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PubMed2004

Aortic valve regurgitation in alkaptonuria.

Aortic valve lesions associated with alkaptonuria tend mostly to be due to aortic valve stenosis, while aortic valve regurgitation is only rarely observed. Herein, a case is reported of severe aortic valve regurgitation and a fibrous strand in a patient with alkaptonuria. A 65-year-old male, with a history of inferior myocardial infarction, presented with symptoms of congestive heart failure. Alkaptonuria was diagnosed based on urine coloration, skin pigmentation and ochronotic arthropathy in the vertebrae and hip. Grade IV aortic valve regurgitation with mild aortic valve stenosis and occlusive disease in the right coronary artery indicated a need for aortic valve replacement and coronary artery bypass grafting. Sclerotic change in the cusps, and shrinkage of the non-coronary cusp, impeded normal coaptation of the aortic valve, and the left-coronary cusp also had a fibrous strand suspending the free margin of the cusp from the aortic wall just above the commissure. The sclerotic change in the cusps, and shrinkage of the non-coronary cusp, appeared to be the causative lesion of aortic valve regurgitation, implying that cardiovascular ochronosis may cause aortic valve regurgitation.

Aged↗
PubMed1988

[Ochronotic arthropathy in alkaptonuria. Radiological manifestations and physiopathological signs].

Alkaptonuria is a rare autosomal recessive metabolic disease, due to the lack of homogentisic acid oxidase. The following accumulation of homogentisic acid brings about a black discoloration of both the urine (alkaptonuria) and connective tissue (ochronosis). The ochronotic alterations into joint cartilages cause degenerative arthropathy and osteopenia. The radiological features of three unrelated cases of alkaptonuria are reported. Radiographic abnormalities of ochronotic arthropathy are found in both the spine and the extraspinal joints. In the spine, the progressive calcification and "vacuum" phenomenon of disc spaces are the most characteristic findings. Disc space narrowing is associated with calcification and marginal sclerosis of vertebral bodies and is accentuated by osteopenia. Osteophytes are usually absent or of small size; nevertheless progressive formation of marginal intervertebral bridges and obliteration of disc spaces at multiple levels ("pseudoblock vertebrae") may occur. In extraspinal sites, space narrowing, bone sclerosis and fragmentation may also be observed. Diagnosis of ochronotic arthropathy is often suggested by radiographs of the spine, and it is confirmed afterwards by clinical and laboratory findings. The characteristic radiological findings of ochronotic spondylitis, in the final stage, include narrowing of at least four lumbar disc spaces, associated with their calcification and "vacuum" phenomenon, "pseudoblock vertebrae", marginal sclerosis and osteopenia of vertebral bodies.

Aged↗
PubMed1979

Alkaptonuria.

Alkaptonuria is found relatively frequently in Slovakia, Eastern Czechoslovakia (1 in 25,000 inhabitants). Reported herein are the clinical, radiographic, and biochemical aspects and genetics of 126 patients with alkaptonuria. Forty-seven were diagnosed in childhood; the sequential appearance of each manifestation is documented by decade. A simple screening method for this disorder is described. Pedigree analyses confirm recessive inheritance. Possible genetic and sociologic factors responsible for this high frequency of alkaptonuria are discussed.

Adolescent↗
PubMed1982

[Clinical aspects of alkaptonuria].

The research laboratory of clinical genetics in Martin has initiated an extensive study on alkaptonuria since 1968. The incidence of that disease among the newborn in Slovakia is 1:21,500 and 140 patients have so far been recorded (136 in Slovakia and 13 from Moravia frontier regions). Though the incidence and clinical manifestation of alkaptonuria differ in the separate cases, the progress of the disease is associated with the age of the patient. Of particular significance for the clinical diagnosis of alkaptonuria is not only the knowledge of the clinical manifestations in general but also the clinical picture among the various age groups. Our experiment is presented in the paper from that point of view.

Adolescent↗
PubMed1994

aku, a mutation of the mouse homologous to human alkaptonuria, maps to chromosome 16.

Alkaptonuria is a human hereditary metabolic disease characterized by a very high urinary excretion of homogentisic acid, an intermediary product in the metabolism of tyrosine, in association with ochronosis and arthritis. This disease is due to a deficiency in the enzyme homogentisic acid oxidase and is inherited as an autosomal recessive condition. We have found a new recessive mutation (aku) in the mouse that is homologous to human alkaptonuria, during a mutagenesis program with ethylnitrosourea. Affected mice show high levels of urinary homogentisic acid without signs of ochronosis or arthritis. This mutation has been mapped to Chr 16 close to the D16Mit4 locus, in a region of synteny with human 3q.

Alkaptonuria↗
PubMed1997

Cloning of the homogentisate 1,2-dioxygenase gene, the key enzyme of alkaptonuria in mouse.

We determined 48 amino acid residues from five peptides from the homogeneous monomer of homogentisate 1,2-dioxygenase (HGO; E.C. 1.13. 11.15) of mouse liver. After digestion with trypsin, peptides were separated by reversed phase chromatography and amino acid sequenced. The deduced codon sequence of three peptides was used to derive degenerated oligomeres. By combining these oligos, we were able to amplify fragments from 100 to 300 bases (b) from mouse liver cDNA by polymerase chain reaction after reverse transcription (RT-PCR). A fragment of 200 b was cloned and used as a probe to screen a mouse liver cDNA library. One clone from this library contained the complete cDNA-insert for HGO as determined by sequencing. The cDNA encodes for a protein of 50 kDa, as predicted. The cDNA of mouse HGO has an overall identity of 41% to the corresponding gene hmgA from Aspergillus. Sequence similarities to human expressed sequence tags (EST) clones ranged from 70% to 20%. The positions of 122 conserved amino acids could be determined by multiple sequence alignment. We identified one first intron of 928 b in the mouse gene. The gene for HGO seems to be expressed in various tissues, as shown by RT-PCR on different cDNAs. FISH experiments with the whole murine cDNA as probe clearly revealed signals at the human chromosomal band 3q13. 3-q21. This corresponds well to the previous assignment of the locus for the human alkaptonuria gene (AKU) to the same chromosomal region by multipoint linkage analysis. We therefore conclude that the HGO cDNA encodes the gene responsible for alkaptonuria.

Alkaptonuria↗
PubMed2006

Bilateral spontaneous rupture of the quadriceps tendon as an initial presentation of alkaptonuria--a case report.

Unilateral rupture of the quadriceps tendon is not uncommon, but bilateral spontaneous quadriceps tendon rupture is a rare occurrence and is usually associated with some underlying predisposing condition. We describe a case of a previously healthy patient who presents with bilateral spontaneous rupture of both quadriceps tendon. Investigations revealed that he had underlying alkaptonuria which was previously undiagnosed. Alkaptonuria is a rare inborn metabolic disease, which results in the derangement of homogentisic acid metabolism. Excessive accumulation of homogentisic acid is known to affect multiple organ systems, resulting in tendinopathy and arthropathy in the muscoskeletal system.

Accidental Falls↗
PubMed1998

The success of dietary protein restriction in alkaptonuria patients is age-dependent.

Alkaptonuria is characterized by an increased urinary excretion of homogentisic acid, pigmentation of cartilage and connective tissues, and ultimately the development of inflammatory arthropathy. Various diets low in protein have been designed to decrease homogentisic acid excretion and to prevent the ochronotic pigmentation and arthritic lesions. However, limited information is available on the long-term beneficial effects of these diets. We reviewed the medical records of 16 patients aged 3-27 years (4 > 18 years) to ascertain the age of diagnosis, growth, development, social behaviour, signs of complications and longitudinal dietary compliance. The diagnosis of alkaptonuria was made at an average age of 1.4 years (2 months-4 years); following the diagnosis all patients were prescribed a diet with a protein content of 1.5 g/kg per day. All patients showed normal growth and development, and no major complications of the disease. Behavioural problems associated with poor dietary compliance emerged as the main problem. Dietary compliance decreased progressively with age. The effect of dietary protein restriction in homogentisic acid excretion was studied by fixing the amounts of protein in the diet at 1 g/kg per day and 3.5-5 g/kg per day during 8 days. Twelve patients, aged 4-27 years, participated in the investigation. Protein restriction resulted in a significantly lower excretion of homogentisic acid in the urine of children younger than 12 years (p < 0.01), whereas this effect was less obvious for adolescent and adult patients. The results suggest that restriction of protein intake may have a beneficial effect on alkaptonuric children; but continuation of this regimen to older age seems questionable and not practical.

Adolescent↗
PubMed1996

The molecular basis of alkaptonuria.

Alkaptonuria (AKU) occupies a unique place in the history of human genetics because it was the first disease to be interpreted as a mendelian recessive trait by Garrod in 1902. Alkaptonuria is a rare metabolic disorder resulting from loss of homogentisate 1,2 dioxygenase (HGO) activity. Affected individuals accumulate large quantities of homogentisic acid, an intermediary product of the catabolism of tyrosine and phenylalanine, which darkens the urine and deposits in connective tissues causing a debilitating arthritis. Here we report the cloning of the human HGO gene and establish that it is the AKU gene. We show that HGO maps to the same location described for AKU, illustrate that HGO harbours missense mutations that cosegregate with the disease, and provide biochemical evidence that at least one of these missense mutations is a loss-of-function mutation.

Alkaptonuria↗
PubMed2004

Alkaptonuria, ochronosis, and ochronotic arthropathy.

OBJECTIVES: To describe the clinical presentation and course of a relatively large group of Italian adult patients screened for mutation of the homogentisate dioxygenase gene causing alkaptonuria (AKU) and ochronosis, and to review typical and atypical facets of this condition. METHODS: We reviewed the medical records of 9 patients affected by ochronotic arthropathy who were observed in our institutions between 1979 and 2001. All patients were diagnosed as having AKU through a rapid urine test with alkali. Mutation screening was performed by single-strand conformation analysis of all homogentisate dioxygenase exons, followed by sequencing of altered conformers. RESULTS: Our 9 cases had similar clinical features and they reflected those described in the literature: a progressive degenerative arthropathy mainly affecting axial and weight-bearing joints associated with extraarticular manifestation. Musculoskeletal symptoms began in most of our patients around the age of 30 years with back pain and stiffness: involvement of the large peripheral joints usually occurred several years after spinal changes. Ochronotic peripheral arthropathy generally was degenerative, but joint inflammation was observed in some cases; this could be attributed to an inflammatory reaction of the ochronotic shard in the synovial membrane. CONCLUSIONS: Ochronosis is a model of arthropathy with known etiologic factors. Over time, AKU, the genetically determined metabolic defect, leads to the accumulation of pigment and the development of this crippling condition. Most of the clinical findings may be explained by inhibition of collagen crosslinks, but some require additional interpretation. For example, inflammatory features of the ochronotic joint only occur in a minority of cases, and may be attributable to ochronotic shards. Further studies are needed to establish the genotype-phenotype correlation to identify mutations that are predictive of severe disease. For this purpose, the Italian Study Group on Alkaptonuria (www.dfc.unifi.it/aku) is enrolling affected patients in an on-line database to characterize the molecular defects and their relationship to clinical data.

Aged↗
PubMed2005

Ochronotic arthropathy: disappearance of alkaptonuria after liver transplantation for hepatitis B-related cirrhosis.

The deficiency of homogentisic acid oxidase, an enzyme that is mainly found in hepatocytes, is associated with alkaptonuria and ochronosis. We report a patient with clinical and radiologic findings of ochronotic arthropathy in whom alkaptonuria disappeared and the progressive course of the disease stopped after liver transplantation for hepatitis B-related cirrhosis.

Alkaptonuria↗
PubMed2001

Alkaptonuria: a case report.

Alkaptonuria is a rare, autosomally recessive, metabolic disorder caused by a deficiency in homogentisic acid oxidase. It results in accumulation and deposition of homogentisic acid in cartilage, eyelids, forehead, cheeks, axillae, genital regions, nail beds, buccal mucosa, larynx, tympanic eardrum, and the tendons. We report a 33-year-old woman who presented with alkaptonuria and ochronotic pigment deposited in articular cartilage and cartilage of the ear and sclera.

Adult↗
PubMed1997

Molecular defects in alkaptonuria.

At the dawn of human genetics Sir Archibald Garrod used alkaptonuria as a paradigm to demonstrate the applicability of the Mendelian laws to men and to develop the concept of inborn errors of metabolism. The human cDNA for homogentisate 1,2 dioxygenase was identified due to its homology to the corresponding mouse enzyme and was screened for mutations in alkaptonuric patients from Slovakia. Homozygous mutations were found in four unrelated families and their segregation with the disease was demonstrated. One of the mutations, observed in two families, leads to a frame-shift and thus is unlikely to produce functional protein. The data formally establish the homogentisate 1,2 dioxygenase gene (HGD) as the molecular cause of alkaptonuria and allow for the development of molecular carrier tests in populations at risk.

Alkaptonuria↗
PubMedDate not supplied

Early detection of alkaptonuria.

Alkaptonuria is a rare disorder of metabolism characterized by deficiency of homogentisic acid oxidase. This leads to the characteristic features like darkening of urine, ochronosis and arthropathy. Darkening of urine is one of the first symptoms noticed by the parents of the child suffering from this disorder. Ochronosis is seen in various organs like eyes, skin, tendons and joints. A case of 10 year old boy is reported who was brought to this clinic with the presenting complaint of bluish discoloration of sclerae. This discoloration led to eliciting positive history of dark urine off and on. Further investigations confirmed alkaptonuria.

Alkaptonuria↗
PubMed2001

Dura mater involvement in ochronosis (alkaptonuria).

Clinical manifestations of alkaptonuria have been well described and are most commonly characterized by ochronosis or pigmentation of connective tissue. Sites most commonly involved in ochronosis include joints, heart, skin, and kidney. We describe a 66-year-old woman with a history of alkaptonuria who had widespread ochronosis. The dura mater showed extensive pigment deposition, which was evident both grossly and microscopically at autopsy. To our knowledge, description of dura mater involvement by ochronosis has not been previously reported in the literature.

Aged↗
PubMed1999

[Ochronotic changes in alkaptonuria: a case report].

Alkaptonuria is a rare metabolic condition caused by congenital homogentisate oxidase deficiency of recessive autosomal inheritance. Homogentisate polymers are accumulated and cause urine darkening (alcaptonuria), brown/black pigmentation of connective tissue (ochronosis), articular cartilage pathology, osteoporosis and patomorphologic changes in internal organs. A case of 61 female with ochronotic polyarthropathy is presented. An early result of Weller THR is encouraging. Pathogenesis, clinical picture, diagnostics and treatment of alkaptonuria is presented on the ground of the literature.

Alkaptonuria↗
PubMed1975

[Alkaptonuria with ochronosis and monoclonal gammopathy].

A case of alkaptonuria with ochronosis is described. It is suggested that such cases are not so much rare as unobserved. Their aetiology is to be sought in a metabolic error, though the pathogenesis is not clear. The syndrome is of interest because ochronosis, wich is the articular manifestation, is one of the few rheumatological affections with a certain aetiology. The case described is unusual on account of the presence of monoclonal gammopathy. Since the presence of myeloma and macroglobulinaemia could be excluded, an immunological relation was sought between the alkaptonuria and the particular serological picture.

Adult↗