Clinical features of homozygous FIG4‐p.Ile41Thr Charcot‐Marie‐Tooth 4J patients

Lafontaine, Maxime; Lia, Anne‐Sophie; Bourthoumieu, Sylvie; Beauvais‐Dzugan, Hélène; Derouault, Paco; Arné-Bès, Marie-Christine; Sarret, Catherine; Laffargue, Fanny; Magot, Armelle; Sturtz, Franck; Magy, Laurent; Magdelaine, Corinne

doi:10.1002/acn3.51175

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…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).…”

Section: Introductionmentioning

confidence: 99%

Roles of PIKfyve in multiple cellular pathways

Rivero-Ríos

Weisman²

2022

Current Opinion in Cell Biology

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Section: Introductionmentioning

confidence: 99%

Roles of PIKfyve in multiple cellular pathways

Rivero-Ríos

Weisman²

2022

Current Opinion in Cell Biology

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“…In this family, the patient’s father is of Northern European descent and likely carries this ancestral mutation originating in Europe. It has been reported that compound heterozygotes with this mutation diagnosed with CMT4J usually show early onset with rapid progression [ 9 ]. In contrast, our patient demonstrates that even in those carrying this mutation, the onset can be late and progression slow.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Analysis of a Patient with CMT4J

Peddareddygari¹,

Grewal

2022

Neurology International

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We report the clinical and genetic analysis of a patient with a rare form of an autosomal recessive genetic neuropathy, Charcot Marie Tooth (CMT) disease type 4J. She presented at age 62 years with signs and symptoms consistent with a mild neuropathy. The onset of symptoms began approximately ten years earlier. Electrophysiological testing confirmed a demyelinating neuropathy and a comprehensive neuropathy screening for common causes of neuropathy was unrevealing. She underwent commercial whole exome sequencing, analyzing more than eighty genes known to cause neuropathy. Two mutations were detected, c.122T > C, p.Ile41Thr and c.2247dupC, p.Ser750GlnX10 in the FIG4 gene. The p.Ile41Thr mutation, which is paternally inherited, is a recurrent mutation reported in a number of unrelated families of European descent. The patient’s father, also of European descent, provides further evidence supporting a founder effect for this mutation. In most patients carrying the p.Ile41Thr mutation, the neuropathy, unlike our patient, is often severe with early onset. The second mutation, c.2247dupC, p.Ser750GlnX10 is maternally inherited and not previously reported. Furthermore, based upon our protein modeling analysis, c.2247dupC is disease producing, representing a novel pathogenic mutation. Our study of this patient expands the clinical and genetic spectrum of patients with CMT 4J.

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“…Thirty CMT4J cases with homozygous or compound heterozygous FIG4 variants that were involved with CNS anomalies have been reported (Table 2). The p.I41T variant was a recurrent mutation reported in a number of unrelated families (11). It has been estimated that the population frequency of this allele was 0.001 (1).…”

Section: Literature Reviewmentioning

confidence: 99%

Case report and literature review: Novel compound heterozygous FIG4 variants causing both of peripheral and central nervous system defects

Yang

Yin²,

Ma³

et al. 2022

Front. Pediatr.

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BackgroundPathogenic variants in the FIG4 gene have been described to be associated with a diverse spectrum of syndromes, such as autosomal recessive bilateral temporooccipital polymicrogyria (OMIM 612691), autosomal dominant amyotrophic lateral sclerosis-11 (ALS11; OMIM 612577), autosomal recessive Charcot-Marie-Tooth disease, type 4J (CMT4J; OMIM 611228), and autosomal recessive Yunis-Varon syndrome (YVS; OMIM 216340). Heterozygous FIG4 variants are responsible for ALS11 characterized by progressive muscular weakness, atrophy, and bulbar palsy. CMT4J is a disorder of peripheral nervous system defects mainly presenting with a highly variable onset of proximal and/or distal muscle weakness. YVS is a disorder of severe neurological involvement with central nervous system (CNS) dysfunction and extensive skeletal anomalies.Case PresentationWe reported two Chinese siblings born with a weakness in all limbs. They experienced rapidly progressive weakness in distal limbs. At the age of 6 years, the elder brother presented with severe scoliosis and cervical kyphosis. They both had global developmental delay and a CNS involvement with cognitive deficits and swallowing problems. Genetic screening in the patients' family for inherited diseases was recommended. Novel compound heterozygous variants in the FIG4 gene (c.2148delTinsAA and c.317A > G) were found by whole-exome sequencing in the patients. These variants were confirmed by Sanger sequencing in family members.ConclusionsHerein, we reported two Chinese male patients with CMT4J who presented with abnormal CNS features. CMT4J with CNS involvement has been very rarely reported. We hoped this study could expand the phenotypic and genetic spectrum of FIG4-related diseases. And we helped physicians to understand the genotype–phenotype correlation.

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Clinical features of homozygous FIG4‐p.Ile41Thr Charcot‐Marie‐Tooth 4J patients

Cited by 7 publications

References 11 publications

Roles of PIKfyve in multiple cellular pathways

Roles of PIKfyve in multiple cellular pathways

Clinical and Genetic Analysis of a Patient with CMT4J

Case report and literature review: Novel compound heterozygous FIG4 variants causing both of peripheral and central nervous system defects

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