Related Disorders

CLINICAL CHARACTERISTICS

related disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the clinical manifestations are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate features of the disease.

DIAGNOSIS/TESTING: The diagnosis of a related disorder is established in a male proband by identification of a hemizygous pathogenic variant involving . The diagnosis of a related disorder is usually established in a female with neurologic signs, a family history of a related disorder, and a heterozygous pathogenic variant in identified by molecular genetic testing.

MANAGEMENT

A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care. Treatment may include respiratory support as needed; gastrostomy for individuals with severe dysphagia; routine management of spasticity including physical therapy, exercise, medications (baclofen, diazepam, tizanidine), orthotics, and surgery for joint contractures; anti-seizure medication for seizures; developmental, educational, and neurobehavioral support; physical and occupational therapy for ataxia with adaptive devices as needed; individuals with scoliosis benefit from proper wheelchair seating and physical therapy; surgery may be required for severe scoliosis; management of ocular manifestations as per ophthalmology; management of spastic urinary bladder as per urology; treatment of osteopenia as per endocrinologist. : Growth, nutrition, and feeding assessment at each visit; neurologic evaluation for weakness, hypotonia, spasticity, ataxia, and ambulation every six to 12 months; EEG as needed; developmental and educational assessment every six to 12 months in children and adolescents; cognitive assessment every six to 12 months in older individuals; orthopedic assessment of scoliosis, contractures, presence of joint dislocations, and physical medicine, occupational and physical therapy assessment of mobility and self-help skills every six to 12 months; assess for low bone density as needed; ophthalmologic evaluation to assess for nystagmus and visual impairment as recommended by ophthalmology; assess for urinary dysfunction as recommended by urology; assess family and social work needs. Elevated body temperature, as with fever, may cause neurologic manifestations to transiently worsen.

GENETIC COUNSELING

related disorders are inherited in an X-linked manner. pathogenic variants have been reported. The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant may be asymptomatic or manifest mild-to-moderate signs of the disorder. Heterozygous female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild. Once the pathogenic variant has been identified in an affected family member, heterozygote detection and prenatal and preimplantation genetic testing are possible.