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Transketolase (TKT) is a thiamin-dependent enzyme in the non-oxidative pentose phosphate pathway, encoded by the TKT gene (TKT). Transketolase deficiency (MONDO:0014881) presents as a multisystem inborn error of metabolism inherited in an autosomal recessive manner. Bi-allelic loss-of-function and hypomorphic variants in TKT disrupt NADPH and nucleotide synthesis critical for growth and neurodevelopment.
Genetic evidence derives from whole-exome sequencing in three unrelated families with five affected individuals aged 4–25 years (PMID:27259054). Two Ashkenazi Jewish families harbored a homozygous 18 bp in-frame insertion; a third family was compound heterozygous for nonsense and missense alleles. One representative variant is c.952C>T (p.Arg318Cys) (PMID:27259054). Segregation analysis included two additional affected siblings confirming co-segregation of bi-allelic TKT variants (PMID:27259054).
The clinical spectrum includes short stature (HP:0004322), global developmental delay (HP:0001263), and congenital heart defects (HP:0001627) in four of five cases. Older individuals also exhibited chronic diarrhea (HP:0002028) and cataracts (HP:0000518), reflecting progressive metabolic impairment. Carrier frequency in Ashkenazi Jewish populations suggests a potential founder effect for the 18 bp insertion.
Functional studies demonstrated markedly reduced transketolase activity in patient fibroblasts and erythrocytes with accumulation of erythritol, arabitol, ribitol, and pentulose-5-phosphates in urine and plasma (PMID:27259054). These findings confirm a loss-of-function mechanism leading to impaired NADPH production and nucleic acid synthesis, consistent with growth failure and neurodevelopmental delay.
No conflicting reports have been described to date. The genetic and biochemical data converge on a clear pathogenic role for TKT deficiency in this syndrome.
Integration of clinical, genetic, and functional evidence supports a Strong gene-disease association for autosomal recessive transketolase deficiency, guiding molecular diagnosis and enabling targeted metabolic assessment. Key take-home: Bi-allelic TKT variants cause a distinct AR syndrome of short stature, developmental delay, and congenital heart defects with diagnostic metabolic biomarkers.
Gene–Disease AssociationStrong5 affected individuals across three unrelated families, segregation in two affected siblings, concordant enzymatic functional data Genetic EvidenceStrongFive probands in three families with homozygous and compound heterozygous variants and segregation observed in two siblings Functional EvidenceModerateMarkedly reduced transketolase activity and accumulation of pentose phosphate metabolites in patient samples |