Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4

Abstract

Charcot-Marie-Tooth disease is a genetically heterogeneous group of motor and sensory neuropathies associated with mutations in more than 30 genes. Charcot-Marie-Tooth disease type 4J (OMIM 611228) is a recessive, potentially severe form of the disease caused by mutations of the lipid phosphatase FIG4. We provide a more complete view of the features of this disorder by describing 11 previously unreported patients with Charcot-Marie-Tooth disease type 4J. Three patients were identified from a small cohort selected for screening because of their early onset disease and progressive proximal as well as distal weakness. Eight patients were identified by large-scale exon sequencing of an unselected group of 4000 patients with Charcot-Marie-Tooth disease. In addition, 34 new FIG4 variants were detected. Ten of the new CMT4J cases have the compound heterozygous genotype FIG4(I41T/null) described in the original four families, while one has the novel genotype FIG4(L17P/nul)(l). The population frequency of the I41T allele was found to be 0.001 by genotyping 5769 Northern European controls. Thirty four new variants of FIG4 were identified. The severity of Charcot-Marie-Tooth disease type 4J ranges from mild clinical signs to severe disability requiring the use of a wheelchair. Both mild and severe forms have been seen in patients with the same genotype. The results demonstrate that Charcot-Marie-Tooth disease type 4J is characterized by highly variable onset and severity, proximal as well as distal and asymmetric muscle weakness, electromyography demonstrating denervation in proximal and distal muscles, and frequent progression to severe amyotrophy. FIG4 mutations should be considered in Charcot-Marie-Tooth patients with these characteristics, especially if found in combination with sporadic or recessive inheritance, childhood onset and a phase of rapid progression.

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

“…However, the contribution of FIG4 variants to ALS pathogenesis has been debated because in smaller cohorts no deleterious FIG4 variants were found, and some non-penetrant FIG4 variant carriers have been described. [16][17][18] Our sequence analysis of the FIG4 gene in 201 almost exclusively central European ALS patients confirms known and identifies novel or rare heterozygous variants.…”

“…Protein sequence variants are given according to the Human Genome Variation Society recommendation v2.0; the exon structure of the human FIG4 gene (NG_007977.1, NM_014845.5) was based on Alamut Visual 2.6.1. 16 The novel variant FIG4:c.1619C4T, p.(T540I) was detected in sALS patient VALS007. Threonine at position 540 is part of the N-terminal turn of the α9-helix.…”

“…In a previous study, a missense variant in close proximity, p.E302K, was shown to act as a functional null allele of FIG4. 16 The substitution by Figure 2 Rare heterozygous deleterious FIG4 missense variants in five sALS patients detected by whole-exome and targeted sequencing. (a) Electropherograms demonstrating rare heterozygous FIG4 missense variants in five sALS patients (affected nucleotides are designated by an arrow).…”

“…(d) Summary of FIG4 variants detected in ALS patients in this or previous studies or previously in CMT4J patients. Variants found in ALS patients from our cohort are indicated in red; variants previously described in ALS patients 6,19,33 are indicated in green; variants previously described in CMT4J patients 9,16 are indicated in blue. Protein sequence variants are given according to the Human Genome Variation Society recommendation v2.0; the exon structure of the human FIG4 gene (NG_007977.1, NM_014845.5) was based on Alamut Visual 2.6.1.…”

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

“…Patients typically present with a length dependent progressive demyelinating motor and sensory polyneuropathy 2. There have been isolated case reports of people with CMT4J also having central nervous system (CNS) features, such as parkinsonism 3. In addition, people with disease‐causing variants in FIG4 have also been identified with Yunis‐Varon syndrome and familial epilepsy with polymicrogyria syndrome, both early onset diseases with severely abnormal CNS development and pathology.…”