Clinical Guidance

Some genotype-phenotype correlations exist. Most individuals with PLP1 duplications have classic PMD; however, some are classified as having connatal PMD and may have three or more copies of the PLP1 locus . Variation in the extent of duplication or location(s) of the breakpoints or reinsertion sites may account for clinical variability. The most severe phenotypes are typically caused by missense variants (especially nonconservative amino acid substitutions) and other PLP1 single-nucleotide variants or indels. SPG2 is most often caused by conservative amino acid substitutions in presumably less critical regions of the protein. The locations of these pathogenic variants do not provide a clear correlation between amino acid position and clinical phenotype.

Source: GeneReviews — "PLP1-Related Disorders"

Penetrance

PLP1 pathogenic variants are believed to be completely penetrant in males.

Source: GeneReviews — "PLP1-Related Disorders"

Diagnostic Criteria

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care . No consensus clinical diagnostic criteria for PLP1-related disorders have been published.

Suggestive Findings

A PLP1-related disorder should be suspected in probands with the following clinical, imaging, and family history findings.

Clinical Findings

Suggestive clinical findings include:

• Infantile or early childhood onset of nystagmus, hypotonia, and cognitive impairment

• Progression to severe spasticity and ataxia

• Spastic paraparesis with or without CNS involvement

• Spastic urinary bladder

Imaging Findings

Brain MRI findings by phenotype (T2-weighted or fluid-attenuated inversion recovery [FLAIR] scans):

Source: GeneReviews — "PLP1-Related Disorders"

Differential Diagnosis

Individuals with PLP1-related disorders are often initially diagnosed with cerebral palsy or static encephalopathy. Pelizaeus-Merzbacher Disease (PMD) The combination of nystagmus within the first two years of life, initial hypotonia, and abnormal white matter changes on the brain MRI (e.g., abnormal signal in the posterior limbs of the internal capsule, the middle, and superior cerebellar peduncles and the medial and lateral lemnisci, all of which should be myelinated in a normal newborn) should suggest the diagnosis of PMD, especially if the family history is consistent with an X-linked disorder. Hypomyelination occurs in several disorders with clinical phenotypes distinct from PMD. POLR3-related leukodystrophy (4H leukodystrophy) is the most frequent hypomyelinating disorder after PMD, individuals with 4H leukodystrophy usually do not have nystagmus, ataxia is prominent, and spasticity is mild or not present. Hypomyelination with atrophy of the basal ganglia and cerebellum (see TUBB4A-Related Leukodystrophy) can present with pure hypomyelination, similar to PMD. Oculodentodigital dysplasia presents sometimes in adulthood, with a SPG-like phenotype; nystagmus is usually not present . (For MRI characteristics and differential diagnosis of hypomyelination see also and ). Approximately 20% of males with clinical findings consistent with a PLP1-related disorder do not have an identifiable PLP1 pathogenic variant. Other genetic disorders associated with PMD-like phenotypes and hypomyelination on brain MRI include those listed in . Table 3. Genes of Interest in the Differential Diagnosis of Pelizaeus-Merzbacher Disease

Management Guidelines

No clinical practice guidelines for PLP1-related disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a PLP1-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended:

Table 4.

PLP1-Related Disorders: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Respiratory

| Assess severity of respiratory difficulties |

Gastrointestinal /

Feeding

| Gastroenterology / nutrition / feeding team eval | • To incl eval of aspiration risk nutritional status

• Consider eval for gastrostomy tube placement in persons w/dysphagia /or aspiration risk.

Neurologic

| Neurologic eval for weakness, hypotonia, spasticity, ataxia, ambulation | Consider EEG if seizures are a concern esp those w/most severe (connatal) phenotype.

• Brain MRI to determine severity of myelination abnormalities

• Brain MRS in older children adults to ascertain atrophy

| Brain MRI is more helpful in those age ≥9 mos

NCV to assess peripheral nerve function identify individuals w/PLP1 null syndrome | NCV studies are probably reliable in those age ≥4 yrs

Development

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

Source: GeneReviews — "PLP1-Related Disorders"

Clinical Guidance

Elevated body temperature, as with fever, may cause neurologic manifestations to transiently worsen.

Source: GeneReviews — "PLP1-Related Disorders"

Therapies Under Investigation

CNS stem cells were transplanted into brains of individuals with PMD in a US FDA-approved Phase I trial . The procedure was well tolerated, however minimal evidence of myelination was thought to be present in the transplanted regions. Several years later, the situation was unchanged . Pharmacologic agents that lower expression of PLP1 should be of theoretic benefit in individuals with extra copies of PLP1, as well as those with pathogenic variants associated with protein overexpression. Gene therapy using inhibitory RNA (antisense oligonucleotides) is currently being evaluated in a clinical trial and was effective in disease models . Deferiprone, an iron chelator, is currently being evaluated in a clinical trial and has shown to improve the phenotype of cell and animal models in PMD .

Source: GeneReviews — "PLP1-Related Disorders"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. Table 6. PLP1-Related Disorders: Recommended Surveillance

Source: GeneReviews — "PLP1-Related Disorders"