1. Biochemistry, molecular biology and molecular genetics of galactosemia

Galactosemia is an autosomal recessive disorder of Galactose metabolism, characterized by inability to metabolize galactose. Three enzymes are principally involved in the metabolic conversion of galactose to glucose: a galactose specific kinase (GALK), galactose-1-phosphate uridyl transferase (GALT) and uridine diphosphate galactose-4-epimerase (GALE). On the basis of defective enzyme the disease is categorized into three forms viz., Type I Galactosemia due to GALT enzyme Deficiency, Type II Galactosemia due to GALK enzyme Deficiency, Type III Galactosemia due to GALE enzyme Deficiency. The GALT gene is present on the short arm of the chromosome 9. It consists of 11 exons and codes for a 379 amino acid long protein. More than 200 mutations in the GALT gene have been reported. Two common mutations viz. Q188R and K285N account for more than 70% galactosemia mutations in the Caucasian population. Recently from our laboratory characterization of underlying GALT gene lesions was performed in 55 unrelated galactosemia patients. The GALT mutational spectrum comprised 16 distinct mutations including 10 previously unreported mutations. N314D was the most common mutation with a frequency of 40% followed by Q188R at 2.7%. The novel GALT gene mutations included 6 missense mutations viz. Y89H, Q103R, P166A, S181F, K285R, R333L; one nonsense Correspondence/Reprint request: Prof. Rajendra Prasad, Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh -160012, India. E-mail: [email protected] Rajendra Prasad et al. 2 mutation, S307X and 3silent mutations. Moreover we have also characterized spectrum of mutations in GALK gene from Indian patients. Two hundred infants with congenital cataracts were screened for galactokinase (GALK) enzyme deficiency. Total of 5 distinct mutations were identified in GALK gene in 5 different patients out of which 4 were novel mutations viz. S79F, S79Y, S205S and F275Y. Patients with galactosemia often presents with failure to thrive, jaundice, hepatosplenomegaly, cataracts, sepsis and perhaps even death within a few days of exposure to milk. In contrast to the multiple systems that are affected by GALT deficiency, cataract is usually the major manifestation of galactokinase (GALK) deficiency, also known as Type II galactosemia. Epimerase deficiency galactosemia (Type III) is a very rare disorder worldwide. The most important step in the initial management of patients with galactosemia is the immediate removal of galactose from the diet as soon as the diagnosis is suspected.