inheritance.<unk>  is an autosomal recessive disorder, which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Genetic basis Various human GALE mutations resulting in Type III<unk> mia have been identified. Functional analysis of these mutant GALE isoforms suggests that reduced catalytic efficiency and increased likelihood of proteolytic digestion act causatively in Type III<unk> mia. Mutated Residue Biochemical Effect Clinical Manifestation V94M, K257R, L313M, R335H Strongly impaired turnover number and specificity constant Severe generalized<unk> mia. S81R, T150M, P293L Mild turnover number impairment Intermediate<unk> mia. L183P, D103G, G90E, N34S Strongly impaired turnover number and specificity constant; increased proteolytic digestion. Severe generalized<unk> mia. Biochemical basis Pathways, intermediates, and enzymes involved in<unk>  metabolism. GALE deficiency inhibits UDP-glucose regeneration, preventing the formation of glucose-1-phosphate and leading to the accumulation of<unk>  and<unk> -1-phosphate. High<unk> -1-phosphate levels have been shown to interfere with phosphoglucomutase, glycogen phosphorylase, UDP-glycopyrophosphorylase, activity in bacterial models and in vitro, yet in vivo mechanisms toxicity have yet to be confirmed. Regardless, median<unk> -1-phosphate levels act as the most accurate predictors of the severity of symptoms associated with Type III<unk> mia. Blockage of the Leloir pathway by GALE deficiency or dysfunction activates alternate pathways of glucose metabolism and leads to galactitol and galactonate formation. Galactonate is metabolized by the pentose phosphate pathway, and is not considered toxic. Galactitol, however, may accumulate in lens fibers, perturbing lens epithelial cell permeability and leading to cell death and cataract formation. GALE deficiency also perturbs glycolipid and glycoprotein biosynthesis due to decreased production of UDP-GalNAc from UDP-GlcNAc.
Galactose epimerase deficiency
Malonyl-CoA decarboxylase deficiency
Galactose-1-phosphate uridylyltransferase deficiency
Ornithine aminotransferase deficiency
Enolase deficiency
Glutaminase deficiency
Pyruvate kinase deficiency
Holocarboxylase synthetase deficiency