Patients with
nonketotic hyperglycinemia and deficient
glycine cleavage
enzyme activity, but without mutations in AMT, GLDC or GCSH, the genes encoding its constituent
proteins, constitute a clinical group which we call 'variant
nonketotic hyperglycinemia'. We hypothesize that in some patients the aetiology involves genetic mutations that result in a deficiency of the cofactor lipoate, and sequenced genes involved in lipoate synthesis and
iron-sulphur cluster biogenesis. Of 11 individuals identified with variant
nonketotic hyperglycinemia, we were able to determine the genetic aetiology in eight patients and delineate the clinical and biochemical phenotypes. Mutations were identified in the genes for lipoate synthase (LIAS), BolA type 3 (BOLA3), and a novel gene
glutaredoxin 5 (GLRX5). Patients with GLRX5-associated variant
nonketotic hyperglycinemia had normal development with childhood-onset
spastic paraplegia, spinal lesion, and
optic atrophy. Clinical features of BOLA3-associated variant
nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development. Additional features include leukodystrophy,
cardiomyopathy and
optic atrophy. Patients with lipoate synthase-deficient variant
nonketotic hyperglycinemia varied in severity from mild static
encephalopathy to
Leigh disease and cortical involvement. All patients had high serum and borderline elevated cerebrospinal fluid
glycine and cerebrospinal fluid:plasma
glycine ratio, and deficient
glycine cleavage
enzyme activity. They had low
pyruvate dehydrogenase enzyme activity but most did not have
lactic acidosis. Patients were deficient in lipoylation of
mitochondrial proteins. There were minimal and inconsistent changes in cellular
iron handling, and respiratory chain activity was unaffected. Identified mutations were phylogenetically conserved, and transfection with native genes corrected the biochemical deficiency proving pathogenicity. Treatments of cells with lipoate and with mitochondrially-targeted lipoate were unsuccessful at correcting the deficiency. The recognition of variant
nonketotic hyperglycinemia is important for physicians evaluating patients with abnormalities in
glycine as this will affect the genetic causation and genetic counselling, and provide prognostic information on the expected phenotypic course.