Ochronotic rheumatism in Algeria: clinical, radiological, biological and molecular studies—a case study of 14 patients in 11 families (original) (raw)
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Sequence analysis of the homogentisate 1,2 dioxygenase gene in a family affected by alkaptonuria
Journal of medical genetics, 1999
Sequence analysis of the homogentisate 1,2 dioxygenase gene in a family aVected by alkaptonuria EDITOR-Alkaptonuria (AKU) is a disorder of the catabolism of aromatic amino acids. A defect of homogentisate 1,2 dioxygenase (HGO) leads to an accumulation of homogentisic acid (HGA) and subsequently to deposition of polymerised HGA, a brown-black pigment, in connective tissue, primarily in cartilage. 1 2 This phenomenon is known as ochronosis. It results in debilitating arthropathy which typically becomes manifest in the fourth decade of life. Large amounts of HGA are excreted in the urine and cause its black discolouration upon oxidation. In 1891, homogentisic acid was first isolated by Wolkow and Baumann 3 from the urine of an AKU patient from a remote area of the Black Forest in south western Germany. In 1902, Garrod, aware of this biochemical finding, observed the autosomal recessive mode of inheritance of AKU and thereby showed for the first time that mendelian laws also apply to human genetics. 4 Garrod postulated that AKU results from an enzyme deficiency and introduced the concept of the "inborn error of metabolism". 5 Recently, the human gene encoding HGO was cloned by Fernádez-Cañón et al. 6 Two diVerent mutations of this gene were identified in two unrelated AKU aVected families. These mutations cosegregated with manifest disease and could be shown to abrogate enzymatic activity of HGO protein. 6 Homozygosity for these mutations, therefore, was the cause of AKU in the two families. Two additional mutations in the HGO gene were found to cosegregate with AKU in two Slovakian pedigrees. 7 One of these mutations caused a frameshift in an upstream exon and was thus likely to result in a loss of HGO activity. For an additional mutation, complete cosegregation with AKU was reported in an extensively studied Canarian family. 8 Various diVerent mutations of the HGO gene were found in 14 unrelated AKU patients. 9 We performed sequence analysis of the HGO gene in an AKU aVected family from the Black Forest. AKU with severe ochronosis including involvement of the sclerae was diagnosed at necropsy of a 71 year old farmer (fig 1, No 1). The diagnosis of AKU had not been established during the patient's lifetime. He died of recurrent myocardial infarction. Subsequently, the patient's family underwent physical examination. A sister (fig 1, No 2) and a first cousin (fig 1, No 3) were found to be aVected by the disease. These patients have been suVering from arthritic symptoms of AKU since the fourth decade of life and show the typical discolouration of the urine and the ochronotic pigmentation of the sclerae. However, the condition had until then been misdiagnosed as degenerative polyarthritis. A brother (fig 1, No 4) of patient 1 was healthy as were the three children (fig 1, Nos 5, 6, and 7) of patient 2. Anamnestically, a brother (fig 1, No 8) and a first cousin (fig 1, No 9), who died in 1988 and 1995, respectively, were reported to have suVered from debilitating early onset polyarthropathy and the typical ochronotic involvement of the sclerae. They were very probably affected by AKU. No characteristic AKU symptoms were reported
Familiar ochronotic arthropathy–caused by a gene mutation traced three hundred years
Joint Bone Spine, 2010
Authors trace an ochronotic Hungarian family, which moved from Slovakia to Hungary 300 years ago. As the family members lived in a relatively close village community the gene mutation had been survived silently for ages before the clinical symptoms developed. Family tree analysis could detect with the use of allele specific PCR amplification-the p.G161R mutation of the homogentisic acid 1,2-dioxygenase (HGD) gene, which resulted in a specific genotype appearing in the Slovak population. We found a heterozygote member of this family who has children with an alkaptonuria-homozygote and known-heterozygote genotypes so there would be a high risk of alkaptonuria in their offsprings. Therefore genetic counselling is highly recommended to minimize the risk factors.
Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences, 2011
Alkaptonuria (AKU) is a disorder of phenylalanine/tyrosine metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD). This recessive disease is caused by mutations in the HGD gene. We report a 14-year-old girl who was referred after presenting black urine. Careful examination revealed ochronosis of the conjunctiva. There was no affection of the cardiac valves. Elevated excretion of homogentisic acid in urine was found. Sequence analysis of the HGD gene from genomic DNA revealed that the patient is a compound heterozygote with a previously described mutation (c.473C > T, p.Pro158Leu), and a novel one (c.821C > T, p.Pro274Leu). Her mother is heterozygous for the novel mutation, while the brother is heterozygous for the previously described mutation. In summary, we describe an alkaptonuric patient with ocular ochronosis and a novel HGD mutation, c.821C > T, p.Pro274Leu.
European Journal of Human Genetics, 2015
Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T4A), Slovakia (c.500C4T) and France (c.440T4C), three in patients from India (c.469+6T4C, c.650-85A4G, c.158G4A), and six in patients from Italy (c.742A4G, c.614G4A, c.1057A4C, c.752G4A, c.119A4C, c.926G4T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.
R58fs Mutation in the HGD Gene in a Family with Alkaptonuria in the UAE
Annals of Human Genetics, 2009
This study was conducted to determine the prevalence of alkaptonuria in the UAE population and to identify the genotype of affected individuals. In a 3 stage sampling technique 2981 pupils from Government schools in Al Ain and private schools in Dubai were selected to take part in the study, of whom 2857 provided urine samples. Urine collected was analysed for homogentisic acid by gas chromatography-mass spectrometry. Genomic DNA was isolated from the white blood cells of all family members of the affected case following standard established protocols. Specific PRC primers were designed to amplify all 14 exons of the HGD gene with the flanking intronic sequences including the splice site sequences. 2857 children returned a viable urine sample, of which one was highly positive for homogentisic acid. All 12 members of this girl's family were studied and one, a 22 year old brother, was found to excrete HGA. Another, a sister who had not provided a urine sample, was discovered by genetic testing. There were no complaints of joint pain or other symptoms in any member of this family. Parents were first cousins. We found a single nucleotide deletion c.342delA, located in exon 3, which resulted in a frameshift at amino acid position 58 (p.Arg58fs or p.R58fs). Alkaptonuria may be more common than it is thought to be with an allele prevalence estimated at 0.0107 (95% CI 0.000392-0.03473). The R58fs mutation is old, perhaps having occurred several thousand years ago, and has spread over a large geographical area.
British Journal of Ophthalmology, 1999
Aims-To assess the involvement of the recently identified human homogentisate 1,2-dioxygenase gene (HGO) in alkaptonuria (AKU) in two unrelated patients with ochronosis of the conjunctiva, sclera, and cornea. Methods-A mutation screen of the entire coding region of the HGO gene was performed using single stranded conformational analysis after polymerase chain reaction with oligonucleotide primers flanking all 14 exons of the HGO gene. Fragments showing aberrant mobility were directly sequenced. Results-Two homozygous missense mutations, L25P and M368V, were identified, each of which leads to the replacement of a highly conserved amino acid in the HGO protein. Conclusions-The authors describe a novel mutation, L25P, in the German population and bring to 18 the total number of known HGO mutations.
2012
Alkaptonuria (AKU) is characterised by a typical bluish-black pigmentation in connective tissue (ochronosis) that usually occurs after the age of 30 years. AKU is the first inborn error of metabolism to be understood as a recessive trait. It is caused by mutations within the gene located on the human chromosome 3q13.33, coding for the enzyme homogentisate 1,2-dioxygenase (HGD). About 650 AKU patients have been reported worldwide, and mutation analysis performed so far in about 270 cases shows a rather high heterogeneity, since 117 AKU-causing mutations have been found, also summarized in a novel HGD mutation database. Several ethnicities have been reported in which an increased incidence of AKU is observed, compared to its worldwide low prevalence (1 : 250 000 – 1 : 1 000 000). S t r e s z c z e n i e
BMC Pediatrics, 2015
Background: Krabbe disease (KD) or globoid cell leukodystrophy is an autosomal recessive lysosomal disorder, which affects metabolic and neurologic systems. This pathology has different forms. Infantile onset is about 85 % to 90 % of individuals with Krabbe disease. Disorder's onset is characterized, in early childhood, by hyperirritability, psychomotor deterioration associated to episodes of fever. To date, all reported cases have been attributed to mutations in galactosylceramidase gene (GALC gene) that encodes an enzyme which degrades galactosyl-sphingolipids (galactosylceramide, psychosine), essential in myelin production. A child compounded with two new mutations in the GALC gene was detected. Case presentation: An eleven month old male child of Moroccan origin presented to our genetic consultation with severe symptoms that included hypotonia, fever, vision loss and feeding difficulties. He was suffering from the 4th month of life. Krabbe disease was suspected. Galactocerebrosidase deficiency was confirmed by biochemical analysis. DNA sequencing revealed a novel heterozygous compound mutation in GALC gene. The child was compounded with two mutations c.860G > A; p.Cys287Tyr and c.1622G > A; p.Trp541*. Conclusion: These new mutations could affect GALC structure and therefore its function. The identification of these mutations and their associated phenotypes are important to predict the prognosis and to confer to families an adequate genetic counseling.