Neuropediatrics 2006; 37 - MP68
DOI: 10.1055/s-2006-943665

THE CLINICAL SPECTRUM OF MTDNA DEPLETION DUE TO MUTATIONS IN THE THYMIDINE KINASE (TK2) GENE

M Oskoui 1, G Davidzon 1, J Pascual 1, R Erazo 3, J Gurgel-Giannetti 2, S Krishna 1, E Bonilla 1, DC De Vivo 1, S Shanske 1, S DiMauro 1
  • 1Department of Neurology, Columbia University Medical Center, New York, NY
  • 2Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte, Brazil
  • 3Division of Pediatric Neurology, Hospital Luis Calvo MacKenna, Santiago, Chile

Background : Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder characterized by decreased mtDNA copy number in affected tissues. MDS has been linked to four genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2), deoxyguanosine kinase (DGUOK), polymerase gamma (POLG), and SUCLA2, the gene encoding the â -subunit of the ADP-forming succinyl CoA synthetase ligase. Children with TK2 mutations have a predominantly myopathic syndrome.

Design: Review of patients with MDS and mutations in the TKT2 gene.

Objectives : To highlight the variability in the clinical spectrum of TK2-related MDS, we report 4 cases and review the literature.

Setting: Tertiary care University setting with international collaboration.

Results : Patient 1 had evidence of lower motor neuron disease and was initially diagnosed as spinal muscular atrophy type 3. He was compound heterozygous for a previously reported I212N mutation and a novel AT insertion at nucleotide 337 (exon 5) resulting in a premature stop codon. Patient 2, who is still alive and ambulatory at 9 years of age, presented at age 2 years with a slowly progressive mitochondrial myopathy: she harbors the same AT insertion in exon 5 as Patient 1 and a novel N93S mutation in exon 4. Patient 3 suffered from a more severe myopathy, with onset in infancy and death at age 6 from respiratory failure: she had a previously reported homozygous change (H121N) in exon 5. Patient 4 had a rapidly progressive congenital myopathy with rigid spine syndrome and died at 19 months: he harbored two novel mutations in exon 5, a missense change, T108M, and a nonsense change, Q125X.

Conclusion : The clinical spectrum of TK2 mutations is not limited to severe infantile myopathy with motor regression and early death, but includes spinal muscular atrophy type 3– like presentation, rigid spine syndrome, and subacute myopathy without motor regression and with longer survival.