Muscle-eye-brain disease (ORPHA:588)
A rare, congenital muscular dystrophy due to dystroglycanopathy characterized by early onset muscular dystrophy, severe muscular hypotonia, severe intellectual disability and typical brain and eye malformations including pachygyria, polymicrogyria, agyria, brainstem and cerebellar structural anomalies, severe myopia, glaucoma, optic nerve and retinal hypoplasia. A broad clinical spectrum is observed with variable involvement of each organ system.
Epidemiology
Prevalence is unknown but it is very rare among other congenital muscular dystrophies. It is more frequently observed in Northern European countries (Scandinavian region) due to a founder mutation.
Clinical description
Patients carrying the Finish founder mutation present with marked hypotonia and global developmental delay from birth. They have generalized muscle weakness, including facial and neck muscles. Severe eye disease is often present and includes congenital myopia, pachygyria, polymicrogyria, agyria, cerebellar and brainstem hypoplasia, cerebellar cysts, congenital glaucoma, pallor of the optic discs, and /or retinal hypoplasia. Adults have severe intellectual and motor disability, extremely limited communication skills, visual impairment, epilepsy, and spine and joint deformities. Many patients have associated behavioral difficulties (bruxism, autism, temper tantrums, self-mutilation). Creatine kinase (CK) levels are increased, and the biopsy shows abnormal alpha-dystroglycan expression. Brain MRI may reveal cortical neuronal migration disorder, with type II lissencephaly in the most severe cases, white matter abnormalities, flat brainstem, cerebellar hypoplasia, and hydrocephalus. Electroencephalograms are abnormal and often show paroxysmal tracing. Patients with other mutations present with a broad clinical spectrum ranging from severe (prenatal death, and brain and posterior fossa malformations) to mild muscular dystrophies (with or without eye or brain structural abnormalities, constant speech and cognitive delay, but possible acquired walking). Almost all develop seizures, such as myoclonic jerks or refractory partial/generalized epilepsy.
Etiology
Muscle-eye-brain disease (MEB) is caused by mutations in the POMGnT1 gene (Chr 1p32-34), encoding protein O-linked mannose b1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). Other gene variants have been identified in a small number of patients.
Diagnostic methods
Diagnosis is suspected on clinical presentation, characteristic neuroimaging and electromyography findings, muscle biopsy results, and molecular genetic testing.
Differential diagnosis
Differential diagnosis includes other dystroglycanopathies and muscular dystrophies with brain and/or cognitive impairment. Patients presenting with MEB symptoms would be diagnosed with Fukuyama congenital muscular dystrophy (FCMD) in Japan. Therefore, there is an increasing tendency to use the global term MEB/FCMD syndrome. Other dystroglycanopathies include CMD due to FKRP, ISPD with brain involvement or cognitive delay, Walker-Warbourg Syndrome, laminin subunit alpha 2-related congenital muscular dystrophy, Duchenne muscular dystrophy with cognitive involvement, CDG-syndromes, and chromosomal disorders.
Antenatal diagnosis
Genetic prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management includes physiotherapy, treatment of orthopedic, respiratory and cardiac complications, respiratory aid, and medical or surgical treatment for spinal or joint contractures, nutritional and gastrointestinal problems. Control of seizures requires antiepileptic drugs. Surveillance includes monitoring for respiratory and cardiac function. Severe intellectual disability and behavior disturbances may require specific care and management in specialized centers.
Prognosis
Prognosis depends mainly on the severity of neurologic, cardiac or respiratory complications. Patients may remain ambulant into adulthood.

                            Last update: 
                            January 2023


                            - Expert reviewer(s): 
                            Pr Enrico BERTINI | EURO-NMD* - Pr Susana QUIJANO-ROY | EURO-NMD*


                                * European Reference Network