Combined Oxidative Phosphorylation Deficiency 1

A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-1 (COXPD1) leading to early fatal progressive hepatoencephalopathy is caused by homozygous or compound heterozygous mutation in the gene encoding the mitochondrial elongation factor G1 (GFM1, EFG1; 606639) on chromosome 3q25.

Description

Combined oxidative phosphorylation deficiency is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (summary by Smits et al., 2011).

Genetic Heterogeneity of Combined Oxidative Phosphorylation Deficiency

See also COXPD2 (610498), caused by mutation in the MRPS16 gene (609204) on 10q22; COXPD3 (610505), caused by mutation in the TSFM gene (604723) on 12q14; COXPD4 (610678), caused by mutation in the TUFM gene (602389) on 16p11; COXPD5 (611719), caused by mutation in the MRPS22 gene (605810) on 3q23; COXPD6 (300816), caused by mutation in the AIFM1 gene (300169) on Xq26; COXPD7 (613559), caused by mutation in the C12ORF65 gene (613541) on 12q24; COXPD8 (614096), caused by mutation in the AARS2 gene (612035) on 6p21; COXPD9 (614582), caused by mutation in the MRPL3 gene (607118) on 3q22; COXPD10 (614702), caused by mutation in the MTO1 gene (614667) on 6q13; COXPD11 (614922), caused by mutation in the RMND1 gene (614917) on 6q25; COXPD12 (614924), caused by mutation in the EARS2 gene (612799) on 16p13; COXPD13 (614932), caused by mutation in the PNPT1 gene (610316) on 2p16; COXPD14 (614946), caused by mutation in the FARS2 gene (611592) on 6p25; COXPD15 (614947), caused by mutation in the MTFMT gene (611766) on 15q; COXPD16 (615395), caused by mutation in the MRPL44 gene (611849) on 2q36; COXPD17 (615440), caused by mutation in the ELAC2 gene (605367) on 17p11; COXPD18 (615578), caused by mutation in the SFXN4 gene (615564) on 10q26; COXPD19 (615595), caused by mutation in the LYRM4 gene (613311) on 6p25; COXPD20 (615917), caused by mutation in the VARS2 gene (612802) on 6p21; COXPD21 (615918), caused by mutation in the TARS2 gene (612805) on 1q21; COXPD22 (616045), caused by mutation in the ATP5A1 gene (164360) on 18q12; COXPD23 (616198), caused by mutation in the GTPBP3 (608536) gene on 19p13; COXPD24 (616239), caused by mutation in the NARS2 gene (612803) on 11q14; COXPD25 (616430), caused by mutation in the MARS2 gene (609728) on 2q33; COXPD26 (616539), caused by mutation in the TRMT5 gene (611023) on 14q23; COXPD27 (616672), caused by mutation in the CARS2 gene (612800) on 13q34; COXPD28 (616794), caused by mutation in the SLC25A26 gene (611037) on 3p14; COXPD29 (616811), caused by mutation in the TXN2 gene (609063) on 22q12; COXPD30 (616974), caused by mutation in the TRMT10C gene (615423) on 3q12; and COXPD31 (617228), caused by mutation in the MIPEP gene (602241) on 13q12; COXPD32 (617664), caused by mutation in the MRPS34 gene (611994) on 16q13; COXPD33 (617713), caused by mutation in the C1QBP gene (601269) on 17p13; and COXPD34 (617872), caused by mutation in the MRPS7 gene (611974) on 17q25; COXPD35 (617873), caused by mutation in the TRIT1 gene (617840) on 1p34; COXPD36 (617950), caused by mutation in the MRPS2 gene (611971) on 9q34; COXPD37 (618329), caused by mutation in the MICOS13 gene (616658) on 19p13; COXPD38 (618378), caused by mutation in the MRPS14 gene (611978) on 1q23; and COXPD39 (618397), caused by mutation in the GFM2 gene (606544) on 5q13.

Clinical Features

Coenen et al. (2004) described 2 sibs, born of consanguineous Lebanese parents, who died at ages 27 days and 5 months, respectively, and were found to have a severe defect in mitochondrial translation, reduced levels of oxidative phosphorylation complexes containing mitochondrial DNA (mtDNA)-encoded subunits, and progressive hepatoencephalopathy. Postmortem examination showed extensive necrosis of the liver, hypoplasia of the corpus callosum, and generalized atrophy of the brain.

Valente et al. (2007) described an infant with neonatal lactic acidosis, rapidly progressive encephalopathy, severely decreased mitochondrial protein synthesis, and combined deficiency of mtDNA-related mitochondrial respiratory chain (MRC) complexes. The patient was born of nonconsanguineous, unaffected Italian parents. She was evaluated at the age of 7 days for the presence of dysmorphic signs including flat nasal bridge, low-set ears, small hands and feet, epicanthus, and high, arched palate. Tibial bones were short by radiography. By age 3 months, the neurologic examination showed reduced spontaneous movements and severe axial hypotonia, with preservation of deep tendon reflexes. At age 5 months, she presented with recurrent episodes of vomiting, and a combined increase of lactate and pyruvate was identified. Hepatic enzymes, bilirubin, and ammonia remained consistently normal in the blood during the entire course of her life, and no signs of liver involvement were detected. However, she had microcephaly, severely delayed motor and mental development, decreased axial and increased limb muscle tone, brisk deep-tendon reflexes, and purposeless movements. Lactic acid was persistently high. At age 16 months, the patient died from respiratory insufficiency. Valente et al. (2007) noted that the clinical features of their patient, unlike those described by Coenen et al. (2004), clearly indicated primary involvement of the central nervous system which overwhelmed by far that of other organs, notably, skeletal muscle, liver, and heart.

Smits et al. (2011) reported a girl, born of consanguineous parents, with COXPD1 characterized by onset in the first days of life of axial hypotonia, spasticity, refractory seizures, feeding problems, and increased serum and CSF lactate. She had a severe, rapidly progressive encephalopathy and died at age 2 years. Laboratory studies showed decreased enzyme activities of respiratory complexes II, III, and IV in fibroblasts, although muscle biopsy showed low levels only of complex III. However, the capacity of the mitochondrial energy-generating system was reduced in muscle tissue, as indicated by impairments in pyruvate oxidation and ATP production. Immunoblot analysis revealed a severe reduction in the steady-state level of the GFM1 protein in patient fibroblasts.

Mapping

Coenen et al. (2004) mapped the defective gene in combined oxidative phosphorylation deficiency to the long arm of chromosome 3 by the use of microcell-mediated chromosome transfer to identify a normal human chromosome that could functionally complement the biochemical defect in the fibroblast from the index patient. Deletion mapping of the donor chromosome in isolated clones was used for fine mapping of the genomic region containing the complementing gene. Microsatellite mapping with a panel of polymorphic markers showed that one of the complementing clones contained only marker D3S1279, and that the fibroblast line from the patient was homozygous for 2 markers. These data suggested that the candidate gene maps to the region 3q22-q26.2.

Molecular Genetics

By sequence analysis of the EFG1 gene, which had been mapped within the critical region for combined oxidative phosphorylation deficiency, Coenen et al. (2004) identified a homozygous asn174-to-ser mutation in the EFG1 gene (N174S; 606639.0001) in affected sibs.

Valente et al. (2007) identified compound heterozygosity for mutations in the EFG1 gene (606639.0002, 606639.0003) in an infant with combined oxidative phosphorylation deficiency.

In a girl, born of consanguineous parents, with COXPD1, Smits et al. (2011) identified a homozygous mutation in the GFM1 gene (R250W; 606639.0004). The patient was part of a cohort of 27 patients with combined OXPHOS deficiencies.

Associations Pending Confirmation

For discussion of a possible association between COXPD and variation in the KARS gene, see 601421.