Charcot Marie Tooth disease type 4J with complex central nervous system features

Abstract

We describe a family with Charcot Marie Tooth disease type 4J presenting with features of Charcot Marie Tooth disease plus parkinsonism and aphemia. Genetic testing found two variants in the FIG4 gene: c.122T>C (p.I41T) – the most common Charcot Marie Tooth disease type 4J variant – and c.1949‐10T>G (intronic). Proband fibroblasts showed absent FIG4 protein on western blot, and skipping of exon 18 by RT‐PCR. As most patients with Charcot Marie Tooth disease type 4J do not have central nervous system deficits, we postulate the intronic variant and I41T mutation together are causing loss of FIG4 protein and subsequently the central nervous system findings in our family.

Myelin abnormality in Charcot–Marie–Tooth type 4J recapitulates features of acquired demyelination

“…Case 2 in the teenage onset group presented with Parkinson-like symptoms in addition to polyneuropathy. 24 DNA testing for whole chromosomes was not Minor trauma has been associated with rapidly progressive asymmetric weakness in Case 10 (amyotrophic lateral sclerosis [ALS]-like phenotype), which was irreversible until her death. 14 Furthermore, genetic studies in 2 large cohorts of patients with ALS have revealed some FIG4 variants as genetic risk factors but not causal for the disease.…”

Roles of PIKfyve in multiple cellular pathways

“…Defects in the PIKfyve complex are linked to human diseases, especially those of the nervous system [ 32 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ], although the underlying molecular mechanisms are not clear. For example, mutations in Fig4 predicted to have a modest effect in the regulation of PI(3,5) 2 are linked to Charcot-Marie-Tooth syndrome (CMT4J), a peripheral neuropathy, as well as some cases of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS).…”

Whole exome sequencing establishes diagnosis of Charcot–Marie–Tooth 4J, 1C, and X1 subtypes

“…Patient #1 was suffering from CMT 4J due to two pathogenic mutations in the FIG4 gene (p.Ile41Thr and p.His599Ilefs*24, respectively). The p.Ile41Thr FIG4 variant is the most common variant described in patients with CMT 4J (Chow et al, ; Cottenie et al, ; Gentil et al, ; Menezes et al, ; Orengo, Khemani, Day, Li, & Siskind, ; Zhang et al, ), with a population frequency of 0.001 by screening 5,769 Northern European controls (Nicholson et al, ). A functional study by Lenk et al (), showed that the p.Ile41Thr amino acid substitution results in an unstable protein in vivo.…”