Abstract
Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (
TK2
,
SUCLA2
,
SUCLG1
,
RRM2B
,
DGUOK
, and
TYMP
) or mtDNA replication (
POLG
and
C10orf2
). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. Myopathic MDS, caused by mutations in
TK2
, usually present before the age of 2 years with hypotonia and muscle weakness. Encephalomyopathic MDS, caused by mutations in
SUCLA2
,
SUCLG1
, or
RRM2B
, typically present during infancy with hypotonia and pronounced neurological features. Hepatocerebral MDS, caused by mutations in
DGUOK
,
MPV17
,
POLG
, or
C10orf2
, commonly have an early-onset liver dysfunction and neurological involvement. Finally,
TYMP
mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. Nutritional modulation and cofactor supplementation may be beneficial. Liver transplantation remains controversial. Finally, stem cell transplantation in MNGIE disease shows promising results.