Mitochondrial Complex V (Atp Synthase) Deficiency, Nuclear Type 2

A number sign (#) is used with this entry because of evidence that mitochondrial complex V (ATP synthase) deficiency nuclear type 2 (MC5DN2) can be caused by homozygous or compound heterozygous mutation in the TMEM70 gene (612418) on chromosome 8q21.

For a general phenotypic description of the nuclear type of mitochondrial complex V deficiency and a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see 604273.

Clinical Features

Cizkova et al. (2008) reported 8 children from 6 Romani Gypsy families with neonatal mitochondrial encephalocardiomyopathy associated with ATP synthase deficiency. Clinical features included psychomotor retardation, microcephaly, hypotonia, growth retardation, hypertrophic cardiomyopathy, dysmorphism, hypospadias, lactic acidosis, and 3-methylglutaconic aciduria.

Spiegel et al. (2011) reported 6 patients from 4 unrelated consanguineous Arab-Muslim families with MC5DN2. All patients presented either in utero or in the first days of life. Early features included oligohydramnios, early delivery, intrauterine growth retardation, and neonatal hypotonia. Other prominent features included hypertrophic cardiomyopathy, psychomotor retardation, lactic acidosis, and increased urinary 3-methylglutaconic aciduria. Most had dysmorphic facial features, including flat occiput, long philtrum, and low-set ears. Some had respiratory insufficiency in the neonatal period. Three patients had a severe neonatal course marked by lactic acidosis, encephalopathy, and multiorgan failure leading to death in the first week of life. One patient died at age 3 years. Five patients had gastrointestinal abnormalities, including delayed gastric emptying and pseudoobstruction. Two brothers had cataracts. Skeletal muscle complex V deficiency was reduced to less than 30% of control values.

Catteruccia et al. (2014) reported 9 children from 8 families with MC5DN2 confirmed by genetic analysis. Five of the families were of Roma origin. All patients presented at birth with severe hypotonia associated with lactic acidosis, hyperammonemia, and increased urinary 3-MGA. Five of the children developed persistent pulmonary arterial hypertension in the neonatal period, requiring intubation and mechanical respiration. Eight patients had hypertrophic cardiomyopathy, which was apparent in the neonatal period or within the first 8 months of life, and 5 developed cardiac arrhythmias. All had delayed psychomotor development and poor overall growth. Only 2 had a seizure disorder. More variable features included facial dysmorphism, cryptorchidism, leukoencephalopathy on brain imaging, and cerebellar atrophy.

Molecular Genetics

In affected individuals from 6 Romani Gypsy families with neonatal mitochondrial encephalocardiomyopathy associated with ATP synthase deficiency, Cizkova et al. (2008) identified a homozygous splice site mutation in the TMEM70 gene (c.317-2A-G; 612418.0001).

The same homozygous mutation was identified in 23 additional patients. Cooccurrence of cases with severe and milder phenotypes with the same mutation was thought to represent varying quality and functionality of individual nonsense-mediated RNA decay systems.

In 6 patients from 4 unrelated consanguineous Arab-Muslim families with MC5DN2, Spiegel et al. (2011) identified 4 different homozygous mutations in the TMEM70 gene (see, e.g., 612418.0003-612418.0005).

In 9 children from 8 families with MC5DN2, Catteruccia et al. (2014) identified homozygous or compound heterozygous mutations in the TMEM70 gene. Six patients were homozygous for the common c.317-2A-G splice site mutation.