NDRG1 – Charcot-Marie-Tooth disease type 4D

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive demyelinating neuropathy characterized by early‐onset motor and sensory deficits with sensorineural hearing loss. Biallelic pathogenic variants in NDRG1 underlie CMT4D, with at least nine unrelated probands from seven families described to date, and segregation confirmed in sibships and consanguineous pedigrees ([PMID:19364063], [PMID:27982524], [PMID:35149926], [PMID:28776325]).

Inheritance of CMT4D is autosomal recessive, and segregation analysis has demonstrated concordant genotype–phenotype co-segregation in affected siblings and unaffected carrier parents, supporting a recessive model of inheritance.

The founder nonsense variant c.442C>T (p.Arg148Ter) was first reported homozygous in two Gypsy siblings with early gait disturbance, distal muscle wasting, areflexia, dysarthria, and hearing impairment ([PMID:19364063]). Additional alleles include the frameshift c.739delC (p.His247ThrfsTer74) in a non-Romani Italian patient ([PMID:27982524]), a novel splice-donor deletion c.537+2_537+10del causing an in-frame 14-amino-acid insertion ([PMID:35149926]), and two homozygous missense variants c.437T>C (p.Leu146Pro) and c.701G>A (p.Arg234Gln) in Chinese families ([PMID:28776325]). A cohort of 104 CMT patients revealed a splice-acceptor IVS8-1G>A variant accounting for 2.88% of demyelinating cases ([PMID:12872253]).

Cellular assays of p.Leu146Pro and p.Arg234Gln showed accelerated NDRG1 degradation and impaired DiI-LDL uptake, while Rab4a binding remained intact, indicating a trafficking defect in Schwann cells ([PMID:28776325]).

Ndrg1‐deficient mice exhibit peripheral nerve demyelination and motor deficits mirroring human CMT4D, confirming haploinsufficiency and loss‐of‐function as the pathogenic mechanism ([PMID:21636852]).

Collectively, extensive genetic evidence across multiple variant classes, concordant segregation, and functional concordance in cellular and animal models establish a Strong clinical validity for NDRG1–CMT4D. Clinical testing for NDRG1 is recommended in patients with early‐onset demyelinating neuropathy and hearing loss. Key take-home: Biallelic NDRG1 variants cause autosomal recessive CMT4D with a consistent phenotype and mechanistic support.

References

• Acta myologica • 2008 • Hereditary motor and sensory neuropathy Lom type in a Serbian family. PMID:19364063
• Journal of the peripheral nervous system • 2017 • A novel NDRG1 mutation in a non-Romani patient with CMT4D/HMSN-Lom. PMID:27982524
• Neurological sciences • 2022 • A splice altering variant in NDRG1 gene causes Charcot-Marie-Tooth disease, type 4D. PMID:35149926
• Human mutation • 2017 • Identification and functional characterization of two missense mutations in NDRG1 associated with Charcot-Marie-Tooth disease type 4D. PMID:28776325
• Human mutation • 2003 • Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease. PMID:12872253
• The Journal of biological chemistry • 2011 • NDRG4 protein-deficient mice exhibit spatial learning deficits and vulnerabilities to cerebral ischemia. PMID:21636852

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