Dr Ira Shah
M.D, DNB, DCH(Gold Medalist), FCPS

A 4-month-old female child born of non-consanguineous marriage presented with jaundice and high colored urine since birth. There was no history of clay colored stools. On examination, the child had icterus and a firm hepatosplenomegaly. There were no cataracts and no signs of liver cell failure. The child had no dysmorphic features. A diagnosis of neonatal cholestasis was considered. Her hemoglobin was 8 gm% and WBC count was 17,000/cumm with platelet count of 1,29,000/cumm suggestive of thrombocytopenia. Total serum bilirubin was 35.6 mg% and direct bilirubin of 21.6 mg% and indirect bilirubin of 14 mg%. Her liver enzymes were deranged with SGOT of 444 IU/L and SGPT of 120 IU/L. Her prothrombin time and partial thromboplastin time were normal. She had hypoalbuminemia with total serum albumin being 2.1 gm% suggestive of chronic liver disease. Ultrasound of the abdomen showed prominent hepatic artery with coarse liver echotexture. Common bile duct was 5 mm. HIDA scan showed poor tracer uptake with non-visualization of intra hepatic biliary tree, gall bladder or extrahepatic biliary tree. There was no tracer seen in the gut even after 24 hours. However, duodenal aspirate was positive for bile salts and pigments ruling out biliary atresia. Her TORCH times were negative and thyroid function tests were normal. Her serum alpha-1 antitrypsin levels were normal. There was no evidence of metabolic acidosis. Urine showed presence of reducing substances that was confirmed to be galactose, with presence of galactitol & galactonate by urine chromatography (MILS method). Thus she was diagnosed as Galactosemia and started on galactose free diet (soya milk) with supplementation of Vitamin E, K, A, C and Ureodeoxycholic acid. Her blood for transferase and epimerase enzyme studies has been sent and reports are awaited.

Galactosemia is a disorder of galactose metabolism. Three inherited disorders of galactose metabolism have been described. They are all transmitted by autosomal recessive inheritance.

The clinical manifestations in infants are due to toxic effects of prolonged exposure to galactose.

The most common initial clinical sign is failure to thrive. Vomiting or diarrhea starts in a few days with milk ingestion. Jaundice presents in a few weeks and is initially unconjugated. Untreated it may progress to liver disease and cirrhosis. Ascitis may be a prominent early finding. Histopathology of liver reveals fatty infiltration and inflammatory changes at an early stage. As the disease progresses, bile stasis, pseudoacinar formation and partial fibrosis is seen eventually leading to cirrhosis. Cataracts can be observed within a few days of birth. Mental retardation becomes apparent after several months of life. There is a high frequency of neonatal death due to E.coli sepsis.

Diagnosis: Deranged liver enzymes, hyperchloremic metabolic acidosis, aminoaciduria, hypoglycemia is common. Renal dysfunction may present as albuminuria. Preliminary diagnosis is demonstrated by presence of reducing substance in urine while patient is receiving milk-containing lactose. The reducing substance can be identified by chromatography or by an enzymatic test specific for galactose. Enzyme analysis of transferase deficiency in red blood cells is confirmatory and red cells show increase in galactose-1 – phosphate.

Treatment:The mainstay of therapy is lactose free diet as failure to eliminate galactose results in progressive liver failure and death. In infants with manifestations of toxicity, the galactose free diet results in regression of all symptoms and signs – nausea & vomiting cease, weight gain ensues, liver abnormalities clear, galactosuria & albuminuria clear, and cataracts regress. In infants soy milk is beneficial. Milk restriction is to be maintained life-long. Assay of RBC galactose – 1 – phosphate is used for monitoring adherence to the diet. In well treated galactosemics, RBC galactose – 1 – phosphate should not exceed 100 umol/L.

Prognosis : Though dietary therapy may decrease toxicity, CNS disease and ovarian dysfunction may still manifest. Patients may have delay in acquisition of language skills and females may have primary ovarian failure

Prenatal diagnosis: Carrier testing and prenatal diagnosis can be performed by direct enzyme analysis of amniocytes or chorionic villi. Testing can also be DNA based. There are several enzymatic variants of galactosemia of which the Duarte Variant has diminished red cell enzyme activity but no clinical significance and some African-American patients have milder symptoms despite the absence of measurable transferase activity in RBCs as these patients retain about 10% enzyme activity in liver and intestinal mucosa.

These children present solely as cataract as the only metabolites accumulated due to galactokinase deficiency are galactose and galactitol.

Diagnosis: Presence of reducing substance in urine with increased concentration of blood galactose levels and absence of galactokinase activity in RBCs.

Treatment : Dietary restriction of lactose.

The abnormal metabolites accumulated are similar to those with transferase deficiency. There are 2 distinct types. In children with benign form, the enzyme deficiency is limited to RBCs and WBC and children are asymptomatic and no treatment is required. The second form is severe and resembles transferase deficiency with additional symptoms of hypotonia & sensorineural deafness. This condition is quite rare and must be considered in a symptomatic patient with normal transferase activity.

Diagnosis : Epimerase enzyme analysis in RBCs. Gene analysis.

Treatment : Patients with epimerase deficiency cannot make galactose. Because it is an essential component of many nervous system structural proteins, patients are placed on a galactose restricted diet rather than galactose free diet.