Galactokinase deficiency: lessons from the GalNet registry

Abstract

Purpose: Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype. Methods: Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers in 11 countries from December 2014 to April 2020. Results: Neonatal or childhood cataract was reported in 15 and 4 patients respectively. The occurrence of neonatal hypoglycemia and infection were comparable with the general population, whereas bleeding diathesis (8.1% versus 2.17-5.9%) and encephalopathy (3.9% versus 0.3%) were reported more often. Elevated transaminases were seen in 25.5%. Cognitive delay was reported in 5 patients. Urinary galactitol was elevated in all patients at diagnosis; five showed unexpected Gal-1-P increase. Most patients showed enzyme activities ≤1%. Eleven different genotypes were described, including six unpublished variants. The majority was homozygous for NM_000154.1:c.82C>A (p.Pro28Thr). Thirty-five patients were diagnosed following newborn screening, which was clearly beneficial. Conclusion: The phenotype of GALK1 deficiency may include neonatal elevation of transaminases, bleeding diathesis, and encephalopathy in addition to cataract. Potential complications beyond the neonatal period are not systematically surveyed and a better delineation is needed.

Current and Future Treatments for Classic Galactosemia

“…The strategy aims to reduce the accumulation of Gal-1-P in GALT deficiency, as Gal-1-P is considered a major key player in the pathogenic mechanism in classic galactosemia [ 4 , 12 , 21 ]. The milder clinical picture of type II (GALK1 deficiency) galactosemia supported this view although standardized follow-up data are currently lacking [ 87 , 88 ]. Inhibition of GALK1 appears to be an attractive therapeutic target, since GALK1, as member of the GHMP kinase family, is highly substrate specific and no other undesired inhibitions are to be expected [ 89 , 90 ].…”

“…This leads to an osmotic phenomenon with subsequent cell swelling and ultimately apoptosis [ 97 , 98 ]. The high expression of aldose reductase in the epithelial cells of the lens leads to the formation of galactosemic cataracts [ 88 , 99 ]. Galactitol involvement in cognitive and neurological symptoms has been suggested [ 61 , 100 ].…”

The Discovery of GALM Deficiency (Type IV Galactosemia) and Newborn Screening System for Galactosemia in Japan

“…The maximum galactose levels were 17.3–41.9 mg/dL during follow-up. This elevation of galactose appears to be mild compared to that observed in GALK1 deficiency, in which galactose (and total galactose (galactose + galactose-1-phosphate)) levels in the blood reach up to several hundred mg/dL in some patients [ 16 ]. It is worthy to note that galactose-1-phosphate (Gal-1-P) was detected during the neonatal period (0.3–10.8 mg/dL at NBS; cut-off value, 10–15 mg/dL), although the levels did not exceed the cut-off value in most cases.…”

“…In contrast, cataracts are the only consistent symptom in patients with GALK1 deficiency (type II galactosemia). Recently, bleeding diathesis, encephalopathy, and an elevation of transaminase during the neonatal period have been reported to be associated with GALK1 deficiency [ 16 ]. GALE deficiency (type III galactosemia) has two subtypes: the “general” type [ 17 ] and the “peripheral” type [ 18 ].…”

[13C]‐galactose breath test in a patient with galactokinase deficiency and spastic diparesis

“…This condition is considered to be mainly associated with cataracts, which resolve with galactose restriction. However, reports of patients with pseudotumor cerebri, hepatosplenomegaly, intellectual disability, recurrent seizures and deterioration of neurological function have been described 2‐4 . Hitherto, it is not clear whether severely decreased galactokinase (GALK1; EC 2.7.1.6) activity is the sole cause of a more severe phenotype.…”