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Clinical and genetic features of patients suffering from CMT4J

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Abstract

Mutations in the FIG4 gene have been identified in various diseases, including amyotrophic lateral sclerosis, Parkinson’s disease, and Charcot–Marie–Tooth 4 J (CMT4J), with a wide range of phenotypic manifestations. We present eight cases of CMT4J patients carrying the p.Ile41Thr mutation of FIG4. The patients were categorized according to their phenotype. Six patients had a pure CMT; whereas, two patients had a CMT associated with parkinsonism. Three patients had an early onset and exhibited more severe forms of the disease. Three others experienced symptoms in their teenage years and had milder forms. Two patients had a late onset in adulthood. Four patients showed electrophysiological evidence of conduction blocks, typically associated with acquired neuropathies. Consequently, two of them received intravenous immunoglobulin treatment without a significant objective response. Interestingly, two heterozygous patients with the same mutations exhibited contrasting phenotypes, one having a severe early-onset form and the other experiencing a slow disease progression starting at the age of 49. Notably, although 7 out of 8 patients in this study were compound heterozygous for the p.Ile41Thr mutation, only one individual was found to be homozygous for this genetic variant and exhibited an early-onset, severe form of the disease. Additionally, one patient who developed the disease in his youth was also diagnosed with hereditary neuropathy with pressure palsies. Our findings provide insights into the CMT4J subtype by reporting on eight heterogeneous patient cases and highlight the potential for misdiagnosis when conduction blocks or asymmetrical nerve conduction study results are observed in patients with FIG4 mutations.

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Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ALS:

Amyotrophic lateral sclerosis

CIDP:

Chronic inflammatory demyelinating polyneuropathy

CMAP:

Compound motor action potential

CMT:

Charcot–Marie–Tooth disease

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DML:

Distal motor latency

DTR:

Deep tendon reflexes

HNPP:

Hereditary neuropathy with liability to pressure palsies

MRC:

Medical Research Council

NCS:

Nerve conduction study

NCV:

Nerve conduction velocity

NGS:

Next-generation sequencing

ONLS:

Overall Neuropathy Limitations Scale

Plt:

Pale tremor

WGS:

Whole genome sequencing

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Authors and Affiliations

  1. Reference Center for Neuromuscular Disorders and ALS, Timone University Hospital, Aix-Marseille University, 264 Rue Saint Pierre, 05 13385, Marseille, Cedex, France

    Sadia Beloribi-Djefaflia, Farzad Fatehi, Jean Pouget & Shahram Attarian

  2. Filnemus, European Reference Network of Rare Diseases (ERN), Marseille, France

    Sadia Beloribi-Djefaflia, Farzad Fatehi, Jean Pouget & Shahram Attarian

  3. Aix Marseille Université–Inserm UMR 1251, Medical Genetics and Functional Genomics, Marseille, France

    Jean Pouget, Nathalie Bonello-Palot & Shahram Attarian

  4. Neuromuscular Unit. Neurology Department, Vall d’Hebron University Hospital. Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

    Raul Juntas Morales

  5. Pediatric Neurology Department, Reference Centre for Neuromuscular Diseases, Armand Trousseau Hospital, APHP, Sorbonne University, 26, Avenue du Docteur Arnold Netter, 75012, Paris, France

    Arnaud Isapof

  6. MDUK Oxford Neuromuscular Centre and NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

    Laurent Servais

  7. Neuromuscular Reference Center, Department of Paediatrics, University and University Hospital of Liege, Liege, Belgium

    Laurent Servais

  8. Neuromyology, Reference Center of Neuromuscular Disorders, Pitié Salpétrière Hospital, APHP, 47-83 Boulevard de L’Hôpital, 75651, Paris Cedex 13, France

    Sarah Leonard-Louis

  9. Reference Center for Neuromuscular Disorders, Central Nancy University Hospital, 29 Avenue Maréchal de Lattre de Tassigny, 54035, Nancy, France

    Maud Michaud

  10. Clinique Saint-Hilaire, 76000, Rouen, France

    Pierre Verdure

  11. I-Motion Institute, Hôpital Trousseau, Paris, France

    Teresa Gidaro

  12. Department of Molecular Genetics Pharmacogenomics and Hormonology, APHP, CHU de Bicêtre, 94276, Le Kremlin-Bicêtre, France

    Vianney Poinsignon

Authors
  1. Sadia Beloribi-Djefaflia
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  2. Raul Juntas Morales
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  3. Farzad Fatehi
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  4. Arnaud Isapof
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  5. Laurent Servais
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  6. Sarah Leonard-Louis
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  7. Maud Michaud
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  8. Pierre Verdure
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  9. Teresa Gidaro
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  10. Jean Pouget
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  11. Vianney Poinsignon
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  12. Nathalie Bonello-Palot
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  13. Shahram Attarian
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Contributions

SBD collected and analyzed the data, wrote and reviewed the manuscript. RJM, FF, AI, LS, SLL, MM, PV, TG, and JP followed patients, performed neurological examination, and reviewed the paper. VP and NBD performed the genetic analysis and reviewed the manuscript. SA was the principal investigator, designed and coordinated the project, performed neurological examination, analyzed the data, wrote and reviewed the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shahram Attarian.

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Beloribi-Djefaflia, S., Morales, R.J., Fatehi, F. et al. Clinical and genetic features of patients suffering from CMT4J. J Neurol 271, 1355–1365 (2024). https://doi.org/10.1007/s00415-023-12076-4

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  • DOI: https://doi.org/10.1007/s00415-023-12076-4

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