Features and outcome of galactokinase deficiency in children diagnosed by newborn screening

Abstract

Galactokinase deficiency (GALK-D), an autosomal recessive disorder in the Leloir pathway, results in accumulation of galactose, galactitol, and galactonate and leads to early onset of juvenile bilateral cataract. Highest incidence of GALK-D is found in Romani populations. The migration wave due to the Yugoslavian civil war has changed the spectrum of inborn errors of metabolism within Europe. Hence, newborn screening (NBS) in the Berlin region, performed from 1991 until 2010 in 683,675 neonates, revealed an increased incidence of GALK-D of 1:40,000, comparable to that of galactose-1-phosphate-uridyltransferase deficiency. A total of 44% of GALK-D patients were of Romani origin. All patients of Bosnian or Serbian origin were homozygous for the Romani founder mutation p.P28T. Detection of GALK-D by NBS and early start of galactose-restricted diet resulted in regression or prevention of cataracts. Slight cataracts without visual impairment occurred in 50% of the patients, 56% of whom were noncompliant. Further clinical symptoms, e.g., hypoglycemia, mental retardation, microcephaly, and failure to thrive, were associated with noncompliance. With treatment, galactose in blood decreased from 8,892 ± 5,243 to 36.5 ± 49.3 μmol/l, galactose in urine from 31,820 ± 32,103 to 30.0 ± 36.1 μmol/mmol creatinine, galactitol in RBC from 1,584 ± 584 to 12.3 ± 9.4 μmol/l, and galactitol in urine from 11,724 ± 4,496 to 236 ± 116 μmol/mmol creatinine. This is the first presentation of outcome and clinical features in GALK-D patients diagnosed by NBS. As our data suggest, GALK-D should be considered for inclusion in NBS in populations expected to have substantial numbers of GALK-D carriers, e.g., Yugoslavian immigrants.

Newborn Screening for Galactosemia in the United States: Looking Back, Looking Around, and Looking Ahead

“…GALK deficiency is diagnosed in (<1/100,000) US newborns but may be more common in some populations (e.g., the Romani) (Hennermann et al 2011;Janzen et al 2011;Kalaydjieva et al 1999;Sangiuolo et al 2004). …”

Laboratory diagnosis of galactosemia: a technical standard and guideline of the American College of Medical Genetics and Genomics (ACMG)

“…24 Other clinical abnormalities including epilepsy, intellectual disability, pseudotumor cerebri, and neurofibromatosis were variably reported in a small percentage of patients (2%). 25 In patients identified through newborn screening, dietary galactose restriction initiated within the first two months of life resulted in complete resolution of cataracts.…”

“…25 In patients identified through newborn screening, dietary galactose restriction initiated within the first two months of life resulted in complete resolution of cataracts. 24 While blood galactose may reach normal levels in treated patients, galactitol in urine and blood remains elevated. 24 …”

“…24 While blood galactose may reach normal levels in treated patients, galactitol in urine and blood remains elevated. 24 …”

“…12 The prevalence of GALK deficiency ranges from 1:2,200,000 to 1:50,000, with the highest incidence in the Romani population of Bulgaria and Bosnia. 24 Profound (generalized) GALE deficiency is very rare; epimerase deficiency identified by newborn screening, comprising mostly peripheral/intermediate, is 1:70,000 in infants of European descent and 1:6,700 in African Americans. 26 …”