Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.
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.


OBJECTIVE
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.
Mancuso
M
M
Department of Neurology, P&S Building 5-431, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Salviati
L
L
Sacconi
S
S
Otaegui
D
D
Camaño
P
P
Marina
A
A
Bacman
S
S
Moraes
C T
CT
Carlo
J R
JR
Garcia
M
M
Garcia-Alvarez
M
M
Monzon
L
L
Naini
A B
AB
Hirano
M
M
Bonilla
E
E
Taratuto
A L
AL
DiMauro
S
S
Vu
T H
TH
D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D009132:Muscles / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D013937:Thymidine Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D004272:DNA, Mitochondrial; D017853:Phosphotransferases (Alcohol Group Acceptor); C105339:thymidine kinase 2; C019165:deoxyguanosine kinase; D013937:Thymidine Kinase