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Mitochondrial encephalo-cardio-myopathy due to TMEM70 deficiency

Orpha number ORPHA1194
Synonym(s) Mitochondrial encephalo-cardio-myopathy due to ATP synthase deficiency
Mitochondrial encephalo-cardio-myopathy due to F1Fo ATPase deficiency
Mitochondrial encephalo-cardio-myopathy due to mitochondrial respiratory chain complex V deficiency
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • G71.3
ICD-O -
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT -

Summary

Mitochondrial encephalo-cardio-myopathy due to TMEM70 mutation is characterized by early neonatal onset of hypotonia, hypetrophic cardiomyopathy and apneic spells within hours after birth accompanied by lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria.

Prevalence is unknown. To date fewer than 100 cases have been reported in the literature.

Neonatal onset of the disease is frequent and clinical symptoms include low birth weight due to prematurity or intrauterine growth retardation, hypotonia, apneic spells, respiratory failure requiring ventilator support, and hypertrophic cardiomyopathy. Most patients who survive the neonatal period have mild cranio-facial dysmorphism with low set ears, prominent nasal bridge and retrognathia, persisting muscular hypotonia and moderate psychomotor developmental delay. Hypospadias and/or cryptorchidism are present in 50 % of boys. Hypertrophic cardiomyopathy is non-progressive and may even disappear.

Mitochondrial encephalo-cardio-myopathy due to ATP synthase deficiency is a result of an isolated decrease in the tissue content and activity of mitochondrial FoF1 ATP synthase caused by depressed biosynthesis of the enzyme. This enzyme defect is present in all tissues and is due to autosomal recessive mutations in the TMEM70 gene (8q21.11), encoding ancillary factor of ATP synthase biogenesis. The mutation c.317-2A>G is prevalent, particularly in the Roma population.

The most important diagnostic tool for this disease is molecular genetic analysis which confirms the presence of pathogenic mutations in the TMEM70 gene. Diagnosis of the enzyme defect is based on biochemical methods (Blue Native electrophoresis and Western blot analysis) confirming the decreased presence of ATP synthase and/or decreased activity of ATP synthase (both synthetic and hydrolytic activities are decreased) in tissue biopsy or cultivated fibroblasts.

Differential diagnoses include ATP synthase deficiency due to ATPAF2 mutation and other ATP synthase disorders including NARP/MILS syndrome (see this term). Mitochondrial encephalo-cardio-myopathy due to isolated ATP synthase deficiency should be considered in critically ill neonates, especially in those with early onset of hypotonia and hypertrophic cardiomyopathy accompanied with lactic acidosis and/or hyperammonemia.

Prenatal diagnosis in affected families is available using molecular genetic testing.

Treatment is reliant on early diagnosis and includes appropriate intensive care during the neonatal period and optimizing nutrition to prevent catabolism in patients who survive this period.

Mortality is high, usually in the neonatal period or during early childhood. Most of the patients who survive the neonatal period have persisting muscular hypotonia and moderate intellectual deficit. Treatment may improve the life expectancy of affected patients.

Expert reviewer(s)

  • Dr Josef HOUSTEK
  • Dr Stanislav KMOCH

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