Muscle–eye–brain disease

The main signs and symptoms of MEB includes: • Muscle dystrophies: muscle weakness, hypotonia, muscle atrophy • Ocular abnormalities: lack of visual response, severe myopia, glaucoma • Central nervous system abnormalities: intellectual disability, cortical malformation Muscle dystrophies The most prevalent signs of MEB is infants being born floppy. 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. Its cause behind is mainly the severe muscular dystrophy and partly brain abnormalities. More than 80% of the patients reported visual impairment. Cataract affects 30% - 79% of individuals. Clinical features include severe intellectually disability in all aspects. Most individuals have intellectual disabilities of a range of severity. Progressive deterioration in behavioral development has been recorded. Aplasia may occur on top of hypoplasia. Flattened brainstem, ventriculomegaly, pachygyria, Type II lissencephaly have been reported. == Causes ==

File:Human chromosome 01 - 400 550 850 bphs.png|thumb|Cytogenetic location of the POMGnT 1 gene is 1p34.1. Different mutations were observed in MEB patients from different countries, namely Finland, Sweden, Norway, Estonia, USA, Israel, Spain and Italy. == Pathophysiology ==

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. 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. == Diagnosis ==

Medical diagnosis for the MEB usually involves the study of family history, measurement of serum CPK level, molecular testing, muscle biopsy and imaging study. Physical examination People with MEB have distinctive facial dysmorphisms. Rounded forehead, thin and drooping lip, micrognathia, midface retrusion, short nasal bridge are the possible indicative evidence for diagnosis. Several mutations like [c.1539+1G→A], [c.879+5G→T] are the prevalent nucleotide change found in affected people. 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. 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. Further diagnostic test is required to make confirmation. Clinically, MRI is preferred over CT scan for its ability to reveal the neuron migration more precisely. Enzymatic assay 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. Immunochemistry Western-blot (immunoblot) can be used to detect the O-mannosyl ß-1,2-N-acetylgucosaminyltransfersase 1 for diagnosis. It helps to evaluate the glycosylation state of the protein which it supposed to do. Difficulties As a subtype of muscular dystrophy-dystroglycanopathy, MEB is often confused with other sub-type including Walker–Warburg syndrome and Fukuyama congenital muscular dystrophy. All these 3 diseases share similar clinical presentation and are classified as the Type A(severe). 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 == Management ==

There is no current curative treatment for any form of muscle dystrophies and only symptomatic care is available for the patients. The corresponding supportive care to symptoms is: == Prognosis ==

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. 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. == Epidemiology ==

The majority of MEB occurrence is reported in the Finnish population. It is estimated to affect 1 in 50,000 newborns in Finland. MEB is also identified outside of Finland, there were cases of suspected MEB in Japan and Korea. However, worldwide distribution is unclear. 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. == History ==

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. In 1980, 14 more people with similar symptoms were identified in Finland. Similar cases were also published in 1989. The disease was found in Dutch in 1992, 6 people were affected coming from 4 families. After that, more cases were reported outside the Finnish population. 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. In the same year, Dobyns further examined the relation of WWS and MEB. In 2001, the cause of MEB was first demonstrated as the mutations in the POMGNT1 gene, causing loss of its function. ==References==