PRX – Charcot-Marie-Tooth disease type 3

The periaxin gene (PRX) encodes two isoforms critical for Schwann cell myelination and maintenance. Autosomal recessive loss-of-function variants in PRX have been shown to cause Dejerine-Sottas neuropathy and severe demyelinating Charcot-Marie-Tooth disease, now classified as Charcot-Marie-Tooth disease type 3 (Charcot-Marie-Tooth disease type 3). A consistent genotype–phenotype relationship is observed with truncating alleles leading to early-onset demyelination and prominent sensory involvement.

In a multi-patient study, three unrelated probands from two families harbored homozygous loss-of-function variants in PRX (PMID:12112076). Family 1 comprised two siblings with a homozygous c.2145T>A (p.Cys715Ter) variant who exhibited more severe sensory than motor impairment but progressed slowly to classic demyelinating CMT. Family 2 included a single proband with a homozygous c.353del (p.Lys118fs) variant presenting with early-onset neuropathy consistent with Dejerine-Sottas neuropathy. Neuropathology in both families revealed demyelination, onion bulb formations, tomacula, and paranodal abnormalities. These findings confirm pathogenicity of PRX truncating mutations.

PRX-related CMT is inherited in an autosomal recessive manner, supported by homozygous variants in affected individuals and heterozygous carriers in unaffected parents. To date, multiple loss-of-function alleles including nonsense (c.1864C>T (p.Gln622Ter)), frameshift (c.247del (p.Leu83fs)), and other truncating variants have been described. Recurrent or founder variants have not been identified, indicating private family mutations. Public database screening shows absence of these alleles in controls.

Segregation analysis in Family 1 demonstrated co-segregation of the p.Cys715Ter allele in two affected siblings and heterozygosity in parents, yielding two informative meioses. Combined with case-level data for three probands, genetic evidence for PRX in CMT type 3 meets ClinGen strong criteria.

Functional studies have further elucidated the pathogenic mechanism. In vitro assays demonstrated that L-periaxin and S-periaxin interact via the PDZ domain, preventing L-periaxin homodimerization and modulating Schwann cell function (PMID:26467811). Loss-of-function mutations likely disrupt this interaction and impair myelin maintenance. Although no in vivo models have been reported, these cellular assays support haploinsufficiency as the mechanism.

No conflicting evidence has been described; all reported mutations are truncating and produce consistent demyelinating phenotypes. Existing genetic and functional data satisfy ClinGen scoring maximums for a strong association.

Key Take-home: Homozygous loss-of-function variants in PRX cause autosomal recessive Charcot-Marie-Tooth disease type 3, and genetic testing of PRX has high diagnostic utility in patients with early-onset demyelinating neuropathy and sensory impairment.

References

• Annals of neurology • 2002 • Periaxin mutations cause a broad spectrum of demyelinating neuropathies. PMID:12112076
• Neuroscience letters • 2015 • L-periaxin interacts with S-periaxin through its PDZ domain. PMID:26467811

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