Distinctive genetic and clinical features of CMT4J

A severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4

Garth Nicholson, Guy M. Lenk, Stephen W. Reddel, Adrienne E. Grant, Charles F. Towne, Cole J. Ferguson, Ericka Simpson, Angela Scheuerle, Michelle Yasick, Stuart Hoffman, Randall Blouin, Carla Brandt, Giovanni Coppola, Leslie G. Biesecker, Sat D. Batish, Miriam H. Meisler

Research output: Contribution to journalArticle

58 Citations (Scopus)

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 FIG4I41T/null described in the original four families, while one has the novel genotype FIG4L17P/null. 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.

Original languageEnglish (US)
Pages (from-to)1959-1971
Number of pages13
JournalBrain
Volume134
Issue number7
DOIs
StatePublished - Jul 2011

Fingerprint

Phosphoric Monoester Hydrolases
Mutation
Charcot-Marie-Tooth Disease
Genotype
Genetic Databases
Wheelchairs
Muscle Weakness
Electromyography
Denervation
Gene Frequency
phosphatidylinositol 3,5-diphosphate
Exons
Tooth
Lipids
Muscles
Type 4j Charcot-Marie-Tooth Disease
Population
Genes

Keywords

  • Charcot-Marie-Tooth disease
  • clinical characteristics
  • demyelinating disease
  • molecular genetics
  • neurodegenerative disorders

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., ... Meisler, M. H. (2011). Distinctive genetic and clinical features of CMT4J: A severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4. Brain, 134(7), 1959-1971. https://doi.org/10.1093/brain/awr148

Distinctive genetic and clinical features of CMT4J : A severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4. / Nicholson, Garth; Lenk, Guy M.; Reddel, Stephen W.; Grant, Adrienne E.; Towne, Charles F.; Ferguson, Cole J.; Simpson, Ericka; Scheuerle, Angela; Yasick, Michelle; Hoffman, Stuart; Blouin, Randall; Brandt, Carla; Coppola, Giovanni; Biesecker, Leslie G.; Batish, Sat D.; Meisler, Miriam H.

In: Brain, Vol. 134, No. 7, 07.2011, p. 1959-1971.

Research output: Contribution to journalArticle

Nicholson, G, Lenk, GM, Reddel, SW, Grant, AE, Towne, CF, Ferguson, CJ, Simpson, E, Scheuerle, A, Yasick, M, Hoffman, S, Blouin, R, Brandt, C, Coppola, G, Biesecker, LG, Batish, SD & Meisler, MH 2011, 'Distinctive genetic and clinical features of CMT4J: A severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4', Brain, vol. 134, no. 7, pp. 1959-1971. https://doi.org/10.1093/brain/awr148
Nicholson, Garth ; Lenk, Guy M. ; Reddel, Stephen W. ; Grant, Adrienne E. ; Towne, Charles F. ; Ferguson, Cole J. ; Simpson, Ericka ; Scheuerle, Angela ; Yasick, Michelle ; Hoffman, Stuart ; Blouin, Randall ; Brandt, Carla ; Coppola, Giovanni ; Biesecker, Leslie G. ; Batish, Sat D. ; Meisler, Miriam H. / Distinctive genetic and clinical features of CMT4J : A severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4. In: Brain. 2011 ; Vol. 134, No. 7. pp. 1959-1971.
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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 FIG4I41T/null described in the original four families, while one has the novel genotype FIG4L17P/null. 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.",
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AU - Grant, Adrienne E.

AU - Towne, Charles F.

AU - Ferguson, Cole J.

AU - Simpson, Ericka

AU - Scheuerle, Angela

AU - Yasick, Michelle

AU - Hoffman, Stuart

AU - Blouin, Randall

AU - Brandt, Carla

AU - Coppola, Giovanni

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N2 - 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 FIG4I41T/null described in the original four families, while one has the novel genotype FIG4L17P/null. 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.

AB - 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 FIG4I41T/null described in the original four families, while one has the novel genotype FIG4L17P/null. 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.

KW - Charcot-Marie-Tooth disease

KW - clinical characteristics

KW - demyelinating disease

KW - molecular genetics

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