Clinical characteristics: Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a slowly progressive leukodystrophy that typically presents during the neonatal or early-infantile period with nystagmus, commonly associated with hypotonia, delayed acquisition of motor milestones, speech delay, and dysarthria. Over time the hypotonia typically evolves into spasticity that affects the ability to walk and communicate. Cerebellar signs (gait ataxia, dysmetria, intention tremor, head titubation, and dysdiadochokinesia) frequently manifest during childhood. Some individuals develop extrapyramidal movement abnormalities (choreoathetosis and dystonia). Hearing loss and optic atrophy are observed in rare cases. Motor impairments can lead to swallowing difficulty and orthopedic complications, including hip dislocation and scoliosis. Most individuals have normal cognitive skills or mild intellectual disability – which, however, can be difficult to evaluate in the context of profound motor impairment.
Diagnosis/testing: The diagnosis of PMLD1 is established in a proband with suggestive clinical and neuroimaging findings and identification of biallelic pathogenic variants in GJC2 on molecular genetic testing.
Management: Treatment of manifestations: To date no definite treatment is available; treatment is mainly supportive and includes assuring adequate nutrition and providing standard treatment for developmental delay/cognitive impairment, neurologic complications (spasticity, ataxia, epilepsy, extrapyramidal movement disorders), communication difficulties, hearing loss, and visual impairment.
Surveillance: Routine assessment of growth, weight gain, vision, and hearing. Routine monitoring of disease progression, spine for evidence of scoliosis and hips for evidence of dislocation, and needs related to physical therapy, communication, and swallowing/feeding.
Genetic counseling: PMLD1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (heterozygote), and a 25% chance of being unaffected and not a carrier. Once the GJC2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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