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Background <p>Alkaptonuria (AKU) is a rare autosomal recessive inborn error of metabolism caused by deficiency of homogentisate 1,2-dioxygenase (HGD), its deficiency results in homogentisic acid (HGA) accumulation, which oxidizes to form melanin-like pigments that deposit in connective tissues, leading to ochronosis and progressive multisystem complications. We describe two unrelated Colombian female patients with AKU, emphasizing clinical variability and novel genetic findings.</p> Case reports <p>Case 1: Female with onset of symptoms at age 16, including scleral pigmentation, glaucoma, retinal detachment, and joint pain. Arthroscopy revealed ochronotic pigmentation and cystic changes in the glenohumeral cartilage, pigmented deposits were observed in the ears and sclera during adulthood. Whole-exome sequencing (WES) identified two <i>HGD</i> variants: c.164_166del (p.Thr55del) and c.774+69C&gt;T, both classified as variants of uncertain significance (VUS). Case 2: Female with reddish urine noted perinatally and recurrent darkened urine episodes during infections. At age 8, she developed intermittent bilateral bone pain in knees and wrists, worsened by physical activity. No evident ochronosis was observed. Whole genome sequencing (WGS) revealed compound heterozygosity for <i>HGD</i> variants: c.808G&gt;A (p.Gly270Arg), likely pathogenic, and c.774+69C&gt;T (VUS).</p> Conclusions <p>Both patients shared the intronic <i>HGD</i> variant c.774 + 69&#xa0;C &gt; T in heterozygosity, a VUS located outside the canonical splice site. Its recurrence in two unrelated individuals with AKU-compatible features and an additional <i>HGD</i> variant suggests potential pathogenic relevance. This report highlights the value of molecular diagnosis for confirming AKU and genetic counseling, and describes a previously unreported <i>HGD</i> variant in a Latin American population, contributing to the understanding of the disorder’s genetic heterogeneity and the importance of genomic characterization in underrepresented groups.</p>

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Alkaptonuria in two Colombian patients: identification of HGD variants including a novel finding

  • 期刊论文

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  • 发表日期：

    2026年4月10日

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  • María Camila León – Sanabria,
  • Ana María Zarante-Bahamón

摘要

Background

Alkaptonuria (AKU) is a rare autosomal recessive inborn error of metabolism caused by deficiency of homogentisate 1,2-dioxygenase (HGD), its deficiency results in homogentisic acid (HGA) accumulation, which oxidizes to form melanin-like pigments that deposit in connective tissues, leading to ochronosis and progressive multisystem complications. We describe two unrelated Colombian female patients with AKU, emphasizing clinical variability and novel genetic findings.

Case reports

Case 1: Female with onset of symptoms at age 16, including scleral pigmentation, glaucoma, retinal detachment, and joint pain. Arthroscopy revealed ochronotic pigmentation and cystic changes in the glenohumeral cartilage, pigmented deposits were observed in the ears and sclera during adulthood. Whole-exome sequencing (WES) identified two HGD variants: c.164_166del (p.Thr55del) and c.774+69C>T, both classified as variants of uncertain significance (VUS). Case 2: Female with reddish urine noted perinatally and recurrent darkened urine episodes during infections. At age 8, she developed intermittent bilateral bone pain in knees and wrists, worsened by physical activity. No evident ochronosis was observed. Whole genome sequencing (WGS) revealed compound heterozygosity for HGD variants: c.808G>A (p.Gly270Arg), likely pathogenic, and c.774+69C>T (VUS).

Conclusions

Both patients shared the intronic HGD variant c.774 + 69 C > T in heterozygosity, a VUS located outside the canonical splice site. Its recurrence in two unrelated individuals with AKU-compatible features and an additional HGD variant suggests potential pathogenic relevance. This report highlights the value of molecular diagnosis for confirming AKU and genetic counseling, and describes a previously unreported HGD variant in a Latin American population, contributing to the understanding of the disorder’s genetic heterogeneity and the importance of genomic characterization in underrepresented groups.