FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome

Charcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death. To an...

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Bibliographic Details
Published in:Parkinsonism & related disorders 2020-05, Vol.74, p.6-11
Main Authors: Zimmermann, Milan, Schuster, Stefanie, Boesch, Sylvia, Korenke, G. Christoph, Mohr, Julia, Reichbauer, Jennifer, Kernstock, Christoph, Kotzot, Dieter, Spahlinger, Veronika, Schüle-Freyer, Rebecca, Schöls, Ludger
Format: Article
Language:English
Subjects:
Adult
Aged
Cerebellar ataxia
Charcot-Marie-Tooth Disease - genetics
Charcot-Marie-Tooth Disease - physiopathology
Charcot-marie-tooth type 4J
Cleidocranial Dysplasia - genetics
Cleidocranial Dysplasia - physiopathology
CMT4J
Ectodermal Dysplasia - genetics
Ectodermal Dysplasia - physiopathology
Female
Fibroblasts
Flavoproteins - genetics
Hereditary peripheral neuropathy
Humans
Limb Deformities, Congenital - genetics
Limb Deformities, Congenital - physiopathology
Male
Micrognathism - genetics
Micrognathism - physiopathology
Middle Aged
Mutation
Parkinsonian Disorders - genetics
Parkinsonian Disorders - physiopathology
Parkinsonism
Pedigree
Phenotype
Phosphoric Monoester Hydrolases - genetics
Young Adult
Yunis varón syndrome
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Description
Summary:Charcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death. To analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein. Phenotyping of five new patients with FIG4-related disease. Western Blot analyses of FIG4 from patient fibroblasts. Next generation sequencing revealed compound heterozygous variants in FIG4 in five patients. All five patients presented with peripheral neuropathy, various degree of dysmorphism and a central nervous system involvement comprising Parkinsonism in 3/5 patients, cerebellar ataxia (1/5), spasticity of lower limbs (1/5), epilepsy (1/5) and/or cognitive deficits (2/5). Onset varied between the first and the seventh decade. There was no residual FIG4 protein detectable in fibroblasts of the four analysed patients. This study extends the phenotypic spectrum of FIG4-related disease to Parkinsonism as a feature and demonstrates new phenotypes on a continuum between CMT4J and Yunis Varón syndrome. •FIG4 mutations can lead to a phenotypical continuum between CMT4J and Yunis Varón syndrome.•FIG4-mutations can lead to a syndrome comprising a peripheral neuropathy, dysmophism and a central nervous system involement.•The syndrome can include a predominant Parkinsonism.
ISSN:1353-8020
1873-5126
DOI:10.1016/j.parkreldis.2020.03.021