HGD – Alkaptonuria

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by biallelic pathogenic variants in the homogentisate 1,2-dioxygenase gene (HGD). Patients typically present in early adulthood with dark urine, progressive ochronosis (HP:0030764), and severe arthropathy (HP:0001369) due to connective tissue deposition of homogentisic acid (HGA). Absence of functional HGD activity results in systemic pigment accumulation affecting cartilage, heart valves, and kidneys, with variable extraskletal manifestations such as nephrolithiasis and cardiac valvular calcification.

Genetic studies have identified over 90 unique HGD variants in AKU patients worldwide, including missense, nonsense, frameshift, splice site, and deep intronic changes. Notably, c.808G>A (p.Gly270Arg) was first reported as a compound heterozygous allele in a Turkish patient (PMID:12872815) and recurs as a founder variant in multiple populations. Loss-of-function mutations such as c.175del (p.Ser59fs) and splice-site defects are distributed across all 14 exons of HGD, with certain hot‐spot motifs contributing to regional prevalence.

Segregation analysis in four unrelated families formally established the autosomal recessive inheritance of AKU, with homozygosity or compound heterozygosity for HGD mutations segregating with disease status in affected sibships (PMID:9154114). Carrier frequency estimates vary by population, with high prevalence reported in Slovakia (1:19,000) and among select consanguineous communities.

Biochemical and cellular assays have demonstrated markedly reduced or absent HGD enzymatic activity in patient‐derived samples and recombinant mutant proteins. Structural analyses of human HGD reveal a hexameric enzyme sensitive to disruption by single‐residue substitutions; kinetic studies of 43 mutant enzymes confirmed severe activity loss consistent with haploinsufficiency (PMID:11001939). Computational modeling and high‐throughput screening systems further classify variants by their impact on protein stability and oligomerization.

ClinGen classification for the HGD–AKU association meets Definitive criteria based on extensive genetic and experimental concordance over >20 years, with comprehensive variant catalogs and functional validation. Genetic evidence is Strong, supported by dozens of probands harboring pathogenic alleles and segregation in multiple families; functional evidence is Moderate owing to in vitro and in silico assays confirming loss of function.

Integration of genetic testing for HGD variants with biochemical assays of HGA excretion enables definitive diagnosis, informs genetic counseling for autosomal recessive inheritance, and guides emerging therapies such as nitisinone. Early molecular diagnosis is critical for patient management and potential clinical trials targeting HGD restoration.

Key Take-home: HGD mutation analysis in conjunction with biochemical confirmation of homogentisic aciduria provides a definitive diagnostic framework for alkaptonuria, supporting therapeutic intervention and family screening.

References

• Cytogenetics and cell genetics • 1997 • Molecular defects in alkaptonuria PMID:9154114
• Human molecular genetics • 2000 • Structural and functional analysis of mutations in alkaptonuria PMID:11001939
• Human mutation • 2009 • Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria PMID:19862842
• Genetic counseling (Geneva, Switzerland) • 2003 • Alkaptonuria caused by compound heterozygote mutations PMID:12872815

Evidence Based Scoring (AI generated)