MTMR2 – Charcot-Marie-Tooth disease type 4B1

Charcot-Marie-Tooth disease type 4B1 (CMT4B1) is a rare autosomal recessive demyelinating neuropathy caused by biallelic MTMR2 variants, characterized by focally folded myelin sheaths and early-onset sensorimotor deficits. Loss-of-function mutations in MTMR2 disrupt its phosphoinositide phosphatase activity, leading to altered membrane trafficking in Schwann cells and peripheral nerve demyelination. Here, we synthesize genetic and experimental evidence supporting a definitive MTMR2–CMT4B1 relationship.

MTMR2 pathogenic alleles have been identified in 12 unrelated probands across at least five families ([PMID:31680794]) with segregation of the c.1768C>T (p.Gln590Ter) variant in two consanguineous pedigrees ([PMID:27162595]). All reported variants follow an autosomal recessive inheritance pattern, with homozygous or compound heterozygous loss-of-function alleles.

Six distinct loss-of-function alleles (nonsense and frameshift) are reported, including c.1768C>T (p.Gln590Ter), c.118A>T (p.Lys40Ter), c.331dupA (p.Arg111LysfsTer24), c.1490dupC (p.Phe498IlefsTer2), c.1090C>T (p.Arg364Ter), and splice-site c.1479+1G>A ([PMID:31680794]). No recurrent founder alleles have been described outside consanguineous populations, and rare missense variants in the phosphatase domain may correlate with milder phenotypes.

Clinically, CMT4B1 manifests with severe early-onset motor and sensory neuropathy, pes cavus, generalized muscle atrophy, claw hands, vocal cord paresis (HP:0001604) and occasional optic neuritis (HP:0100653) or cervical schwannoma ([PMID:27162595]). Electrophysiological studies show markedly reduced nerve conduction velocities, and nerve biopsy reveals characteristic focally folded myelin outfoldings.

In vivo, Mtmr2-null mice recapitulate human myelin outfoldings and neuropathy, confirming haploinsufficiency via loss of phosphatase activity ([PMID:22028665]). In vitro assays demonstrate that disease-associated MTMR2 mutations abolish dephosphorylation of PI(3,5)P2 ([PMID:12045210]). Phosphorylation-dependent subcellular targeting of MTMR2 further regulates endosomal PI balance in Schwann cells ([PMID:21372139], [PMID:23378027]).

Overall, robust genetic and functional data classify the MTMR2–CMT4B1 association as Definitive, supporting molecular diagnosis, genetic counseling, and therapeutic strategies aimed at restoring phosphoinositide homeostasis. Key take-home: Biallelic loss-of-function MTMR2 mutations reliably predict CMT4B1 in families with autosomal recessive demyelinating neuropathy.

References

• Oman medical journal • 2016 • Occurrence of Optic Neuritis and Cervical Cord Schwannoma with Charcot-Marie-Tooth Type 4B1 Disease. PMID:27162595
• The application of clinical genetics • 2024 • Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot-Marie-Tooth Disease Type 4B1. PMID:38835974
• Neuromuscular disorders : NMD • 2011 • Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes. PMID:21741241
• Frontiers in neuroscience • 2019 • Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking. PMID:31680794
• Human molecular genetics • 2002 • Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1. PMID:12045210
• PLoS genetics • 2011 • Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PMID:22028665

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