Multiple Mitochondrial Dysfunctions Syndrome 2 With Hyperglycinemia

A number sign (#) is used with this entry because of evidence that multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is caused by homozygous mutation in the BOLA3 gene (613183) on chromosome 2p13.

Description

Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014).

For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).

Clinical Features

Seyda et al. (2001) reported a male infant, born of first-cousin East Indian parents, who developed epileptic seizures associated with elevated levels of serum glycine and cerebrospinal fluid (CSF) glycine at age 4 months. At age 6 months, he was developmentally delayed, and subsequently developed dilated cardiomyopathy and epileptic encephalopathy. He had recurrent vomiting, lethargy, respiratory distress, and hepatomegaly. At age 7 months, he became acidotic. His CSF glycine rose to very high levels, and he died at 11 months of age. Studies of skin fibroblasts showed lactate/pyruvate ratios that were 6 times greater than those of controls. Fibroblasts showed decreased activity of the pyruvate dehydrogenase complex, branched-chain alpha-keto acid dehydrogenase (608348), and mitochondrial respiratory chain complexes. In contrast, the activities of fibroblast pyruvate carboxylase (608786), mitochondrial aconitase (100850), and citrate synthase (118950) were normal.

Baker et al. (2014) reported 3 unrelated children with a severe metabolic disorder resulting in neurologic dysfunction. The patients were of Caucasian, Indian, and African American descent, respectively. All had normal development in early infancy, but then showed regression in motor skills with loss of head control and severe hypotonia beginning between 6 and 8 months of age. Two had seizures, 2 had optic atrophy with poor vision, and 2 had spasticity with abnormal movements. All developed hypertrophic cardiomyopathy. The patients died at ages 7 months, 22 months, and 11 years. Brain MRI of the 2 patients who died in infancy showed signal abnormalities involving the deep white matter. The 11-year-old child lost the ability to walk, became nonverbal, and had severe malnutrition and contractures. All patients had increased serum and CSF levels of glycine and lactate, leading to a diagnosis of 'variant' nonketotic hyperglycinemia. Biochemical studies showed impaired enzymatic activity of the glycine cleavage system and deficient pyruvate dehydrogenase (PDH) activity, both consistent with a defect in lipoate biosynthesis. Patient fibroblasts showed reduced to absent lipoylation of proteins. Mitochondrial respiratory chain enzymes were normal in fibroblasts isolated from 2 of the patients, with a partial decrease in the liver of the third.

Inheritance

The transmission pattern of MMDS2 in the families reported by Baker et al. (2014) was consistent with autosomal recessive inheritance.

Mapping

Complementation studies by Seyda et al. (2001) indicated that the defect in the patient with multiple mitochondrial dysfunctions syndrome-2 maps to chromosome 2p14-p13.

Molecular Genetics

In the East Indian patient with MMDS2 reported by Seyda et al. (2001), Cameron et al. (2011) identified a homozygous truncating mutation in the BOLA3 gene (613183.0001). Transduction of fibroblast lines with retroviral vectors expressing the mitochondrial, but not the cytosolic, isoform of BOLA3 corrected the defects in respiratory chain and oxoacid dehydrogenase complex function. The results indicated that BOLA3 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 3 unrelated children with MMDS2, Baker et al. (2014) identified a homozygous truncating mutation in the BOLA3 gene (R46X; 613183.0002). The mutation was found by sequencing of candidate genes involved in lipoate synthesis, as 2 of the patients who were studied had reduced lipoylated E2 subunits of the PDH and alpha-ketoglutarate dehydrogenase (alpha-KGDH) complexes. The unaffected parents were heterozygous for the mutation.