Clinical characteristics: PLP1 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 signs are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate signs of the disease.
Diagnosis/testing: The diagnosis of a PLP1 disorder is established in a male proband by identification of a hemizygous pathogenic variant involving PLP1. The diagnosis of a PLP1 disorder is usually established in a female with neurologic signs, a family history of a PLP1 disorder, and a heterozygous pathogenic variant in PLP1 identified by molecular genetic testing.
Management: Treatment of manifestations: A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care. Treatment may include gastrostomy for individuals with severe dysphagia; anti-seizure medication for seizures; and routine management of spasticity including physical therapy, exercise, medications (baclofen, diazepam, tizanidine), orthotics, and surgery for joint contractures. Individuals with scoliosis benefit from proper wheelchair seating and physical therapy; surgery may be required for severe scoliosis. Specialized education and assessments are generally necessary, and assistive communication devices may be helpful.
Prevention of secondary complications: Proper wheelchair seating and physical therapy may help prevent scoliosis; speech and swallowing evaluations can identify patients who may need a feeding tube for safer and/or adequate nutrition and hydration.
Surveillance: Semiannual to annual neurologic and physical medicine evaluations during childhood to monitor developmental progress, spasticity, and orthopedic complications.
Genetic counseling: PLP1 disorders are inherited in an X-linked manner. De novo pathogenic variants have been reported.
If the mother has a PLP1 pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant may manifest mild-to-moderate signs of the disorder. (PLP1 alleles that cause relatively mild neurologic signs in affected males are more likely to be associated with neurologic manifestations in heterozygous females.)
Males with the PMD phenotype do not reproduce; males with SPG2 phenotype transmit the PLP1 pathogenic variant to all of their daughters and none of their sons.
Prenatal testing for a pregnancy at increased risk is possible if the PLP1 pathogenic variant in the family is known.
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