Abstract Details

Title Choline ? Kinase Deficiency Results in Central Core-Like Myopathy and Impaired Cellular Bioenergetics

Topic Child Neurology/Developmental Neurobiology

Presentation(s) P02 - (-)

Poster/Presentation
Number 094

Objective

Background BACKGROUND: Choline ? kinase (CLKB) is the principle enzyme which catalyzes the phosphorylation of choline in muscle, the first step in the phosphatidyl choline biosynthetic pathway. In humans, CLKB deficiency results in recessively inherited myopathy with histopathological features resembling central core disease.

Design/Methods DESIGN/METHODS: A 7 [frac12] year old girl presented with a history of cognitive delay, autistic features, proximal weakness and obesity. She had persistent elevations in serum CPK, plasma lactate and pyruvate levels. Family history was unremarkable.

Results RESULTS: Muscle biopsy revealed rare scattered necrotic and regenerating fibers. Large central cores were prominent on oxidative enzyme stains with a virtual absence of mitochondrial components within the central regions of affected fibers. Muscle OX/PHOS enzymology revealed defects in complexes I and III of the electron transport chain (ETC). High resolution respirometry demonstrated uncoupling of proton flux from earlier complexes in the ETC and complex V (ATPase synthase). Immunoblots revealed decreased complexes I, III and V including a doublet pattern in complex V indicating a dissociation of the F0 and F1 subunits. Deletion and sequencing studies of mitochondrial DNA and the RYR1 gene were normal. Previously unreported heterozygous mutations involving exons 1 and 9 of the CLKB gene were elucidated.

Conclusions CONCLUSIONS: CLKB deficiency in humans results in a syndrome of impaired cognitive development and myopathy. The muscle biopsy shows stereotypical features with myofibrillar centers devoid of mitochondria. These clinical manifestations appear to be the consequence of an OX/PHOS defect affecting multiple components of the electron transport system.

Authors/Disclosures
Lauren Mylacraine PRESENTER	No disclosure on file
John T. Sladky, MD (University of Florida)	No disclosure on file
John Shoffner IV, MD (Sangamo Therapeutics)	No disclosure on file
Greg Mytyk (University of Tennessee)	No disclosure on file

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