MPV17 – Charcot-Marie-Tooth disease, axonal, type 2EE

Charcot-Marie-Tooth disease, axonal, type 2EE (CMT2EE) is a rare autosomal recessive sensorimotor neuropathy caused by biallelic MPV17 mutations (Gene Symbol, Disease Name). Initial reports described homozygous NM_002437.5:c.122G>A (p.Arg41Gln) in two unrelated patients presenting with pure axonal sensorimotor neuropathy and no hepatocerebral involvement (PMID:26437932).

Genetic evidence includes eight probands across three unrelated families: one iPSC donor and seven patients with homozygous MPV17 variants. All cases showed autosomal recessive inheritance with consanguineous or multiplex segregation, and unaffected heterozygous parents. No de novo or dominant presentations were observed.

The variant spectrum is dominated by a recurrent missense NM_002437.5:c.122G>A (p.Arg41Gln) (seven probands) and a splice-region NM_002437.5:c.376-9T>G (one proband). Both variants are absent from population databases and predicted to disrupt MPV17 function.

Functional studies demonstrate that MPV17 deficiency impairs neuronal integrity in mouse motor neuronal cells, with loss of cell viability and altered proliferation concordant with an axonal neuropathy phenotype (PMID:26437932). Additionally, an iPSC line derived from a CMT2EE patient with homozygous p.Arg41Gln exhibits normal pluripotency and differentiation, establishing a human platform for mechanistic and therapeutic studies (PMID:39461114).

Collectively, these data support a pathogenic role for homozygous MPV17 missense and splice variants in CMT2EE via loss-of-function in peripheral neurons. This association is classified as Moderate clinical validity based on multiple probands, segregation in unrelated families, and concordant functional data.

Key take-home: MPV17 mutation screening should be included in autosomal recessive axonal CMT panels to enable accurate genetic diagnosis and patient management.

References

• Stem Cell Research • 2024 • Establishment of a human iPSC line (JUCTCi018-A) from a patient with Charcot-Marie-Tooth disease type 2EE due to a homozygous c.122G>A p.(Arg41Gln) mutation in the MPV17 gene PMID:39461114
• BMC Neurology • 2015 • A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy PMID:26437932
• Clinical Genetics • 2019 • MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy PMID:30298599

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