Scientific Reports · 5 authors, 3 centres
This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.
This study identified four HGD gene variants (including one novel pathogenic variant) in six young Egyptian patients with alkaptonuria from four unrelated families. All patients presented with dark urine in infancy, and some developed early joint pain, highlighting the need for early genetic diagnosis and family counseling. The findings support the use of nitisinone therapy and premarital genetic screening in populations with high consanguinity.
**Background:** Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by deficiency of homogentisate 1,2-dioxygenase (HGD), leading to accumulation of homogentisic acid (HGA). HGA causes dark urine and, over time, ochronotic arthritis, cardiovascular complications, and other systemic issues. The prevalence of AKU in Egypt is unknown, but consanguineous marriages are common, potentially increasing disease frequency. This study aimed to characterize the clinical and genetic features of Egyptian AKU patients.
**Methods:** Four unrelated Egyptian families with suspected AKU were recruited from Cairo University Children's Hospital. A total of 17 individuals (6 affected patients, 4 females/2 males, age 1–20 years) were included. Diagnosis was based on clinical examination, family history, and qualitative detection of HGA in urine by gas chromatography-mass spectrometry (GC/MS). Genomic DNA was extracted from EDTA blood, and Sanger sequencing of all 14 exons of the HGD gene was performed for each proband, followed by family segregation analysis. Variants were classified according to ACMG criteria.
**Key Results:** Four different missense variants were identified in the HGD gene, all in homozygous state in affected patients and segregating with the disease in families. Family I had a known pathogenic variant c.1078G>C (p.Gly360Arg) in exon 13. Family II had a known pathogenic variant c.808G>A (p.Gly270Arg) in exon 11. Family III had a novel pathogenic variant c.1079G>T (p.Gly360Val) in exon 13, not previously reported in ClinVar. Family IV had a likely pathogenic variant c.473C>T (p.Pro158Leu) in exon 8. All six patients presented with dark urine in infancy (median age 6 months). Three families reported consanguinity (first cousins); one family denied consanguinity but parents originated from the same village. Clinical features included arthralgia of weight-bearing joints (patients I/1, I/2, IV/6), hyperpigmentation (II/3, III/4), dental caries (III/4, IV/6), and in one family (I/2) high myopia, strabismus, deafness, mitral regurgitation, and intellectual disability. No radiographic abnormalities or teeth discoloration were observed, likely due to young age.
**Clinical Implications:** This is the first genetic characterization of AKU in Egypt. The identification of a novel pathogenic variant (c.1079G>T) expands the mutational spectrum of HGD. Early genetic diagnosis is crucial for family counseling and for identifying presymptomatic carriers. The availability of nitisinone, which reduces HGA production by >90% at low doses (0.2–2 mg daily), underscores the importance of early diagnosis to prevent long-term complications. However, nitisinone is expensive and not yet covered by insurance in Egypt. The study highlights the need for premarital genetic counseling and routine screening of family members in populations with high consanguinity. Whole exome sequencing may be warranted for families with complex phenotypes (e.g., intellectual disability and hearing loss in family I).