion that normal brain myelination may partially obscure these signals. [ 6 ]


As most patients with neurocutaneous melanosis are asymptomatic, those who are diagnosed through MR imaging are not guarantied to develop symptoms. Those diagnosed who did not develop symptoms ranged from 10% to 68%. This wide range is most likely due to the large number of asymptomatic, undiagnosed patients with neurocutaneous melanosis. [ 6 ]


Once a patient with neurocutaneous melanosis becomes symptomatic, little can be done to improve prognosis as there is no effective treatment for the disorder. Most therapies are designed to treat the symptoms associated with the disorder, mainly those related to hydrocephalus. A  ventriculoperitoneal shunt  to relieve intracranial pressure is the preferred method. [ 6 ]


Chemotherapy and radiotherapy have been shown to be ineffective in cases of neurocutaneous melanosis where malignancy is present. Additionally, due to the total infiltration of the central nervous system by these lesions, surgical resection is not a viable treatment option. [ 10 ]


It has been demonstrated that early embryonic, post-zygotic somatic mutations in the NRAS gene are implicated in the pathogenesis of NCM. Recently, experimental treatment with MEK162, a MEK inhibitor, has been tried in a patient with NCM and progressive symptomatic leptomeningeal melanocytosis. Pathological studies with immunohistochemical and Western Blot analyses using Ki67 and pERK antibodies showed a potential effect of MEK inhibiting therapy. Further studies are needed to determine whether MEK inhibitors can effectively target NRAS-mutated symptomatic NCM. [ 11 ]


The majority of patients with neurocutaneous melanosis are asymptomatic and therefore have a good prognosis with few complications. Most are not diagnosed, so definitive data is not available. For symptomatic patients, the prognosis is far worse. In patients without the presence of melanoma, more than 50% die within 3 years of displaying symptoms. While those with malignancy have a mortality rate of 77% with most patients displaying symptoms before the age of 2. [ 12 ]


The presence of a Dandy-Walker malformation along with neurocutaneous melanosis, as occurs in 10% of symptomatic patients, further deteriorates prognosis. The median survival time for these patients is 6.5 months after becoming symptomatic. [ 8 ]


Neurocutaneous melanosis was first described in 1861 by Rokitansky. [ 13 ]  It was first named by Van Bongaert in 1948. [ 14 ]
Premortem detection is difficult without the use of MRI. This, combined with the asymptomatic nature of most cases, led to the early belief that all cases were fatal. Therefore, few symptomatic cases (around 100) have been reported to date. [ 10 ]


Neuronal ceroid lipofuscinosis   is a family of at least eight genetically separate  neurodegenerative   lysosomal storage diseases  that result from excessive accumulation of lipopigments ( lipofuscin ) in the body's tissues. [ 1 ]  These lipopigments are made up of fats and  proteins . Their name comes from the word stem "lipo-", which is a variation on  lipid , and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the  liver ,  spleen ,  myocardium , and kidneys.


The classic characterization of the group of neurodegenerative,  lysosomal storage disorders  called the neuronal ceroid lipofuscinoses (NCLs) is through the progressive, permanent loss of motor and psychological ability with a severe intracellular accumulation of lipofuscins, [ 2 ] [ 3 ]  with the United States and Northern European populations having slightly higher frequency with an occurrence of one in 10,000. [ 4 ]  Four classic diagnoses have received the most attention from researchers and the medical field, differentiated from one another by age of symptomatic onset, duration, early-onset manifestations such as blindness or seizures, and the forms which lipofuscin accumulation takes. [ 2 ]


In the early infantile variant of NCL (also called INCL or Santavuori-Haltia),  probands  appear normal at birth, but early visual loss leading to complete retinal blindness by the age of 2 years is the first indicator of the disease; by 3 years of age, a vegetative state is reached, and by 4 years, isoelectric encephalograms confirm brain death. Late infantile variant usually manifests between 2 and 4 years of age with seizures and deterioration of vision. The maximum age before death for late infantile variant is 10–12 years. [ 5 ] [ 6 ] [ 7 ] [ 8 ]  Juvenile NCL (JNCL, Batten disease, or Spielmeyer-Vogt), with a prevalence of one in 100,000, usually arises between 4 and 10 years of age; the first symptoms include considerable vision loss due to retinal dystrophy, with seizures, psychological degeneration, and eventual death in the mid- to late 20s or 30s ensuing. [ 9 ]  Adult variant NCL (ANCL or  Kuf's disease ) is less understood and generally manifests milder symptoms; however, while symptoms typically appear around 30 years of age, death usually occurs 10 years later. [ 1 ]


All the mutations that have been associated with this disease have been linked to genes involved with the neural synapses metabolism – most commonly with the reuse of vesicle proteins. [ citation needed ]


Childhood NCLs are generally  autosomal recessive  disorders; that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry one defective  gene , each of their children faces a one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children. The most commonly identified mutations are in the  CLN3  gene, which is located on the short arm of chromosome 16 (16p12.1). The normal function of the gene is not presently known, but results in a transmembrane protein. [ citation needed ]


Adult NCL may be inherited as an autosomal recessive (Kufs), or less often, as an  autosomal dominant  (Parry's) disorder. In  autosomal dominant   inheritance , all people who inherit a single copy of the disease gene develop the disease. As a result, no carriers of the gene are unaffected. [ citation needed ]


Many authorities refer to the NCLs collectively as Batten disease. [ 10 ]


Because vision loss is often an early sign, NCL may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often, an eye specialist or other physician who suspects NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. To diagnose NCL, the neurologist needs the patient's medical history and information from various laboratory tests. [ citation needed ]


Diagnostic tests used for NCLs include:


The older classification of NCL divided the condition into four types (CLN1, CLN2, CLN3, and CLN4) based upon age of onset, while newer classifications divide it by the associated gene. [ 11 ] [ 12 ]


CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene.


Nonsense  and  frameshift  mutations in the  CLN1  gene (located at
1p32 [ 15 ] [ 16 ] [ 17 ] ) always induce classical INCL, while some  missense mutations  have been associated with ANCL in addition to the infantile and juvenile forms. The mutation typically results in a deficient form of a  lysosomal  enzyme called  palmitoyl protein thioesterase  1 (PPT1). [ 18 ]


The  wild-type  PPT1 is a 306- amino acid   polypeptide  that is typically targeted for transport into  lysosomes  by the  mannose 6-phosphate  (M6P) receptor-mediated pathway. [ 5 ] [ 18 ]  Here, the protein appears to function in removing  palmitate   residues  by cleaving  thioester  linkages in s-acylated (or palmitoylated) proteins, encouraging their breakdown. [ 5 ] [ 6 ]  Defective polypeptides, however, are unable to exit the  endoplasmic reticulum  (ER), most likely due to  misfolding ; further analyses of this pathway could serve to categorize INCL among lysosomal enzyme deficiencies. The human  PPT  gene shows 91% similarity to bovine  PPT  and 85% similarity to rat  PPT ; these data indicate that the  PPT  gene is highly conserved and likely plays a vital role in cell metabolism. [ 5 ]  In addition, buildup of defective PPT1 in the ER has been shown to cause the increased release of Ca2+. This  homeostasis -altering event leads to increased  mitochondrial  membrane permeability and subsequent activation of  caspase-9 , eventually leading to an accumulation of cleft and uncleft poly(ADP-ribose) polymerase  and eventual  apoptosis . [ 6 ]


The  CLN2  gene encodes a 46kDa protein called lysosomal  tripeptidyl peptidase I  ( TPP1 ), which cleaves tripeptides from terminal  amine  groups of partially unfolded proteins. [ 7 ] [ 19 ]  Mutations of this gene typically result in a LINCL phenotype. [ 20 ]


On April 27, 2017, the  U.S. Food and Drug Administration  approved cerliponase alfa (Brineura) as the first specific treatment for NCL. It is  enzyme replacement therapy  manufactured through  recombinant DNA  technology. The active ingredient in Brineura,  cerliponase alfa , is intended to slow loss of walking ability in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as TPP1 deficiency. Brineura is administered into the  cerebrospinal fluid  by infusion via a surgically implanted reservoir and catheter in the head (intraventricular access device). [ 21 ]


All mutations resulting in the juvenile variant of NCL have been shown to occur at the  CLN3  gene on 16p12; [ 16 ]  of the mutations known to cause JNCL, 85% result from a 1.02-kb deletion, with a loss of amino acids 154–438, while the remaining 15% appear to result from either point or  frameshift mutations . [ 9 ]  The wild-type  CLN3  gene codes for a protein with no known function, [ 3 ]  but studies of the yeast  CLN3  ortholog , the product of which is called  battenin  (after its apparent connections to Batten's disease, or JNCL), have suggested that the protein may play a role in lysosomal  pH   homeostasis . Furthermore, recent studies have also implied the protein's role in  cathepsin D  deficiency; the overexpression of the defective protein appears to have significant effects on cathepsin D processing, with implications suggesting that accumulation of ATP synthase subunit C would result. [ 22 ]  Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D. [ citation needed ]


Between 1.3 and 10% of cases are of the adult form. The age at onset is variable (6–62 yr). Two main clinical subtypes have been described: progressive myoclonus epilepsy (type A) and dementia with motor disturbances, such as cerebellar, extrapyramidal signs and dyskinesia (type B). Unlike the other NCLs, retinal degeneration is absent. Pathologically, the ceroid-lipofuscin accumulates mainly in neurons and contains subunit C of the mitochondrial  ATP synthase . [ citation needed ]


Two independent families have been shown to have mutations in the  DNAJC5  gene – one with a transversion and the other with a deletion mutation. [ 23 ]  The mutations occur in a  cysteine -string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of the encoded protein cysteine-string protein alpha (CSPα). The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene. [ 24 ]


Currently, no widely accepted treatment can cure, slow down, or halt the symptoms in the great majority of patients with NCL, but seizures may be controlled or reduced with use of antiepileptic drugs. Additionally, physical, speech, and occupational therapies may help affected patients retain functioning for as long as possible. [ citation needed ]  Several experimental treatments are under investigation. [ citation needed ]


In 2001, a drug used to treat  cystinosis , a rare genetic disease that can cause kidney failure if not treated, was reported to be  useful in treating the infantile form of NCL. Preliminary results report the drug has completely cleared away storage material from the white blood cells of the first six patients, as well as slowing down the rapid neurodegeneration of infantile NCL. Currently, two drug trials are underway for infantile NCL, both using Cystagon. [ citation needed ]


A  gene therapy  trial using an adenoassociated virus vector called AAV2CUhCLN2 began in June 2004 in an attempt to treat the manifestations of late infantile NCL. [ 25 ]  The trial was conducted by Weill Medical College of Cornell University [ 25 ]  and sponsored by the Nathan's Battle Foundation. [ 26 ]  In May 2008,  the gene therapy given to the recipients reportedly was "safe, and that, on average, it significantly slowed the disease's progression during the 18-month follow-up period" [ 27 ]  and "suggested that higher doses and a better delivery system may provide greater benefit". [ 28 ]


A second gene therapy trial for late infantile NCL using an adenoassociated virus derived from the  rhesus macaque  (a species of  Old World monkey ) called AAVrh.10 began in August 2010, and is once again being conducted by Weill Medical College of Cornell University. [ 28 ]  Animal models of late infantile NCL showed that the AAVrh.10 delivery system "was much more effective, giving better spread of the gene product and improving survival greatly". [ 28 ]


A third gene therapy trial, using the same AAVrh.10 delivery system, began in 2011 and has been expanded to include late infantile NCL patients with moderate tosevere impairment or uncommon genotypes, and uses a novel administration method that reduces general anesthesia time by 50% to minimize potential adverse side effects. [ 29 ]


A painkiller available in several European countries,  flupirtine , has been suggested to possibly slow down the progress of NCL, [ 30 ]  particularly in the juvenile and late infantile forms. No trial has been officially supported in this venue, however. Currently, the drug is available to NCL families either from Germany, Duke University Medical Center in  Durham, North Carolina , or the Hospital for Sick Children in  Toronto . [ citation needed ]


On October 20, 2005, the Food and Drug Administration approved a phase-I clinical trial of neural stem cells to treat infantile and late infantile Batten disease. Subsequent approval from an independent review board also approved the stem cell therapy in early March 2006. This treatment will be the first transplant of fetal stem cells performed on humans. The therapy is being developed by Stem Cells Inc and is estimated to have six patients. The treatment was to be carried out in Oregon. [ 31 ]


Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone-marrow or stem-cell transplants for this condition. A bone-marrow transplant has been attempted in the late infantile form of NCL with disappointing results; while the transplant may have slowed the onset of the disease, the child eventually developed the disease and died in 1998. [ citation needed ]


Trials testing the effectiveness of bone-marrow transplants for infantile NCL in Finland have also been disappointing, with only a slight slowing of disease reported. [ 32 ]


In late 2007,  Dr. David Pearce et al. reported that  Cellcept , an  immunosuppressant  medication commonly used in  bone-marrow transplants , may be useful in slowing down the progress of juvenile NCL. [ 33 ]


On April 27, 2017, the U.S. FDA approved cerliponase alfa as the first specific treatment for NCL. [ 21 ]


Incidence can vary greatly from type-to-type, and from country-to-country. [ 34 ]


In Germany, one study reported an incidence of 1.28 per 100,000. [ 35 ]


A study in Italy reported an incidence of 0.56 per 100,000. [ 36 ]


A study in Norway reported an incidence of 3.9 per 100,000 using the years from 1978 to 1999, with a lower rate in earlier decades. [ 37 ]


The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel, [ 38 ] [ 39 ] [ 40 ] [ 41 ]  who described 4 affected siblings in a small mining community in Norway. Although no pathological studies were performed on these children the clinical descriptions are so succinct that the diagnosis of the  Spielmeyer-Sjogren  (juvenile) type is fully justified. [ citation needed ]


More fundamental observations were reported by  F. E. Batten  in 1903, [ 42 ]  and by  Heinrich Vogt  in 1905, [ 43 ]  who performed extensive clinicopathological studies on several families. Retrospectively, these papers disclose that the authors grouped together different types of the syndrome. Furthermore, Batten, at least for some time, insisted that the condition that he described was distinctly different from  Tay–Sachs disease , the prototype of a neuronal  lysosomal disorder  now identified as  GM2 gangliosidosis  type A. Around the same time,  Walther Spielmeyer  reported detailed studies on three siblings, [ 44 ]  who have the Spielmeyer-Sjogren (juvenile) type, which led him to the very firm statement that this malady is not related to  Tay–Sachs disease . Subsequently, however, the pathomorphological studies of  Károly Schaffer  made these authors change their minds to the extent that they reclassified their respective observations as variants of Tay–Sachs disease, which caused confusion lasting about 50 years. [ citation needed ]


In 1913–14,  Max Bielschowsky  delineated the late infantile form of NCL. [ 45 ]  However, all forms were still thought to belong in the group of "familial amaurotic idiocies", of which Tay–Sachs was the prototype.


In 1931,  Torsten Sjögren , a Swedish psychiatrist and geneticist, presented 115 cases with extensive clinical and genetic documentation and came to the conclusion that the disease now called the Spielmeyer-Sjogren (juvenile) type is genetically separate from Tay–Sachs. [ 46 ]


Departing from the careful morphological observations of Spielmeyer, Hurst, and Sjovall and Ericsson, Zeman and Alpert made a determined effort to document the previously suggested pigmentary nature of the neuronal deposits in certain types of storage disorders. [ 47 ]  Simultaneously, Terry and Korey [ 48 ]  and Svennerholm [ 49 ]  demonstrated a specific ultrastructure and biochemistry for Tay–Sachs disease, and these developments led to the distinct identification and also separation of the NCLs from Tay–Sachs disease by Zeman and Donahue. At that time, it was proposed that the late-infantile (Jansky–Bielschowsky), the juvenile (Spielmeyer–Vogt), and the adult form (Kufs) were quite different from Tay–Sachs disease with respect to chemical pathology and ultrastructure and also different from other forms of  sphingolipidoses . [ citation needed ]


Subsequently,  Santavuori and Haltia showed that an infantile form of NCL exists, [ 50 ]  which Zeman and Dyken had included with the Jansky Bielschowsky type. [ citation needed ]


Niemann–Pick disease  ( NP ), also known as  acid sphingomyelinase deficiency , is a group of rare genetic diseases of varying severity. These are inherited  metabolic disorders  in which  sphingomyelin  accumulates in  lysosomes  in cells of many organs. NP types A, A/B, and B are caused by mutations in the  SMPD1  gene, which causes a deficiency of an  acid sphingomyelinase  (ASM).  NP type C  is now considered a separate disease, as  SMPD1  is not involved, and there is no deficiency in ASM.


These disorders involve the dysfunctional metabolism of  sphingolipids , which are fats found in cell membranes. They can be considered as a kind of  sphingolipidosis , which is included in the larger family of  lysosomal storage diseases . [ 2 ]


Symptoms are related to the organs in which sphingomyelin accumulates. Enlargement of the liver and spleen ( hepatosplenomegaly ) may cause reduced appetite, abdominal distension, and pain. Enlargement of the spleen ( splenomegaly ) may also cause low levels of  platelets  in the blood ( thrombocytopenia ). [ citation needed ]


Accumulation of  sphingomyelin  in the  central nervous system  (including the  cerebellum ) results in unsteady gait ( ataxia ), slurring of speech ( dysarthria ), and difficulty swallowing ( dysphagia ).  Basal ganglia  dysfunction causes abnormal posturing of the limbs, trunk, and face ( dystonia ). Upper brainstem disease results in impaired voluntary rapid eye movements (supranuclear gaze palsy). More widespread disease involving the  cerebral cortex  and subcortical structures causes gradual loss of intellectual abilities, causing  dementia  and  seizures . [ citation needed ]


Bones also may be affected, with the disease causing enlarged  bone marrow  cavities, thinned  cortical bone , or a distortion of the hip bone called  coxa vara . Sleep-related disorders also occur with the condition, such as  sleep inversion , sleepiness during the day and wakefulness at night.  Gelastic   cataplexy , the sudden loss of muscle tone when the affected patient laughs, is also seen. [ citation needed ]


Mutations in the  SMPD1   gene  cause Niemann–Pick disease types A and B. They produce a deficiency in the activity of the  lysosomal   enzyme   acid sphingomyelinase , that breaks down the lipid  sphingomyelin . [ 3 ]


Mutations in  NPC1  or  NPC2  cause  Niemann–Pick disease, type C  (NPC), which affects a protein used to transport lipids. [ 3 ]


Type D originally was separated from type C to delineate a group of patients with otherwise identical disorders who shared a common  Nova Scotian  ancestry. Patients in this group are known to share a specific mutation in the  NPC1  gene, so NPC is used for both groups. Before the molecular defects were described, the terms "Niemann–Pick type I" and "Niemann–Pick type II" were proposed to separate the high- and low-sphingomyelin forms of the disease in the early 1980s. [ citation needed ]


Niemann–Pick disease is inherited in an  autosomal recessive  pattern, [ 4 ] [ 5 ]  which means both copies, or  both alleles  of the gene, must be defective to cause the disease. "Defective" means they are altered in a way that impairs their function. Most often, the parents of a child with an autosomal recessive disorder are carriers: they have one copy of the altered gene, but are not affected because the other copy produces the enzyme. If both parents are carriers, each pregnancy has a 25% chance of producing an affected child.  Genetic counseling  and  genetic testing  are recommended for families who may be carriers of the disease. [ citation needed ]


Niemann–Pick diseases are a subgroup of  lipid storage disorders  called  sphingolipidoses  in which harmful quantities of fatty substances, or  lipids , accumulate in the  spleen ,  liver ,  lungs ,  bone marrow , and  brain . [ citation needed ]


In the classic infantile type-A variant, a  missense mutation  causes complete deficiency of  sphingomyelinase . Sphingomyelin is a component of cell membrane including the organellar membrane, so the enzyme deficiency blocks degradation of lipid, resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-monocyte phagocyte lineage. Affected cells become enlarged, sometimes up to 90 μm in diameter, secondary to the distention of lysosomes with sphingomyelin and cholesterol. Histology shows lipid-laden macrophages in the marrow and "sea-blue histiocytes" on pathology. Numerous small vacuoles of relatively uniform size are created, giving the cytoplasm a foamy appearance. [ citation needed ]


For type A and B, levels of sphingomylinase can be measured from a blood sample. To diagnose type C, a skin sample can help determine whether the transporter is affected via the Filipin test which detects build-up of unesterified cholesterol via fluorescent staining. [ 6 ]   [ 7 ]


The four types of Niemann–Pick disease are divided into categories. Patients with ASM deficiency are classified into types A and B. Type A patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement, and are unable to survive beyond two years of age. Type B patients also show hepatosplenomegaly and pathologic alterations of their lungs, but usually without the involvement of their central nervous system. Some can develop significant life-threatening complications, including liver failure, hemorrhage, oxygen dependency, pulmonary infections, and splenic rupture. Some develop coronary arterial or valvular heart disease. In a longitudinal natural history study, nearly 20% of the patients died. For those classified into type C, they may have mild hepatosplenomegaly, but their central nervous system is profoundly affected. [ 8 ]


Niemann–Pick disease type D (or Nova Scotia form) is now believed to be the same condition as Niemann–Pick disease type C. [ 10 ]  Two poorly characterized forms of Niemann–Pick disease have also been described as types E and F. [ 11 ]


In adults with type B, physicians try to keep cholesterol levels down to normal levels. If the spleen is enlarged and platelet levels low, acute episodes of bleeding may require transfusions of blood products. If they have symptoms of interstitial lung disease, they may need oxygen. [ 12 ]


Possible treatments include  enzyme replacement therapy  and  gene therapy .  Bone marrow transplant  has been tried for type B. [ 8 ]


In January 2009,  miglustat  (Zavesca) was authorized in the European Union for the treatment of progressive neurological manifestations in people with Niemann-Pick type C disease. [ 13 ] [ 14 ]  The medication is available to people in the United States on an experimental basis. In March 2010, the US  Food and Drug Administration  (FDA) requested additional pre-clinical and clinical information regarding miglustat from Actelion before making a final decision on approving it in the United States for Niemann-Pick type C disease. [ 15 ]


Olipudase alfa  (Xenpozyme) was approved for medical use in Japan in March 2022. [ 16 ]


Arimoclomol  (Miplyffa) was approved for medical use in the United States in September 2024. [ 17 ]  It is the first medication approved by the FDA to treat Niemann-Pick Disease, Type C. [ 17 ]


Levacetylleucine  (Aqneursa) was approved for medical use in the United States in September 2024. [ 18 ]  Levacetylleucine is the second medication approved by the FDA for the treatment of Niemann-Pick disease type C. [ 18 ]


Highly variable, infantile neurovisceral Niemann–Pick disease (type A ASMD) is usually fatal before 3 years of age. In Type B, severity is highly variable, and many patients live well into adulthood and may reach a normal lifespan. Diagnoses have been made in the 7th decade of life.   [ 19 ] [ 20 ] [ 21 ]


Type C is an entirely different disorder, which also has a highly variable prognosis. [ citation needed ]


The  incidence  among  Ashkenazi Jews  is estimated to be about one in 40,000 for type A of Niemann–Pick disease. [ 3 ]  The incidence of both Niemann–Pick disease types A and B in all other populations is estimated to be one in 250,000. [ 3 ]  The incidence of Niemann–Pick disease type C is estimated to be one in 150,000. [ 3 ]


Albert Niemann  published the first description of what now is known as Niemann–Pick disease, type A, in 1914.  Ludwig Pick  described the pathology of the disease in a series of papers in the 1930s. [ 22 ] [ 23 ] [ 24 ]


In 1961, the classification of Niemann–Pick disease into types A, B, and C was introduced, and also contained a type D, [ 25 ] [ 26 ]  called the "Nova Scotian type". Genetic studies showed that type D is caused by the same gene as type C1, and the type D designation is no longer used. [ 3 ]
The composer Maurice Ravel was diagnosed as having Picks disease after his death in 1937.


Research has been ongoing to better understand the disease and treatments for it, however at present there is no cure.  [ 27 ]


The loss of  myelin  in the central nervous system is considered to be a main pathogenic factor. Research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in the  NPC1  gene as seen in Niemann–Pick type C disease. In this model, the expression of  myelin gene regulatory factor  (MRF) has been shown to be significantly decreased. [ 28 ]  MRF is a  transcription factor  of critical importance in the development and maintenance of  myelin sheaths . [ 29 ]  A perturbation of oligodendrocyte maturation and the myelination process might, therefore, be an underlying mechanism of the neurological deficits. [ 28 ]


Curiously, in 2011  fibroblast  cells derived from patients with Niemann–Pick type C1 disease were shown to be resistant to  Ebola virus  because of mutations in the NPC1 protein, which is needed for viral escape from the vesicular compartment. [ 30 ]


Other studies have uncovered small molecules which inhibit the receptor and may be a potential therapeutic strategy. [ 31 ]


In 2014, the  European Medicines Agency   granted orphan drug designation to  arimoclomol  for the treatment of Niemann–Pick type C. [ 32 ]  This was followed in 2015 by the  U.S. Food & Drug Administration . [ 33 ]  Dosing in a  placebo-controlled  phase II/III  clinical trial  to investigate treatment for Niemann–Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016. [ 34 ]


Researchers at the University of Arizona first proposed the use of 2-hydroxypropyl-β-cyclodextrins for the treatment of Niemann–Pick Type C1 in 2001. [ 35 ]  Researchers noted that HPBCDs, with varying levels of 2-hydroxypropyl substitution, had effects in delaying neurological symptoms and in decreasing liver cholesterol storage in a Niemann–Pick mouse model. Later, researchers at the  University of Texas Southwestern Medical Center  found that when Niemann–Pick type C mice were injected with 2-hydroxypropyl-β-cyclodextrin (HPbCD) when they were seven days old, they showed marked improvement in liver function, much less neurodegeneration, and ultimately, they lived longer lives than the mice that did not receive this treatment. These results suggest HPbCD acutely reverses the storage defect seen in NPC. [ 36 ]


In April 2011, the U.S.  National Institutes of Health , in collaboration with the Therapeutics for Rare and Neglected Diseases Program, [ 37 ]  announced they were developing a  clinical trial  using HPbCD for Niemann–Pick type C1 patients. A clinical trial conducted by Vtesse, LLC began in January 2013, and was completed in March 2017. [ 38 ]


On 26 April 2013, the European Medicines Agency granted International Niemann–Pick Disease Alliance, the United Kingdom, orphan designation for HPbCD for the treatment of Niemann–Pick disease, type C. [ 39 ]


Gene therapy  is being used clinically to treat genetic diseases, including  haemophilia  and  spinal muscular atrophy . It has been used preclinically, in a mouse model of Niemann–Pick type C, using an  adeno-associated virus -derived  viral vector , and has been shown to extend lifespan following injection into the lateral  ventricles  of the neonatal brain. [ 40 ]  In a separate proof-of-concept study, a similar vector, but with a modified  capsid , was injected intravenously into Niemann–Pick type C mice around four weeks of age; this resulted in extended lifespan and improved weight gain. [ 41 ]  Gene therapy has also been used preclinically in a mouse model of Niemann–Pick type A. Injection into the  cisterna magna  at seven weeks of age prevented motor and memory impairment and  neuronal  cell death. [ 42 ]


Norman–Roberts syndrome  is a rare form of  microlissencephaly  caused by a mutation in the  RELN  gene. [ 1 ]  A small number of cases have been described. The syndrome was first reported by  Margaret Grace Norman  and M. Roberts et al. in 1976. [ 2 ]


Lack of reelin prevents normal layering of the  cerebral cortex  and disrupts cognitive development. Patients have  cerebellar hypoplasia ,  congenital lymphedema , and  hypotonia . The disorder is also associated with  myopia ,  nystagmus  and generalized seizures. [ citation needed ]


Norman–Roberts syndrome is one of two known disorders caused by a disruption of the  reelin -signaling pathway. The other is  VLDLR-associated cerebellar hypoplasia , which is caused by a mutation in the gene coding for one of the reelin receptors,  VLDLR . [ citation needed ]


Disruption of the RELN gene in human patients is analogous to the malfunctioning RELN gene in the  reeler  mouse. [ citation needed ]


North Carolina macular dystrophy  is an extremely rare  autosomal dominant   genetic disorder  that primarily affects the eyes. It is a non-progressive disorder which is characterized by an abnormal development of the  macula , multiple  drusen , photoreceptor cells atrophy, and central vision loss. [ 2 ]  This condition is caused by mutations in  chromosome 6q 16 [ 3 ] [ 4 ]


This disease was named after the U.S. state  North Carolina  due to the fact that the first people to be diagnosed with this disorder were members of a four-generation  Irish-American  family in North Carolina, since then,  Latin American ,  European , and  Asian  families have been reported in medical literature to have this disorder as well. [ 5 ]


Oculoauricular syndrome  is a rare genetic condition affecting the eyes and ears. It is due to mutations in the  H6 family homeobox 1  (HMX1) gene. It is also known as the Schorderet-Munier-Franceschetti syndrome.


The clinical features of this condition are as follows: [ citation needed ]


Hearing is normal


This condition is inherited in an autosomal recessive manner. The gene responsible is located on the short arm of  chromosome 4  (4p16.1) [ 1 ]


This is not presently understood. [ citation needed ]


This includes


This condition has only been described in three families to date (2017). [ citation needed ]


This condition was first described in 1945. [ 2 ]  The gene responsible was identified in 2008. [ 1 ]


Opsismodysplasia  is a type of  skeletal dysplasia  (a bone disease that interferes with bone development) first described by Zonana and associates in 1977, and designated under its current name by Maroteaux (1984). Derived from the  Greek   opsismos  ("late"), the name "opsismodysplasia" describes a delay in  bone maturation . In addition to this delay, the disorder is characterized by  micromelia  (short or undersized bones), particularly of the hands and feet, delay of  ossification  (bone cell formation),  platyspondyly  (flattened  vertebrae ), irregular  metaphyses , an array of facial aberrations and  respiratory distress  related to chronic  infection . Opsismodysplasia is  congenital , being apparent at birth. It has a variable mortality, with some affected individuals living to adulthood. The disorder is  rare , with an incidence of less than 1 per 1,000,000 worldwide. It is inherited in an  autosomal   recessive  pattern, which means the defective (mutated) gene that causes the disorder is  located  on an  autosome , and the disorder occurs when two copies of this defective gene are inherited. No specific gene has been found to be associated with the disorder. It is similar to  spondylometaphyseal dysplasia, Sedaghatian type . [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]


Opsismodysplasia can be characterized by a delay in  bone maturation , which refers to "bone aging", an expected sequence of developmental changes in the skeleton corresponding to the chronological age of a person. Factors such as gender and ethnicity also play a role in bone age assessment. The only indicator of physical development that can be applied from birth through mature adulthood is bone age. Specifically, the age and maturity of bone can be determined by its state of  ossification , the age-related process whereby certain  cartilaginous  and soft tissue structures are transformed into bone. The condition of  epiphyseal plates  (growth plates) at the ends of the  long bones  (which includes those of the arms, hands, legs and feet) is another measurement of bone age. The evaluation of both ossification and the state of growth plates in children is often reached through  radiography  (X-rays) of the  carpals  (bones of the  hand  and  wrist ). [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]  In opsismodysplasia, the process of ossification in long bones can be disrupted by a failure of  ossification centers  (a center of organization in long bones, where cartilage cells designated to await and undergo ossification gather and align in rows) [ 12 ]  to form. This was observed in a 16-month-old boy with the disorder, who had no apparent ossification centers in the  carpals  (bones of the hand and wrist) or  tarsals  (bones of the foot). This was associated with an absence of ossification in these bones, as well as disfigurement of the hands and feet at age two. The boy also had no ossification occurring in the lower  femur  (thigh bone) and upper  tibia  (the shin bone). [ 13 ]


Opsismodysplasia is inherited in an autosomal recessive manner. [ 5 ]  This means the defective gene(s) responsible for the disorder is located on an  autosome , and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both  carry  one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Currently, no specific mutation in any gene has been found to cause the disorder. [ 4 ] [ 6 ]


It appears that the gene inositol polyphosphate phosphatase-like 1 is the cause of this condition in at least some cases. [ 14 ]


Opsismodysplasia is a very  rare disorder , and is estimated to occur in less than 1 in 1,000,000 people. [ 6 ]


The disorder was first described by Jonathan Zonana and associates in 1977. [ 2 ]  Further observation of four cases of it was reported by Pierre Maroteaux and colleagues in 1982, [ 15 ]  and Maroteaux was the first to call the disorder "opsismodysplasia", in a 1984 journal report of three affected individuals. [ 3 ]  The name derives from the  Greek   opsismos , meaning "late", [ 4 ]  while the term  dysplasia  refers to development. [ 6 ]


Orofaciodigital syndrome 1  ( OFD1 ), also called  Papillon-Léage and Psaume syndrome , [ 1 ]  is an  X-linked   congenital disorder  characterized by malformations of the  face ,  oral cavity , and  digits  with  polycystic kidney disease  and variable involvement of the  central nervous system . [ 2 ]


Orofaciodigital syndrome type 1 is caused by mutations in the  OFD1  gene.  OFD1 localizes to both  centrosomes  and  basal bodies  within the  human   genetic cellular structure .  This suggests that this syndrome may fall into a broad category of   ciliary diseases . The  ciliary organelles  are present in many cellular types throughout the  human  body.  Cilia defects adversely affect numerous critical developmental signaling pathways essential to cellular development. [ 2 ]


Other types include:


Recent findings in genetic research have suggested that a large number of  genetic disorders , both  genetic syndromes  and  genetic diseases , that were not previously identified in the medical literature as related, may be, in fact, highly related in the  genotypical  root cause of these widely varying,  phenotypically -observed  disorders .  Orofaciodigital syndrome has been found to be a  ciliopathy . Other known ciliopathies include  primary ciliary dyskinesia ,  Bardet–Biedl syndrome ,  polycystic kidney disease  and  polycystic liver disease ,  nephronophthisis ,  Alström syndrome ,  Meckel–Gruber syndrome  and some forms of  retinal degeneration . [ 2 ]


Orofaciodigital syndrome type 1 is diagnosed through  genetic testing . Some symptoms of Orofaciodigital syndrome type 1 are oral features such as, split tongue, benign tumors on the tongue,  cleft palate ,  hypodontia  and other dental abnormalities. Other symptoms of the face include  hypertelorism  and  micrognathia . Bodily abnormalities such as webbed, short, joined, or abnormally curved fingers and toes are also symptoms of Orofaciodigital syndrome type 1. The most frequent symptoms are accessory oral frenulum, broad  alveolar ridges ,  frontal bossing , high palate,  hypertelorism ,  lobulated  tongue, median cleft lip, and wide nasal bridge. Genetic screening of the OFD1 gene is used to officially diagnose a patient who has the syndrome, this is detected in 85% of individuals who are suspected to have Orofaciodigital syndrome type 1. [ 3 ] [ 4 ]


Orofaciodigital syndrome type 1 can be treated with reconstructive surgery or the affected parts of the body. Surgery of cleft palate, tongue nodules, additional teeth, accessory frenulae, and orthodontia for malocclusion. Routine treatment for patients with renal disease and seizures may also be necessary. Speech therapy and special education in the later development may also be used as management. [ 5 ]


Osteochondroprogenitor cells are  progenitor cells  that arise from  mesenchymal stem cells  (MSC) in the  bone marrow . They have the ability to differentiate into  osteoblasts  or  chondrocytes  depending on the signalling molecules they are exposed to, giving rise to either bone or cartilage respectively.
Osteochondroprogenitor cells are important for  bone formation  and maintenance.


Alexander Friedenstein and his colleagues first identified osteoprogenitor cells in multiple mammalian tissues, before any genetic or morphological criteria were put in place for bone marrow or connective tissues. Osteoprogenitor cells can be identified by their associations with existing bone or cartilage structures, or their placement in the embryo, as the sites for osteogenesis and chondrogenesis are now known. [ 1 ]


Osteochondroprogenitor can be found between MSCs and the terminally differentiated osteoblasts and chondrocytes. Via different signalling molecules and combinations the osteochondroprogenitor will differentiate into either osteoblasts or chondrocytes.


Chondrocytes are only present in cartilage where they will produce cartilaginous matrix to maintain the structure.
 Sox9 , L-Sox5 and  Sox6  are needed for the osteochondroprogenitor to undergo chondrocytic differentiation. The  transcription factor  Sox9 can be found in multiple sites in the body (pancreas, central nervous system, intestines) and it is also found in all chondrocyte progenitor cells, suggesting that they are important in  chondrogenesis . [ 3 ]
 [ 4 ]


Osteoblasts are cells that group together to form units, called osteons, to produce bone.  Runx2  (which may also be known as Cbfa1), and Osx (a zinc finger containing transcription factor) are necessary for osteochondroprogenitor cells to differentiate into the osteoblast cell lineage. These factors also have a role in  hypertrophic  chondrocyte maturation. [ 3 ]
 [ 5 ]