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PubMed1998

Alkaptonuria presenting as lumbar disc prolapse: case report and review of literature.

Alkaptonuria is a rare genetic disorder caused by deficiency of the enzyme homogentisic acid oxidase, resulting in accumulation of homogentisic acid in various body tissue; it produces a multisystemic disorder with a characteristic bluish-black discolouration of the skin and cartilage, termed ochranosis. Ochranosis primarily involves the large joints of the body including the spine. Spinal involvement produces loss of flexibility and ankylosis of the thoracic and lumbar segments. The clinical presentation with spondylosis and canal stenosis is common after the third and fourth decades, but intervertebral disc prolapse is unusual in ochranosis.

Adult↗
PubMed1998

Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients.

Alkaptonuria (AKU), a rare hereditary disorder of phenylalanine and tyrosine catabolism, was the first disease to be interpreted as an inborn error of metabolism. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGO); this deficiency causes homogentisic aciduria, ochronosis, and arthritis. We cloned the human HGO gene and characterized two loss-of-function mutations, P230S and V300G, in the HGO gene in AKU patients. Here we report haplotype and mutational analysis of the HGO gene in 29 novel AKU chromosomes. We identified 12 novel mutations: 8 (E42A, W97G, D153G, S189I, I216T, R225H, F227S, and M368V) missense mutations that result in amino acid substitutions at positions conserved in HGO in different species, 1 (F10fs) frameshift mutation, 2 intronic mutations (IVS9-56G-->A, IVS9-17G-->A), and 1 splice-site mutation (IVS5+1G-->T). We also report characterization of five polymorphic sites in HGO and describe the haplotypic associations of alleles at these sites in normal and AKU chromosomes. One of these sites, HGO-3, is a variable dinucleotide repeat; IVS2+35T/A, IVS5+25T/C, and IVS6+46C/A are intronic sites at which single nucleotide substitutions (dimorphisms) have been detected; and c407T/A is a relatively frequent nucleotide substitution in the coding sequence, exon 4, resulting in an amino acid change (H80Q). These data provide insight into the origin and evolution of the various AKU alleles.

Alkaptonuria↗
PubMed1999

Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO).

We recently showed that alkaptonuria (AKU) is caused by loss-of-function mutations in the homogentisate 1,2 dioxygenase gene (HGO). Herein we describe haplotype and mutational analyses of HGO in seven new AKU pedigrees. These analyses identified two novel single-nucleotide polymorphisms (INV4+31A-->G and INV11+18A-->G) and six novel AKU mutations (INV1-1G-->A, W60G, Y62C, A122D, P230T, and D291E), which further illustrates the remarkable allelic heterogeneity found in AKU. Reexamination of all 29 mutations and polymorphisms thus far described in HGO shows that these nucleotide changes are not randomly distributed; the CCC sequence motif and its inverted complement, GGG, are preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in HGO do not involve CpG dinucleotides, which illustrates important differences between HGO and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34.5%) of all mutated bases that have been observed in HGO, we conclude that the CCC triplet is a mutational hot spot in HGO.

Alkaptonuria↗
PubMed2000

Structural and functional analysis of mutations in alkaptonuria.

Alkaptonuria (AKU), the prototypic inborn error of metabolism, was the first human disease to be interpreted as a Mendelian trait by Garrod and Bateson at the beginning of last century. AKU results from impaired function of homogentisate dioxygenase (HGO), an enzyme required for the catabolism of phenylalanine and tyrosine. With the novel 7 AKU and 22 fungal mutations reported here, a total of 84 mutations impairing this enzyme have been found in the HGO gene from humans and model organisms. Forty-three of these mutations result in single amino acid substitutions. This mutational information is analysed here in the context of the HGO structure and function using kinetic assays performed using purified AKU mutant enzymes and the crystal structure of human HGO. HGO is a topologically complex structure which assembles as a functional hexamer arranged as a dimer of trimers. We show how the intricate pattern of intra- and inter-subunit interactions and the extensive surfaces required for subunit folding and association of this oligomeric enzyme can be inactivated at multiple levels by single-residue substitutions. This explains, in part, the predominance of missense mutations (67%) in AKU.

Alkaptonuria↗
PubMed1983

Alkaptonuria and ochronosis. A survey and 5 cases.

A survey of alkaptonuria and ochronosis is given, based on the literature and on 5 additional cases. The disease, which is autosomal recessive, results from a decreased amount of the enzyme homogentisic acid oxidase, due to which tyrosine and phenylalanine cannot be broken down via the normal pathway. The diagnosis is made by determination of urinary urinary homogentisic acid excretion, as the clinical and radiological findings are not pathognomonic. The symptoms, which extend over decades, result from the deposition of pigment in the extracellular macromolecules of the connective tissue, particularly of the skin and joints.

Adult↗
PubMed2005

Alkaptonuria diagnosed by flexible bronchoscopy.

A 68-year-old white man was evaluated for failure to wean from mechanical ventilation after cardiac surgery. Bronchoscopy performed prior to percutaneous dilatational tracheotomy revealed circumferential strikingly dark-colored airways, most prominent in the trachea and mainstem bronchi, extending distally into all airways with overlying desiccated black secretions. Histologic examination of bronchial mucosal biopsy samples and the desiccated secretions showed acute bronchitis and necrotic debris, respectively. This finding and the patient's history led to testing for plasma homogentisic acid, which was found to be elevated at 12.6 mug/mL, establishing the first diagnosis of alkaptonuria made using flexible bronchoscopy.

Aged↗
PubMed1999

Mutational analysis of the HGO gene in Finnish alkaptonuria patients.

Alkaptonuria (AKU), the prototypic inborn error of metabolism, has recently been shown to be caused by loss of function mutations in the homogentisate-1,2-dioxygenase gene (HGO). So far 17 mutations have been characterised in AKU patients of different ethnic origin. We describe three novel mutations (R58fs, R330S, and H371R) and one common AKU mutation (M368V), detected by mutational and polymorphism analysis of the HGO gene in five Finnish AKU pedigrees. The three novel AKU mutations are most likely specific for the Finnish population and have originated recently.

Alkaptonuria↗
PubMed1992

[A rare metabolic disease: alkaptonuria--ochronosis].

The authors describe the case of a 40-year-old female patient. Since childhood her urine had caused black discoloration on her underwear. For about a year the skin of the axillae and pinnae had been bluish-black without subjective complaints. One year before admission, pain in the thoracic and lumbar spine began, with limitation of motion. Examination of the urine, histological and electron microscopical findings, and X-ray examination of the spinal column confirmed the diagnosis of alkaptonuria and congenital ochronosis.

Adult↗
PubMedDate not supplied

Alkaptonuria and renal failure: a case report.

In alkaptonuria, the absence of homogentisic acid oxidase (HGO) results in the accumulation of homogentisic acid (HGA) in the body. Associated renal failure is rare and usually occurs in the later stages of the disease. We report a 33-year-old male who presented, initially, with renal failure, but no past history of illness. He had pigmentation of sclerae and ear helices, intervertebral disk calcifications and mild mitral insufficiency. His disease was confirmed by HGA detection in the urine. As size and thickness of renal parenchyma seen on ultrasonography were normal, renal biopsy was performed and it showed glomerular sclerosis, diffuse tubular atrophy and interstitial fibrosis with inflammation. Wall thickening of small arteries and pigment deposits were identified in some kidney tissue elements. He progressed to end-stage renal disease despite supportive therapy.

Adult↗
PubMed1992

[Alkaptonuria-ochronosis].

The authors describe the case of a 40-year old female patient. Since her childhood she realised of her urine the black discoloration of the underwear. For about a year, without subjective complaints, blue-black color of the skin involved the axillae and pinnae. For a year appeared the increased pain of thoracal and lumbal spine column and the limitation of motion of these parts. The examination of urine, histological and electron microscopical findings, the X-ray photograph of the spinal column confirmed the diagnosis of alkaptonuria or rather congenital ochronosis.

Adult↗
PubMed1989

Alkaptonuria.

A case of alkaptonuria with its various sequelae in the form of ochronosis, ochronotic arthropathy, spondylitis and prostatic calculi is reported. The case is of interest as it presented with hepatocellular failure and hepatitis B surface antigenaemia.

Alkaptonuria↗
PubMed1979

Diagnosis of alkaptonuria in children.

Thirty-nine patiens with alkaptonuria diagnosed in childhood were studied with repeated detailed clinical and biochemical examinations. Darkening of the urine, although varying from time to time, was present in all. Pigmentary changes in axillary regions began to appear at 8--10 years with concomitant staining of underwear. Ear cartilage staining occurred in only 1, and none had scleral involvement or anthropathy. Dark brown to black staining of ear cerumen is present even in earliest childhood. This distinctive symptom in a child with no other ochronotic manifestations and even normal urine colour should alert one to possible alkaptonnuria. Other findings are described in detail.

Adolescent↗
PubMed1983

[Alkaptonuria (ochronosis)].

A 39-year-old male patient observed an increasing bluish pigmentation of the ear cartilage associated with recurrent back-pain. Darkening of the urine after the addition of sodium hydroxide led to the suspected diagnosis of alkaptonuria. This diagnosis was confirmed by the detection of urinary homogentisic acid by thin-layer chromatography.

Adult↗
PubMedDate not supplied

Alkaptonuria in a cynomolgus monkey (Macaca fascicularis).

An eight year old wild caught Cynomolgus monkey was diagnosed as having alkaptonuria, a condition characterized by the passage of a normal-colored urine which darkens upon standing. The underlying cause is the congenital lack of homogentisic acid oxidase with subsequent passage of homogentisic acid in the urine. No other clinical manifestations, such as deposition of pigment in the skin or mucous membranes or development of an ochronitic arthritis, were observed in this animal.

Alkaptonuria↗
PubMed1998

Molecular diagnosis of alkaptonuria mutation by analysis of homogentisate 1,2 dioxygenase mRNA from urine and blood.

Alkaptonuria (AKU) is caused by lack of homogentisate 1, 2 dioxygenase (HGO) activity. From the complete sequence of a human HGO cDNA, primers were designed in order to obtain reverse transcription-polymerase chain reaction products from tissues with ectopic transcription amenable to diagnostic analysis. A search for mutations in HGO cDNA was performed in an AKU family using urine and blood samples. The results show complete cosegregation (Z = 6.32; theta = 0) between a C-->T transition at position 817 of the human HGO cDNA and AKU. This mutation predicts a Pro-->Ser replacement at amino acid 230, and generates an EcoRV site.

Alkaptonuria↗
PubMed1999

Ocular ochronosis in alkaptonuria patients carrying mutations in the homogentisate 1,2-dioxygenase gene.

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.

Aged↗