Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation
Tomás Honzík1, Markéta Tesarová, Johannes A Mayr
1Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Ke Karlovu 2, 128 08 Prague 2, Czech Republic.
Insights
This study characterizes a novel mitochondrial disease caused by TMEM70 gene mutations, highlighting severe neonatal symptoms like hypotonia and cardiomyopathy. Early diagnosis via genetic testing is crucial for managing this rare ATP synthase deficiency.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Mitochondrial energy metabolism disorders are diverse and impact childhood development.
- ATP synthase deficiency represents a specific, yet poorly understood, group of these disorders.
Purpose of the Study:
- To characterize the natural history of a novel mitochondrial disease defined by ATP synthase deficiency and a specific mutation in the TMEM70 gene.
- To identify key clinical and metabolic features for early diagnosis and management.
Main Methods:
- A retrospective analysis of clinical data and metabolic profiles was conducted.
- Twenty-five patients (14 boys, 11 girls) from seven European countries with the c.317-2A-->G mutation in the TMEM70 gene were included.
Main Results:
- Neonates presented with severe hypotonia (92%), apnoic spells (92%), hypertrophic cardiomyopathy (HCMP; 76%), and profound lactic acidosis (92%) with hyperammonaemia (86%).
- Mortality was high in the first six weeks (10/25), with survivors experiencing persistent hypotonia and psychomotor delay.
- All patients showed increased lactate and 3-methylglutaconic acid (3-MGC) excretion; hypospadias (54%) and cryptorchidism (67%) were noted in affected boys.
Conclusions:
- TMEM70-associated ATP synthase deficiency should be considered in neonates with hypotonia, HCMP, lactic acidosis, hyperammonaemia, and 3-MGC-uria.
- Molecular-genetic analysis of the TMEM70 gene is sufficient for diagnosis, obviating the need for muscle biopsy.
- The disease is prevalent in the Roma population, and phenotype severity can vary significantly.
Objective:
Mitochondrial disturbances of energygenerating systems in childhood are a heterogeneous group of disorders. The aim of this multi-site survey was to characterise the natural course of a novel mitochondrial disease with ATP synthase deficiency and mutation in the TMEM70 gene.
Methods:
Retrospective clinical data and metabolic profiles were collected and evaluated in 25 patients (14 boys, 11 girls) from seven European countries with a c.317-2A-->G mutation in the TMEM70 gene.
Results:
Severe muscular hypotonia (in 92% of newborns), apnoic spells (92%), hypertrophic cardiomyopathy (HCMP; 76%) and profound lactic acidosis (lactate 5-36 mmol/l; 92%) with hyperammonaemia (100-520 micromol/l; 86%) were present from birth. Ten patients died within the first 6 weeks of life. Most patients surviving the neonatal period had persisting muscular hypotonia and developed psychomotor delay. HCMP was non-progressive and even disappeared in some children. Hypospadia was present in 54% of the boys and cryptorchidism in 67%. Increased excretion of lactate and 3-methylglutaconic acid (3-MGC) was observed in all patients. In four surviving patients, life-threatening hyperammonaemia occurred during childhood, triggered by acute gastroenteritis and prolonged fasting.
Conclusions:
ATP synthase deficiency with mutation in TMEM70 should be considered in the diagnosis and management of critically ill neonates with early neonatal onset of muscular hypotonia, HCMP and hypospadias in boys accompanied by lactic acidosis, hyperammonaemia and 3-MGC-uria. However, phenotype severity may vary significantly. The disease occurs frequently in the Roma population and molecular-genetic analysis of the TMEM70 gene is sufficient for diagnosis without need of muscle biopsy in affected children.
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