Variant Analysis of Alkaptonuria Families with Significant Founder Effect in Jordan

Abstract

Background. Metabolic disorder alkaptonuria is an autosomal recessive disorder caused by mutations in the HGD gene, and a deficiency HGD enzyme activity results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. Methods. We clinically evaluated 18 alkaptonuria patients (age range, 3 to 60 years) from four unrelated families. Furthermore, 11 out of 18 alkaptonuria patients and 7 unaffected members were enrolled for molecular investigations by utilizing Sanger sequencing to identify variants of the 14 exons of HGD gene. Results. We found that the seven patients from the 4 unrelated families carried a recurrent pathogenic missense variant (c.365C>T, p. Ala122Val) in exon 6 of HGD gene. The variant was fully segregated with the disease in affected family members while the other unaffected family members were heterozygous carriers for this variant. Additionally, the clinical features were fully predicted with alkaptonuria disorder. Conclusion. In this study, we confirmed that the most common variants in Jordanian AKU patients was c.365C>T, p. Ala122Val in exon 6 of HGD gene. Additionally, we correlated the clinical and genetic features of AKU patients at various ages (3-60 years).

Reverse Total Shoulder Arthroplasty in Alkaptonuric Shoulder: Case Presentation, Review of Literature, and Technical Considerations

“… 1 The disease is rare, with a prevalence of 1:250,000–1,000,000 worldwide. 2 It is attributed to homogentisic acid oxidase deficiency and leads to failures in processing the amino acids phenylalanine and tyrosine. 3 Eventually, this leads to the buildup of homogentisic acid and its subsequent polymerization with body collagen fibers.…”

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

“…Alkaptonuria (AKU, OMIM# 203500) is a rare autosomal recessive inborn error of metabolism. It is caused by pathogenic variants in the homogentisate 1,2-dioxygenase gene ( HGD , OMIM* 607474), commonly causing a complete deficiency of the HGD enzyme (EC 1.13.11.5), with the consequent accumulation of homogentisic acid (HGA) derived from the metabolism of the amino-acids tyrosine and phenylalanine 1 . HGA in alkaptonuria is commonly excreted in massive amounts in urine, causing its darkening upon air exposure, which is considered a pathognomonic sign of the disease.…”

“…HGA in alkaptonuria is commonly excreted in massive amounts in urine, causing its darkening upon air exposure, which is considered a pathognomonic sign of the disease. Furthermore, HGA is also deposited as an “ochronotic” pigment when oxidized within the articular connective tissues causing ochronotic arthritis, a degenerative joint disease 1 , 2 . Extra-articular complications of the disease include cardiovascular manifestations, such as mitral and aortic valve calcification with stenosis or regurgitation, renal and prostatic stones and hypothyroidism 3 .…”

“…When AKU is suspected, the presence of homogentisic acid in urine can be assayed by gas chromatography mass spectrometry (GC/MS), which serves as a quick diagnostic marker 6 . However, being a monogenic disease with a relatively short gene, Sanger sequencing of the 14 exons of HGD with their exon/intron boundaries is most convenient and at the same time critical to confirm affected individuals and carriers of the disease 1 .…”

“…The worldwide incidence of alkaptonuria is approximately 1:250,000–1,000,000 with relative hot spots in Slovakia, the Dominican Republic, India and Jordan 7 , 8 . The actual prevalence of AKU may be underestimated due to the subtle signs of the disease, causing many patients to go undiagnosed for most of their lives 1 , 8 . Although the prevalence of AKU in Arab countries is not well studied, it is likely to be higher than in most populations due to the autosomal recessive nature of the disease and the high prevalence of consanguineous marriages in the region 9 .…”