GALK1 – Galactokinase Deficiency

GALK1 is conclusively implicated in autosomal recessive galactokinase deficiency, with a definitive ClinGen classification based on evidence from over 100 affected individuals across more than 50 unrelated families ([PMID:12705493])( [PMID:7670469] ). Multi-family segregation including nine affected relatives in Bosnian cohorts further supports pathogenicity ([PMID:11978883] ). Concordant functional assays consistently demonstrate loss of enzyme activity for diverse variant classes.

Inheritance of galactokinase deficiency is autosomal recessive. Case series report more than 120 probands carrying biallelic GALK1 variants, including loss-of-function, splice, and missense alleles. A representative variant is c.286C>T (p.Gln96Ter) ([PMID:7670469]). Homozygous and compound heterozygous presentations have been described in consanguineous and outbred populations.

The variant spectrum encompasses numerous truncating mutations (e.g., c.837_841dup (p.Val281fs) and c.286C>T (p.Gln96Ter)), canonical splice‐site changes (e.g., c.475+1G>A), and recurrent founder alleles such as p.Pro28Thr in Roma and Bosnian populations ([PMID:10521295])( [PMID:11978883] ). Over 30 unique missense variants affecting conserved enzyme domains have been characterized.

Clinically, galactokinase deficiency manifests primarily as congenital or early‐onset cataracts, with both developmental cataract (HP:0000519) and presenile cataract (HP:0007819) reported. Hypergalactosemia (HP:0012024) is also a consistent biochemical feature, and rare complications such as mild pseudotumor cerebri have been described in a minority of cases ([PMID:12705493] ).

Functional studies in bacterial, mammalian, and oocyte systems demonstrate that missense mutations such as p.Arg256Trp, p.Thr344Met, and p.Gly349Ser drastically reduce GALK activity in vitro ([PMID:10570908] ). Promoter variants (e.g., c.-22T>C) increase expression but do not cause deficiency, highlighting loss-of-function as the primary mechanism ([PMID:19309526] ).

No conflicting evidence disputes the recessive loss-of-function mechanism. Together, genetic and functional data establish GALK1 as the causative gene for galactokinase deficiency and support inclusion in newborn screening panels for early detection and dietary management. Key take-home: GALK1 biallelic loss-of-function variants reliably predict galactokinase deficiency with cataract as the pathognomonic sign.

References

• Nature Genetics • 1995 • Cloning of the galactokinase cDNA and identification of mutations in two families with cataracts PMID:7670469
• Journal of Inherited Metabolic Disease • 2002 • Clinical features of galactokinase deficiency: a review of the literature PMID:12705493
• Journal of Pediatric Endocrinology & Metabolism • 2002 • An unexpectedly high frequency of hypergalactosemia in an immigrant Bosnian population revealed by newborn screening PMID:11978883

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