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.

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

“…This lack of improvement argues against the possibility that CMT 4J in our patient coexists with an acquired disorder, such as CIDP, an occurrence that has been occasionally described (Rajabally, Adams, Latour, & Attarian, ). Furthermore, it has already been shown that patients with CMT 4J can develop parkinsonism and frequent falls in their disease course, again as occurring in our patient (Nicholson et al, ; Orengo et al, ). Finally, the clinical course of the patient's deceased brother and the possible diagnoses of multiple system atrophy or amyotrophic lateral sclerosis, available only through descriptions by the patient's family, could be compatible with the features described in patients with FIG4 pathogenic variants (Nicholson et al, ).…”

“…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.…”

Unmasking the Unexpected: FIG4‐Related Disorder Presenting with Progressive Supranuclear Palsy‐Like Features

“…However, recent reports suggested adult-onset and co-existing central nervous system (CNS) involvement, including parkinsonism. A total of seven patients were [2][3][4][5] described, presenting with CMT4J phenotype and early-onset parkinsonism improved by dopaminergic therapy in four. No symptoms suggestive of atypical parkinsonism were reported except in one which exhibited severe postural instability.…”

“…The association of parkinsonism with FIG4 variants has been previously reported in seven patients. [2][3][4][5] Most of them were females (5/7), mean age of onset was 47 years (range: 30-65-year-old) and main clinical features were classical parkinsonian symptoms. One patient exhibited dystonic dyskinesia and another severe postural instability.…”

“…Other CNS involvement symptoms co-existed in four patients, such as dysmorphic features and mild cognitive impairment. 2,5 When performed, brain MRI found global atrophy while DaT scan showed presynaptic dopaminergic deficiency. Interestingly, dopaminergic therapy (mostly Levodopa) allowed marked clinical improvement in four.…”