Multiple Mitochondrial Dysfunctions Syndrome 1

A number sign (#) is used with this entry because of evidence that multiple mitochondrial dysfunctions syndrome-1 (MMDS1) is caused by homozygous or compound heterozygous mutation in the NFU1 gene (608100) on chromosome 2p13.

Description

Multiple mitochondrial dysfunctions syndrome is a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death (summary by Seyda et al., 2001).

Genetic Heterogeneity of Multiple Mitochondrial Dysfunctions Syndrome

See also MMDS2 (614299), caused by mutation in the BOLA3 gene (613183) on chromosome 2p13; MMDS3 (615330), caused by mutation in the IBA57 gene (615316) on chromosome 1q42; MMDS4 (616370), caused by mutation in the ISCA2 gene (615317) on chromosome 14q24; MMDS5 (617613), caused by mutation in the ISCA1 gene (611006) on chromosome 9q21; and MMDS6 (617954), caused by mutation in the PMPCB gene (603131) on chromosome 7q22.

Clinical Features

Seyda et al. (2001) reported 3 sibs, 1 male and 2 females, born to unrelated Mexican parents, with a fatal mitochondrial disease. The sibs presented with feeding difficulty, weakness, lethargy, and decreasing responsiveness within a few days after birth. Laboratory investigations showed metabolic acidosis with elevated blood lactate levels. Assisted ventilation was necessary because of respiratory failure. All 3 sibs died under 1 month of age. Laboratory studies on skin fibroblasts from these patients showed lactate/pyruvate ratios that were 6 times greater than those of controls. Blood revealed high levels of glycine, leucine, valine, and isoleucine, indicating abnormalities of the glycine-cleavage system and of the branched-chain alpha-keto acid dehydrogenase (see 608348). In contrast, the activities of fibroblast pyruvate carboxylase (608786), mitochondrial aconitase (100850), and citrate synthase (118950) were normal. There was also a significant reduction in activity of mitochondrial respiratory chain complexes.

Navarro-Sastre et al. (2011) reported 10 individuals from 9 unrelated Spanish families with a fatal mitochondrial disorder. Patients presented between 1 and 9 months of age with failure to thrive, pulmonary hypertension, or neurologic regression, and all died on or before 15 months of age. However, detailed clinical evaluation allowed classification of the patients into 3 groups. Three patients, including 2 sibs, had failure to thrive and neurological involvement, mainly hypotonia and irritability. Brain imaging of 1 showed bilateral white-matter lesions, and autopsy studies in all 3 showed spongiform degeneration, astrogliosis, and white-matter necrosis. The second group of patients included 2 who had pulmonary hypertension on presentation and showed neurologic regression after a febrile illness. Four patients were in the third group, in which pulmonary hypertension was the main clinical feature. Three of these 4 had failure to thrive, but only 1 showed mild psychomotor retardation and recurrent hypoglycemia. Although other specific neurological symptoms in this last group were not found, postmortem examination showed demyelination, vacuolization, and astrogliosis. Pulmonary tissue showed obstructive vasculopathy with involvement of proximal and acinar arteries. Laboratory studies showed increased serum lactate and increased CSF lactate in those studied. Plasma, urinary, and CSF glycine were also increased, and there was increased urinary excretion of 2-ketoacids. Patient fibroblasts showed decreased activity of the pyruvate dehydrogenase complex and impaired mitochondrial oxidation, and liver tissue showed low activity of the glycine decarboxylase system (238300). Muscle homogenates from patients showed evidence of defective lipoylation and impaired synthesis of lipoic acid, with decreased levels of pyruvate dehydrogenase (PDH)- and alpha-ketoglutarate dehydrogenase (KGDH)-bound lipoic acid.

Mapping

To elucidate the underlying molecular defect in the MMDS syndrome, Seyda et al. (2001) performed analysis of microcell-mediated chromosome fusion between the fibroblasts of their patients (recipients) and a panel of A9 mouse-human hybrids (donors) developed by Cuthbert et al. (1995). Complementation was observed between the recipient cells and the mouse-human hybrid clone carrying human chromosome 2. Analysis of microsatellite markers mapped the disorder to chromosome 2p14-p13.

Molecular Genetics

In the Mexican sibs reported by Seyda et al. (2001), Cameron et al. (2011) identified a homozygous mutation in the NFU1 gene (608100.0001). There was no detectable mature protein in patient fibroblasts. Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic, isoform of NFU1 corrected the defects in respiratory chain and oxoacid dehydrogenase complex function. The results indicated that NFU1 plays an essential role in the production of iron-sulfur (Fe-S) clusters for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases and for the assembly of the respiratory chain complexes.

In 9 patients from unrelated Spanish families with fatal multiple mitochondrial dysfunctions syndrome-1, Navarro-Sastre et al. (2011) identified a homozygous mutation in the NFU1 gene (G208C; 608100.0002). Studies in yeast cells showed that it impaired NFU1 function. The mutation was found by homozygosity mapping followed by candidate gene sequencing.