TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome
R Spiegel, M Khayat, SA Shalev, Y Horovitz… - Journal of medical …, 2011 - jmg.bmj.com
R Spiegel, M Khayat, SA Shalev, Y Horovitz, H Mandel, E Hershkovitz, F Barghuti, A Shaag…
Journal of medical genetics, 2011•jmg.bmj.comBackground 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 …
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 …
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.
jmg.bmj.com