The portal for rare diseases and orphan drugs

The estimated prevalence is 1/400,000. PMD affects males but some female heterozygotes presenting with a milder phenotype have also been reported (PMD in female carriers; see this term).

The disease has a broad clinical spectrum. The connatal form is the most severe form presenting, since birth, with hypotonia, nystagmus, respiratory distress, and stridor, with subsequent motor and cognitive delay and spastic quadriparesis. The classic form manifests during the first 2 months of life with nystagmus and hypotonia which is progressively replaced by spasticity. Later signs include ataxia, impaired motor development and intellectual deficit. The transitional form is of intermediate severity between the connatal and classic forms. The mildest presentation of PMD (mild developmental and motor delay beginning at 2-3 years old, later associated with spastic paraplegia, ataxia, and/or mild intellectual deficit) is not clearly distinguishable from PLP1 null syndrome (see this term), which consists on mild PMD features associated with peripheral neuropathy, and complicated spastic paraplegia 2 (SPG2; see this term), a disorder primarily characterized by spastic gait in its pure form.

PMD is an X-linked disorder due to mutations or dosage alterations of the PLP1 gene (Xq22) that cause hypomyelination of the central nervous system (CNS). PMD is allelic to SPG2 which is also due to PLP1 mutations. PLP1 encodes the proteolipid protein PLP1, the most abundant protein of the myelin sheath in the CNS, and its alternatively spliced isoform DM20. PLP1 duplications lead to the classic form, missense substitutions from connatal to pure SPG2 forms, and PLP1 null mutations to the null syndrome. Patients without PLP1 mutations but with similar clinical and nearly identical neuroradiologic features as PMD are referred to as having PMD-like disease (PMLD; see this term).

Diagnosis is based on clinical, electrophysiologic, and neuroradiological findings. Magnetic resonance imaging (MRI) reveals complete (connatal, some transitional forms), partial (mild PMD) or diffuse (null syndrome) hypomyelination. Brainstem auditory evoked potentials (BAEP) may be helpful to differentiate PMD (lack of waves II-V) from PMLD (recordable II-V waves). Genetic testing confirms the diagnosis.

Differential diagnosis includes Krabbe disease, Canavan disease, metachromatic leukodystrophy, Alexander disease, familial SPG, PMLD (see these terms), and cerebral palsy.

Prenatal and preimplantation genetic testing are possible when a family's underlying PLP1 mutation has been identified.

Management is multidisciplinary and involves neurologists, physical therapists, orthopedic doctors, pneumologists, and gastroenterologists. Treatment may include gastrostomy for dysphagia, antiepileptic drugs for seizures, physical therapy with antispasticity drugs (baclofen, diazepam, tizanidine) for spasticity, or corrective surgery for pulmonary compromise in case of severe scoliosis. Regular surveillance is necessary.

PMD has a progressive course that varies depending on the phenotype. In the most moderate forms, life expectancy is quite long and the disease progresses slowly after adolescence. In the most severe forms, death usually occurs by the second decade.