Homogentisate 1,2-dioxygenase (HGD) gene variants in young Egyptian patients with alkaptonuria

by Selleckchem | Nov 11 2023

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the homogentisate 1,2-dioxygenase (HGD) gene. This leads to a deficient HGD enzyme with the consequent accumulation of homogentisic acid (HGA) in different tissues causing complications in various organs, particularly in joints, heart valves and kidneys. The genetic basis of AKU in Egypt is completely unknown. We evaluated the clinical and genetic spectrum of six pediatric and adolescents AKU patients from four unrelated Egyptian families. All probands had a high level of HGA in urine by qualitative GC/MS before genetic confirmation by Sanger sequencing. Recruited AKU patients were four females and two males (median age 13 years). We identified four different pathogenic missense variants within HGD gene. Detected variants included a novel variant c.1079G > T;p.(Gly360Val) and three recurrent variants; c.1078G > C;p.(Gly360Arg), c.808G > A;p.(Gly270Arg) and c.473C > T;p.(Pro158Leu). All identified variants were properly segregating in the four families consistent with autosomal recessive inheritance. In this study, we reported the phenotypic and genotypic spectrum of alkaptonuria for the first time in Egypt. We further enriched the HGD-variant database with another novel pathogenic variant. The recent availability of nitisinone may promote the need for genetic confirmation at younger ages to start therapy earlier and prevent serious complications.

Comments:

Thank you for sharing this information about Alkaptonuria (AKU) and the genetic findings in Egyptian patients. AKU is indeed a rare metabolic disorder caused by mutations in the HGD gene, leading to the accumulation of homogentisic acid (HGA) and various complications in affected individuals.

The identification of four different pathogenic missense variants in the HGD gene, including a novel variant (c.1079G > T;p.(Gly360Val)), and three recurrent variants (c.1078G > C;p.(Gly360Arg), c.808G > A;p.(Gly270Arg), and c.473C > T;p.(Pro158Leu)) in these Egyptian families is valuable for understanding the genetic basis of AKU in this population. It confirms the autosomal recessive inheritance pattern, which is consistent with previous knowledge of the disease.

Additionally, the availability of nitisinone, a medication that can help manage AKU by reducing HGA production, underscores the importance of genetic confirmation at a younger age. Early diagnosis and intervention can be crucial in preventing or mitigating serious complications associated with AKU, particularly in the joints, heart valves, and kidneys.

This research contributes to the understanding of AKU's phenotypic and genotypic spectrum in Egypt, and the identification of a novel pathogenic variant enriches the HGD-variant database. Such findings can be valuable for both clinical management and future research into potential therapies for AKU.