TMEM70 – Mitochondrial Disease

Autosomal recessive TMEM70 deficiency is a well-characterized cause of neonatal-onset mitochondrial disease, marked by impaired complex V assembly and profound energy failure. In a cohort of 461 neonatal patients from 331 families, prematurity was observed in one-third of cases, intrauterine growth restriction in one-third, cardiomyopathy in 40%, hyperammonemia in 22 of 52 neonates, and complex V deficiency in 31 neonates (PMID:22231385). TMEM70 was among the nuclear genes implicated in these complex V–deficient neonates.

In an independent series of 591 patients with genetically proven mitochondrial disorders, 11% exhibited 3-methylglutaconic aciduria, and TMEM70 mutations were identified as a key discriminative cause of this biochemical signature (PMID:23355087).

The TMEM70 gene defect was first described in 28 Roma patients homozygous for a founder splice‐donor mutation, c.210+1G>A, presenting with neonatal muscular hypotonia, hypertrophic cardiomyopathy, lactic acidosis, and 3-methylglutaconic aciduria (PMID:21147908). Six additional patients from four unrelated families harbored four novel homozygous deleterious variants, including c.434del (p.Tyr145fs), and the phenotypic spectrum was expanded to include infantile cataract, gastrointestinal dysfunction, congenital hypertonia with contractures, and fetal manifestations such as intrauterine growth retardation and severe oligohydramnios (PMID:21147908).

A cohort of ten Italian patients with neonatal lactic acidosis, respiratory distress, hypotonia, cardiomyopathy, and psychomotor delay carried the founder splice mutation and four novel variants; TMEM70 protein was virtually absent and complex V holocomplexes were nearly undetectable with accumulation of subassemblies, alongside secondary impairments of other OXPHOS complexes and disrupted mitochondrial cristae morphology (PMID:24740313).

A single heterozygous TMEM70‐Ile147Thr allele identified in a family with hypertrophic cardiomyopathy and long QT syndrome showed no genotype–phenotype correlation, supporting a recessive loss-of-function mechanism (PMID:29978770).

Functional studies consistently demonstrate that biallelic TMEM70 mutations abrogate ATP synthase assembly, leading to reduced complex V activity, secondary OXPHOS disruption, and the characteristic neonatal phenotype. Together, the genetic and experimental data establish a strong gene–disease association with autosomal recessive inheritance.

Key Take-home: TMEM70 should be included in diagnostic panels for neonates presenting with cardiomyopathy, lactic acidosis, 3-methylglutaconic aciduria, and intrauterine growth restriction to enable rapid molecular diagnosis and management.

References

• Journal of inherited metabolic disease • 2012 • Neonatal onset of mitochondrial disorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis. PMID:22231385
• Journal of inherited metabolic disease • 2013 • 3-Methylglutaconic aciduria--lessons from 50 genes and 977 patients. PMID:23355087
• Journal of medical genetics • 2011 • TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome. PMID:21147908
• JIMD reports • 2015 • Common and Novel TMEM70 Mutations in a Cohort of Italian Patients with Mitochondrial Encephalocardiomyopathy. PMID:24740313
• Cardiology in the young • 2018 • Investigation of myocardial dysfunction using three-dimensional speckle tracking echocardiography in a genetic positive hypertrophic cardiomyopathy Chinese family. PMID:29978770

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