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 Volume 59, Number 8, October 22, 2002
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Neurology 2002;59:1197-1202
© 2002 American Academy of Neurology

Mitochondrial DNA depletion

Mutations in thymidine kinase gene with myopathy and SMA

M. Mancuso, MD, L. Salviati, MD, S. Sacconi, MD, D. Otaegui, P. Camaño, A. Marina, PhD, S. Bacman, MD, C.T. Moraes, MD, J.R. Carlo, MD, M. Garcia, MD, M. Garcia-Alvarez, MD, L. Monzon, A.B. Naini, PhD, M. Hirano, MD, E. Bonilla, MD, A.L. Taratuto, MD, S. DiMauro, MD and T.H. Vu, MD

From the Departments of Neurology (Drs. Mancuso, Salviati, Sacconi, Naini, Hirano, Bonilla, DiMauro, and Vu, and D. Otaegui, P. Camaño, and L. Monzon) and Biochemistry and Molecular Biophysics (Dr. Marina), Columbia University, College of Physicians and Surgeons, New York, NY; Department of Neurosciences (Dr. Mancuso), University of Pisa, Italy; Department of Pediatrics (Dr. Salviati), University of Padova, Italy; Department of Neurology (Dr. Sacconi), University of Modena, Italy; University of Miami School of Medicine (Drs. Bacman and Moraes), Miami, FL; Clinicas Las Americas (Drs. Carlo and Garcia), San Juan, Puerto Rico; and Pediatric Neurology Department (Drs. Garcia-Alvarez and Taratuto), FLENI, Buenos Aires, Argentina.

Address correspondence and reprint requests to Dr. Tuan H. Vu, Department of Neurology, P&S Building 5-431, Columbia University, New York, NY 10032; e-mail: thv3{at}aol.com

Background: The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder of early childhood characterized by decreased mtDNA copy number in affected tissues. Recently, MDS has been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxy-guanosine kinase (dGK). Mutations in TK2 have been associated with the myopathic form of MDS, and mutations in dGK with the hepatoencephalopathic form.

Objectives: To further characterize the frequency and clinical spectrum of these mutations, the authors screened 20 patients with myopathic MDS.

Results: No patient had dGK gene mutations, but four patients from two families had TK2 mutations. Two siblings were compound heterozygous for a previously reported H90N mutation and a novel T77M mutation. The other siblings harbored a homozygous I22M mutation, and one of them had evidence of lower motor neuron disease. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28% to 37% of controls).

Conclusions: These results show that the clinical expression of TK2 mutations is not limited to myopathy and that the myopathic form of MDS is genetically heterogeneous.




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