Clinical characteristics: Epimerase deficiency galactosemia (GALE deficiency galactosemia) is generally considered a continuum comprising several forms:

1. Generalized. Enzyme activity is profoundly decreased in all tissues tested.

2. Peripheral. Enzyme activity is deficient in red blood cells (RBC) and circulating white blood cells, but normal or near normal in all other tissues.

3. Intermediate. Enzyme activity is deficient in red blood cells and circulating white blood cells and less than 50% of normal levels in other cells tested.

Infants with generalized epimerase deficiency galactosemia develop clinical findings on a regular milk diet (which contains lactose, a disaccharide of galactose and glucose); manifestations include hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose/lactose from their diet resolves or prevents these acute symptoms. Longer-term features that may be seen in those with generalized epimerase deficiency include short stature, developmental delay, sensorineural hearing loss, and skeletal anomalies. In contrast, neonates with the peripheral or intermediate form generally remain clinically well even on a regular milk diet and are usually only identified by biochemical testing, often in newborn screening programs.

Diagnosis/testing: The diagnosis of epimerase deficiency galactosemia is established in a proband with impaired GALE activity in RBC or other cells and/or biallelic pathogenic variants in GALE identified on molecular genetic testing. The degree of GALE enzyme activity impairment in RBC does not distinguish between the clinically severe generalized and the milder intermediate or peripheral forms of epimerase deficiency; further enzymatic testing in other cell types such as stimulated leukocytes or EBV-transformed lymphoblasts is required to make that distinction.

Management: Treatment of manifestations: The common acute and potentially lethal symptoms of generalized epimerase deficiency galactosemia are prevented or corrected by a galactose/lactose-restricted diet. Note: Affected individuals may require trace environmental sources of galactose: infants should be fed a formula (e.g., soy formula) that contains trace levels of galactose or lactose. Continued dietary restriction of dairy products in older children is recommended. In contrast, infants with peripheral epimerase deficiency galactosemia are believed to remain asymptomatic regardless of diet; infants with intermediate epimerase deficiency galactosemia may benefit in the long term from early dietary galactose/lactose restriction, but this remains unclear. Standard treatment for developmental delay, skeletal anomalies, poor weight gain / failure to thrive, mature cataracts, and sensorineural hearing loss.

Prevention of primary manifestations: In generalized epimerase deficiency galactosemia, restriction of dietary galactose/lactose appears to correct or prevent the common acute signs and symptoms of the disorder (hepatic dysfunction, renal dysfunction, and mild cataracts), but not the developmental delay or learning impairment observed in some affected individuals. Because of the difficulty in distinguishing peripheral and intermediate forms of epimerase deficiency galactosemia, dietary restriction of galactose/lactose is recommended for all infants with GALE deficiency, relaxing the restriction, as warranted, once a more accurate diagnosis has been confirmed.

Surveillance: Hemolysate gal-1P (galactose-1-phosphate) or urinary galactitol is monitored, especially if the diet is to be normalized. Acceptable levels of RBC gal-1P are not known, but are estimated to be <3.5 mg/100 mL (normal ≤1.0 mg/100 mL) on data from classic galactosemia. Other parameters that warrant monitoring are growth and developmental milestones, vision, and hearing (particularly in those in whom hearing loss has been identified).

Agents/circumstances to avoid: Dietary galactose/lactose in persons with generalized epimerase deficiency galactosemia, certainly as infants and perhaps for life.

Evaluation of relatives at risk: Each at-risk newborn sib should be treated with dietary restriction of galactose from birth while awaiting results of diagnostic testing for epimerase deficiency galactosemia; either molecular genetic testing (if the pathogenic variants in the family are known) or measurement of GALE enzyme activity in RBC (if the pathogenic variants in the family are not known) can be performed.

Genetic counseling: Epimerase deficiency galactosemia is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GALE pathogenic variant, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.