Abstract
Alkaptonuria is a rare autosomal recessive disorder caused by the absence of homogentisate 1,2 dioxygenase (HGD) in the liver. Ochronosis and arthropathic ochronosis are characteristic sequelae of this metabolic disorder. We report here the clinical and molecular findings in 29 alkaptonuric patients (17 males and 12 females) from mainland France and the Reunion Island. We searched for living members of theses families, 14 to 45 years after their observations were described in the literature, and performed molecular analysis and a clinical evolution of the most relevant organ systems involved by ochronosis. Molecular data from 16 families, revealed the presence of six missense mutations at homozygous (p.Y62C, p.W97G, p.V181F, p.V300G) or heterozygous state (p.D153G, p.V300G and p.M368V), four frameshift mutations at homozygous (p.G152fs and p.T196fs) or heterozygous state (p.F10fs and p.R58fs) and three splice site mutations at heterozygous state (IVS1-1G > A, IVS9-56G > A and IVS13+1G > T). Three patients, natives from La Reunion Island, a French department located in the Indian Ocean, were studied. Molecular analysis revealed in a female a homozygous missense mutation p.V300G and in one male, a compound heterozygous mutations: p.V300G inherited from the caucasian father and p.R58fs from the black mother. The p.R58fs mutation is important for two reasons: it is the first AKU mutation described in a black subject and second it has been described in four other countries (Finland, India, Slovakia and Turkey) sharing the same HGD haplotype, which suggests that it is an old mutation, that probably originated in Africa and spread throughout Eurasia during human migrations.
Keywords: Alkaptonuria, ochronosis, ochronotic arthropathy, homogentisic acid, homogentisate 1,2-dioxygenase, Reunion Island
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