PMD & PMLD resources for
healthcare professionals
Clinical information, diagnostic guidance, and research resources for healthcare professionals caring for individuals affected by PMD and PMLD.
A clinical overview of PMD & PMLD
PMD
Pelizaeus-Merzbacher disease (PMD) is a rare X-linked hypomyelinating leukodystrophy caused by pathogenic variants in the PLP1 gene. Disease severity exists along a clinical spectrum, ranging from severe early-onset disease (PMD) to comparatively mild hereditary spastic paraplegia (SPG2) phenotypes.
Clinical manifestations result from abnormalities in central nervous system myelin development and maintenance. 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.
PMLD
Pelizaeus-Merzbacher-like disease (PMLD) is a slowly progressive leukodystrophy caused by pathogenic variants in the GJC2 gene. It typically presents during the neonatal or early-infantile period with nystagmus, commonly associated with hypotonia, delayed acquisition of motor milestones, speech delay, and dysarthria. Over time the hypotonia typically evolves into spasticity that affects the ability to walk and communicate. Cerebellar signs (gait ataxia, dysmetria, intention tremor, head titubation, and dysdiadochokinesia) frequently manifest during childhood. Some individuals develop extrapyramidal movement abnormalities (choreoathetosis and dystonia).
Estabilshing diagnosis
Diagnosis of PMD
In male probands, the diagnosis of a PLP1-related disorder is established by identification of a hemizygous pathogenic (or likely pathogenic) variant in PLP1 by molecular genetic testing.
In female probands, the diagnosis of a PLP1-related disorder is usually established through neurologic signs, a family history of PLP1-related disorder, and a heterozygous pathogenic (or likely pathogenic) variant in PLP1 identified by molecular genetic testing.
When the phenotypic and laboratory findings suggest the diagnosis of a PLP1-related disorder, molecular genetic testing approaches should be considered in this order:
- targeted deletion/duplication analysis, to identify a PLP1 deletion/duplication
- single-gene testing, to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions
- multigene panel that includes PLP1 and other genes of interest
When the phenotype is indistinguishable from many other inherited disorders characterized by motor and cognitive impairment, comprehensive genomic testing, for example exome sequencing or genome sequencing should be considered.
Estabilshing diagnosis
Diagnosis of PMLD
The diagnosis of PMLD is established in a proband with suggestive clinical and neuroimaging findings and identification of biallelic pathogenic variants in GJC2 on molecular genetic testing.
When the clinical findings and brain MRI findings suggest the diagnosis of a PMLD, molecular genetic testing approaches should be considered in this order:
- single-gene testing of GJC2, including the noncoding exon 1; if only one pathogenic variant is found, perform gene-targeted deletion/duplication analysis
- multigene panel that includes GJC2 and other genes of interest
When the phenotype is indistinguishable from many other inherited leukodystrophies, molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) or comprehensive genomic testing, which includes exome sequencing and genome sequencing.
Explore clinical resources
Further HCP resources
Our Scientific Advisory Board
The PMD Foundation’s Scientific Advisory Board is composed of experts in leukodystrophies, neurology, genetics, and rare disease research.
Our Board provides scientific guidance and helps ensure that the Foundation’s educational materials, research initiatives, and advocacy efforts reflect current evidence and best practice.
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Looking for more HCP resources on PMD?
We welcome inquiries from healthcare professionals seeking information about PMD and PMLD, research initiatives, educational resources, or opportunities for collaboration.
Whether you are supporting a newly diagnosed family, looking for patient materials, or interested in ongoing research efforts, our team can help connect you with the information you need.