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Clinical and Biochemical Heterogeneity in an Italian Family with CPT II Deficiency due to Ser 113 Leu Mutation

Published online by Cambridge University Press:  02 December 2014

Mubeen F. Rafay ,
E. Gordon Murphy ,
J. Denis McGarry ,
Petra Kaufmann ,
Salvatore DiMauro  and
Ingrid Tein
Mubeen F. Rafay*
Affiliation:
Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario
E. Gordon Murphy
Affiliation:
Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario
J. Denis McGarry
Affiliation:
Department of Internal Medicine, Southwestern Medical Centre, Dallas, Texas, USA
Petra Kaufmann
Affiliation:
Department of Neurology, Columbia University, New York, New York, USA
Salvatore DiMauro
Affiliation:
Department of Neurology, Columbia University, New York, New York, USA
Ingrid Tein
Affiliation:
Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, Ontario
*
Division of Neurology, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8 Canada
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Abstract:

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Background:

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder which presents with recurrent myoglobinuria. Heterozygotes are usually asymptomatic.

Methods:

We correlate the clinical, biochemical and molecular features of a family in which the proband is homozygous for CPT II deficiency, due to the common Ser 113 Leu mutation.

Results:

The 20-year-old female proband presented at age three years with episodic myalgia and myoglobinuria, elevated creatine kinase (CK) of 3600 IU/L and had a 33% residual CPT II activity in cultured skin fibroblasts. Her 25-year-old dizygotic twin brothers presented with muscle stiffness following prolonged exercise but no overt pigmenturia and had interictal CKs up to 662 IU/L. Her parents and a 13-year-old brother are asymptomatic. An elder sister, not investigated, had recurrent pigmenturia and died at eight years with myoglobinuria. Molecular analysis revealed that the proband is homozygous for the Ser 113 Leu mutation. Her parents are heterozygotes with CPT II activities of 55% to 70%. Her younger brother is normal with 83% activity. The symptomatic twin brothers are heterozygous but demonstrated unexpectedly low CPT II activities of 40%, which may explain their phenotype.

Conclusion:

We postulate that there may be genetic, environmental and sex hormonal factors accounting for this manifesting heterozygosity and biochemical heterogeneity in CPT II deficiency.

Résumé:

RÉSUMÉ: Introduction:

Le déficit en carnitine palmitoyltransférase II (CPT II) est une maladie récessive autosomique ayant comme mode de présentation une myoglobinurie récurrente. Les hétérozygotes sont habituellement asymptomatiques.

Méthodes:

Nous décrivons les caractéristiques cliniques, biochimiques et moléculaires d’une famille dont le cas index est porteur d’un déficit en CPT II à l’état homozygote dû à une mutation fréquente, une substitution ser 113 leu.

Résultats:

Le cas index, une patiente maintenant âgée de 20 ans, a été vue pour la première fois à l’âge de trois ans parce qu’elle présentait des épisodes de myalgie et de myoglobinurie et un taux élevé de créatine-phosphokinase (CPK) à 3600 U/L. L’activité résiduelle de la CPT II était de 33% dans ses fibroblastes cutanés en culture. Ses deux frères âgés de 25 ans, des jumeaux fraternels, avaient de la raideur musculaire après un exercice prolongé, sans myoglobinurie évidente et un taux interictal de CPK qui atteignait 662 U/L. Ses parents et un frère âgé de 13 ans sont asymptomatiques. Une soeur aînée, qui n’a pas été investiguée, avait une pigmenturie récurrente et elle est décédée à 8 ans d’une myoglobinurie. L’analyse moléculaire a montré une mutation ser 113 leu à l’état homozygote chez le cas index. Ses parents sont hétérozygotes et leur activité CPT II varie de 55% à 70%. Son jeune frère est normal et l’activité CPT II chez-lui est de 83%. Cependant, l’activité CPT II est singulièrement basse à 40% chez ses deux frères jumeaux hétérozygotes qui sont symptomatiques, ce qui peut expliquer leur phénotype.

Conclusion:

Nous postulons que ce tableau clinique et cette hétérogénéité chez des hétérozygotes pour un déficit en CPT II pourraient être dus à des facteurs génétiques, environnementaux ou en relation avec les hormones sexuelles.

Type
Original Article
Information
Canadian Journal of Neurological Sciences , Volume 32 , Issue 3 , August 2005 , pp. 316 - 320
Copyright
Copyright © The Canadian Journal of Neurological 2005

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