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TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome
  1. Ronen Spiegel1,2,3,
  2. Morad Khayat2,
  3. Stavit A Shalev2,3,
  4. Yoseph Horovitz1,3,
  5. Hanna Mandel3,4,
  6. Eli Hershkovitz5,
  7. Flora Barghuti6,
  8. Avraham Shaag7,
  9. Ann Saada7,
  10. Stanley H Korman7,
  11. Orly Elpeleg7,
  12. Ido Yatsiv8
  1. 1Pediatric Department A', Ha'Emek Medical Center, Afula, Israel
  2. 2Genetic Institute, Ha'Emek Medical Center, Afula, Israel
  3. 3Rappaport School of Medicine, Technion, Medical Center, Haifa, Israel
  4. 4Metabolic Unit, Mayer Medical Center, Haifa, Israel
  5. 5Pediatric Endocrinology and Metabolic Unit, Soroka Medical Center, Ben-Gurion University, Beer-Sheva, Israel
  6. 6Palestine Medical Complex, Children Wing, Ramallah, Palestinian Authority
  7. 7Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
  8. 8Pediatric Intensive Care Unit, Hadassah, and Hebrew University Medical Center, Jerusalem, Israel
  1. Correspondence to Dr Ronen Spiegel, Paediatric Department A' and Genetic Institute Ha'Emek Medical Center, Afula, Israel; spiegelr{at}


Background The TMEM70 gene defect was recently identified as a novel cause of autosomal recessive ATP synthase deficiency. Most of the 28 patients with TMEM70 disorder reported to date display a distinctive phenotype characterised by neonatal onset of severe muscular hypotonia hypertrophic cardiomyopathy, facial dysmorphism, profound lactic acidosis, and 3-methylglutaconic aciduria. Almost all share a common Roma descent and are homozygous for a single founder splice site mutation.

Methods Six new patients from four separate families, with clinical and biochemical diagnosis of ATP synthase deficiency, were studied. TMEM70 sequence analysis of the three exons and their flanking splice junction consensus sequences was performed in all patients. In addition their clinical phenotype and disease course was strictly studied.

Results Four novel deleterious homozygous TMEM70 mutations were identified. The previously described clinical spectrum was expanded to include infantile onset cataract, early onset gastrointestinal dysfunction and congenital hypertonia with multiple contractures resembling arthrogryposis. The first characterisation of fetal presentation of the syndrome is also provided, featuring significant intrauterine growth retardation, severe oligohydramnios, fetal hypotonia, and myocardial wall thickening.

Conclusions The current report corroborates the previously described unique phenotype of TMEM70 deficiency. The study identifies TMEM70 gene defect as a pan-ethnic disorder and further redefines it as the most common cause of nuclear-origin ATP synthase deficiency.

  • ATP synthase
  • TMEM70 gene
  • mitochondrial oxidative phosphorylation
  • hypertrophic cardiomyopathy
  • lactic acidosis
  • metabolic disorders
  • clinical genetics
  • molecular genetics

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  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the HaEmek Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.