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Infantile (Hepato)enzephalopathy - DGUOK, MPV17, POLG, TK2, SUCLA2, SUCLG1, RRM2B, PEO1/Twinkle

MtDNA Depletion Syndromes (including Alpers Syndrome)

Clinical Features

MtDNA depletion syndromes are caused by the decreased amount of mtDNA compared to nuclear DNA. The most frequent cause of infantile (hepato)encephalomyopathies with combined respiratory chain deficiency is mtDNA depletion.

There are different phenotypes of mtDNA depletion, caused by mutations of different nuclear genes.

• The hepatic form of mtDNA depletion is most frequently related to mutations in the deoxy-guanosine-kinase (DGUOK) gene. A second disease gene in this phenotype is MPV17. The respiratory chain deficiency is usually present in muscle, however in cases with isolated liver involvement, the respiratory chain enzymes are only decreased in liver tissue. In most of the patients, mtDNA depletion is present in muscle.
• The myopathic form of mtDNA depletion starts usually before 2 years of age and creatine kinase is usually increased. Mutations in the thymidine kinase 2 (TK2) gene are causing this phenotype most frequently.
• Autosomal recessive mutations in the mitochondrial polymerase gamma (POLG1) gene are frequent causes of Alpers syndrome (intractable epilepsy, hepatopathy and cortical blindness). In these patients genetic analysis of the POLG1 gene is required, since the activities of the respiratory chain enzymes in skeletal muscle are often normal.
• MtDNA depletion with encephalomyopathy might be caused by mutations in the succinyl-Co-A synthase (SUCLA2) gene.

Genetic Information

• Hepatic form of mtDNA depletion:
  DGUOK has 7 exons and is located to chromosome 2p13.
  MPV17 on chromosome 2p21-23 consists of 7 exons.

• Alpers-Syndrom:
  POLG1 is located on chromosome 15q22-26 and has 23 exons, exon 1 is not a coding exon.

• (Encephalo)myopathic form of mtDNA depletion:
  The TK2 gene maps to chromosome 16 and consists of 10 coding exons.
  SUCLA2 has 12 exons and maps to chromosome 13.
  Mutations of these nuclear genes make prenatal genetic analysis possible.

Prevalence

In North-Spain the prevalence of mtDNA depletion was found to be 1,59 : 100 000.

In Germany the occurrence of mtDNA depletion is not known yet. Approximately in 30% of children with severe combined respiratory chain deficiency mtDNA depletion is present. The most frequent genetic causes of mtDNA depletion in Germany are mutations in POLG1 and DGUOK genes. 

Diagnostic