The packet lists PLP1 (chromosome X) as the known gene, with ClinGen validity DEFINITIVE, and X-linked inheritance. GeneReviews describes genotype-phenotype correlations: most individuals with PLP1 duplications have classic PMD, though some have connatal PMD and may have three or more copies of the locus; the most severe phenotypes are typically caused by missense variants (especially nonconservative substitutions) and other single-nucleotide variants or indels; SPG2 is most often caused by conservative substitutions; and null variants, including PLP1 deletion, produce a relatively mild demyelinating peripheral neuropathy.

GeneReviews states that PLP1 pathogenic variants are believed to be completely penetrant in males. It reports that in most families the mother of a male proband is heterozygous, that a minority of affected males have a de novo variant, and that maternal gonadal mosaicism is possible in some families.

GeneReviews states that no consensus clinical diagnostic criteria for PLP1-related disorders have been published. Suggestive findings it lists include infantile or early childhood onset of nystagmus, hypotonia, and cognitive impairment, progression to severe spasticity and ataxia, spastic paraparesis, and spastic urinary bladder, with a family history consistent with X-linked inheritance (absence of family history does not preclude the diagnosis).

For PMD, brain MRI is described as showing diffusely increased T2 signal in white matter of the cerebral hemispheres, cerebellum, and brain stem, consistent with hypomyelination; GeneReviews notes that T2 images may not show definitive abnormalities in a young infant. The SPG2 phenotype shows less severe MRI abnormalities.

According to GeneReviews, diagnosis in a male proband is established by a hemizygous pathogenic or likely pathogenic PLP1 variant on molecular genetic testing; in a female proband it is usually established with neurologic signs, a family history, and a heterozygous pathogenic variant. A variant of uncertain significance neither establishes nor rules out the diagnosis. GeneReviews notes that approximately 20% of males with consistent clinical findings have no identifiable PLP1 pathogenic variant, that these individuals are often initially diagnosed with cerebral palsy or static encephalopathy, and that its differential diagnosis includes other hypomyelinating disorders such as POLR3-related and TUBB4A-related leukodystrophy.

No FDA-approved drug with ACTIVE market status for this condition is present in the packet. The packet lists one orphan drug designation, for a 2'-O-(2-methoxyethyl) modified antisense oligonucleotide targeting PLP1 pre-mRNA (sponsor Ionis Pharmaceuticals, Inc.); its status is DESIGNATED, which is not an approval.

GeneReviews states that no clinical practice guidelines for PLP1-related disorders have been published and that its management content reflects the authors' experience. It describes supportive care delivered by a multidisciplinary team spanning neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology. Manifestation-specific items listed include respiratory support as needed; feeding therapy with gastrostomy tube placement for persistent feeding problems in the most severely affected; physical and occupational therapy, orthotics, and anti-spasticity medications such as baclofen, diazepam, and tizanidine for spasticity, with surgery for severe contractures; anti-seizure medication for epilepsy, which occurs typically in the most severe phenotype; orthopedic management of scoliosis; ophthalmology for ocular manifestations; urology for spastic bladder; and early intervention and educational programs for developmental delay.

For surveillance, GeneReviews lists growth and feeding assessment at each visit and neurologic, developmental or cognitive, and musculoskeletal assessments every 6-12 months. It also notes that elevated body temperature, as with fever, may transiently worsen neurologic manifestations.

The packet certifies no prognosis statement beyond the GeneReviews clinical description, which presents natural history by phenotype in males. Connatal PMD is described as never achieving ambulation, with absent speech though comprehension may be possible; affected children may die during infancy or childhood, usually of aspiration, and with attentive care may live into the third decade or longer. Classic PMD is described with assisted ambulation, if achieved, lost in childhood or adolescence. PLP1 null syndrome and SPG2 phenotypes are described with preserved ambulation and speech. The GeneReviews table lists ages at death from infancy to the third decade for connatal PMD and the third to seventh decade for classic PMD. GeneReviews also notes that variants in the PLP1-specific domain (residues 117-151) and intron 3 tend to cause less severe phenotypes. These descriptions summarize published case series and do not predict the course in any individual.

The packet certifies active ClinicalTrials.gov records for this condition. Packet titles and sponsors include a biomarker and disease progression study in PMD and a safety, pharmacokinetics, and pharmacodynamics study of intrathecally administered ION356, both sponsored by Ionis Pharmaceuticals, Inc., along with a myelin disorders biorepository project and studies whose titles refer to cord blood transplant for inherited metabolic diseases and to neurodegenerative disorders.

GeneReviews, under therapies under investigation, reports a Phase I CNS stem cell transplantation trial that was well tolerated with minimal evidence of myelination in transplanted regions; antisense oligonucleotide therapy being evaluated in a clinical trial and effective in disease models; deferiprone being evaluated in a clinical trial after improving phenotype in cell and animal models; and curcumin, which showed promise in cell models but was not effective in a small group of individuals with PMD. The packet's publication digest is dominated by basic science and preclinical work, and lists the PMD Foundation as a patient organization with a registry.