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 Eleven different genotypes were described, including six unpublished variants.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.

Keywords: GALK1 gene variants; neonatal complications; cataract; galactosemias registry; galactokinase 1 deficiency.

Fig. 1. Cataract formation in study population.

A total of 15 patients were reported with cataract in the neonatal period. Characteristics of the patients with neonatal cataract are shown in the figure above. In 4 patients, cataract resolved after initiation of dietary restrictions. In the other 11 patients, the cataract persisted through childhood and in 7 patients surgical removal was performed. Cataract formation throughout childhood was reported in 4 patients; surgical removal was performed in 3. NBS newborn screening.

Fig. 2. The location of the two new disease-associated point variants in the human GALK1 structure.

(a) The three-dimensional structure of human GALK1 is shown in green. Adenosine triphosphate (ATP) (cyan) and galactose (hot pink) are shown bound in the active site. The two affected residues are shown: Asp46 (orange) and Thr352 (yellow). (b) A close-up of the active site showing how Asp46 binds, and helps orientate, the galactose molecule through C3-OH and C4-OH. The structure is based on PDB: 1WUU with gaps filled, selenomethionines converted to methionines, and AMP; PNP to ATP.^, Images created with PyMol.