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PubMed1997

The human homogentisate 1,2-dioxygenase (HGO) gene.

Alkaptonuria (AKU; McKusick No. 203500), a rare hereditary disorder of the phenylalanine catabolism, was the first disease to be interpreted as an inborn error of metabolism (A. E. Garrod, 1902, Lancet 2: 1616-1620). AKU patients are deficient for homogentisate 1,2-dioxygenase (HGO; EC 1.13.11.5). This enzymatic deficiency causes homogentisic aciduria, ochronosis, and arthritis. Recently we cloned the human HGO gene and showed that AKU patients carry two copies of a loss-of-function HGO allele. Here we describe the complete nucleotide sequence of the human HGO gene and the identification of its promoter region. The human HGO gene spans 54,363 bp and codes for a 1715-nt-long transcript that is split into 14 exons ranging from 35 to 360 bp. The HGO introns, 605 to 17,687 bp in length, contain representatives of the major classes of repetitive elements, including several simple sequence repeats (SSR). Two of these SSRs, a (CT)n repeat in intron 4 and a (CA)n repeat in intron 13, were found to be polymorphic in a Spanish population sample. The HGO transcription start site was determined by primer extension. We report that sequences from -1074 to +89 bp (relative to the HGO transcription start site) are sufficient to promote transcription of a CAT reporter gene in human liver cells and that this fragment contains putative binding sites for liver-enriched transcription factors that might be involved in the regulation of HGO expression in liver.

Alkaptonuria↗

PubMed1990

Case report 591: Osteoarthrosis (OA) of hip associated with microscopic gouty tophi.

It has been demonstrated in this 58-year old woman that osteoarthrosis OA coexisted in a hip with microscopic gouty tophi. It is demonstrated that the bone erosions around the hip in this case were due to OA and not gouty arthritis. It is believed that OA is not a consequence of gout and that such an association between gout and OA is exceptional. It is maintained that a true association exists between OA and ochronosis while a relationship may exist between OA and chondrocalcinosis, but the nature of this relationship is not clear.

Female↗

PubMed1999

A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria.

Alkaptonuria is a rare autosomal recessive disorder characterized by homogentisic aciduria, ochronosis, and arthritis. Although a deficiency of homogentisic acid 1,2-dioxygenase has recently been confirmed at the molecular level, no effective treatment regimen has yet been developed for this disorder. In the present study, 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), a potent inhibitor of p-hydroxyphenylpyruvate dioxygenase (which catalyzes the formation of homogentisic acid from p-hydroxyphenylpyruvic acid) was adopted as a possible therapeutic agent for alkaptonuria. NTBC dose-dependently reduced the urinary output of homogentisic acid in a murine model of alkaptonuria that had been created with ethylnitrosourea. These findings suggest that NTBC may be the first potent pharmacotherapeutic agent for alkaptonuria.

4-Hydroxyphenylpyruvate Dioxygenase↗

PubMed2005

Use of nitisinone in patients with alkaptonuria.

Alkaptonuria, a rare autosomal recessive disorder caused by mutations in the HGD gene and deficiency of homogentisate 1,2 dioxygenase, is characterized by ochronosis, arthritis, and daily excretion of gram quantities of homogentisic acid (HGA). Nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, can drastically reduce urinary excretion of HGA in individuals with alkaptonuria. We investigated the safety and the HGA-depleting efficacy of nitisinone in an open-label, single-center study of 9 alkaptonuria patients (5 women, 4 men; 35-69 years of age) over the course of 3 to 4 months. Each patient received nitisinone in incremental doses, 0.35 mg bid followed by 1.05 mg bid, and remained on this dosage and a regular diet for 3 months. Nitisinone reduced urinary HGA levels from an average of 4.0 +/- 1.8 (SD) g/day to 0.2 +/- 0.2 g/day ( P < .001). The average plasma tyrosine concentration, initially 68 +/- 18 mmicro mol/L, rose to 760 +/- 181 micro mol/L ( P < .001). During the final week of the study, 5 patients adhered to a protein-restricted diet (40 g/day), and their mean plasma tyrosine level fell from 755 +/- 167 to 603 +/- 114 mu mol/L. Six of the 7 patients who received nitisinone for more than 1 week reported decreased pain in their affected joints. Weekly ophthalmologic examinations showed no signs of corneal toxicity. Adverse events included the passing of kidney stones, the recognition of symptoms related to aortic stenosis, and elevation of liver transaminase levels. We conclude that low-dose nitisinone effectively reduced urinary HGA levels in patients with alkaptonuria. Future long-term clinical trials are planned to determine the benefits of nitisinone in preventing joint deterioration and providing pain relief, and its long-term side effects.

Adult↗

PubMed2000

[Alkaptonuria: a rare cause of urine discoloration. Report of a case in a newborn].

UNLABELLED: Alcaptonuria is a rare hereditary disease, characterized by an abnormal blackish coloration of the urine and dark pigmentation of the conjunctive tissue which is due to a deficiency in homogentisate 1,2-dioxygenase (HGO), a phenylalanine catabolizing enzyme. An accumulation of homogentisate (HGA) is then formed, and is responsible for the dark coloration which only occurs after the urine has been exposed to air over a period of time. Signs of this disorder therefore frequently remain unnoticed during childhood, because the urine requires a relatively long exposure to air before it changes color. Diagnosis is generally made at a later date, during adulthood, following complications such as ochronosis, inflammatory arthritis, or urinary calculi. CASE REPORT: In this study, the case has been described of alcaptonuria diagnosed in a five-month old infant. No efficient cure has yet been found, although certain treatments, including high doses of vitamin C, do seem to have a beneficial effect on limiting the complications associated with this disorder. Early diagnosis whenever possible is therefore important. CONCLUSION: This case report is interesting because of the early diagnosis involved. In the event of any abnormal coloration of the urine, diagnosis may be established via the addition of an alkylating agent, and the levels of HGA determined by chromatography.

Alkaptonuria↗

PubMed2003

Molecular analyses of the HGO gene mutations in Turkish alkaptonuria patients suggest that the R58fs mutation originated from central Asia and was spread throughout Europe and Anatolia by human migrations.

Alkaptonuria (AKU) is a rare metabolic disorder of phenylalanine catabolism that is inherited as an autosomal recessive trait. AKU is caused by loss-of-function mutations in the homogentisate 1,2-dioxygenase (HGO) gene. The deficiency of homogentisate 1,2-dioxygenase activity causes homogentisic aciduria, ochronosis and arthritis. We present the first molecular study of the HGO gene in Turkish AKU patients. Seven unrelated AKU families from different regions in Turkey were analysed. Patients in three families were homozygous for the R58fs mutation; another three families were homozygous for the R225H mutation; and one family was homozygous for the G270R mutation. Analysis of nine intragenic HGO polymorphisms showed that the R58fs, R225H and G270R Turkish AKU mutations are associated with specific HGO haplotypes. The comparison with previously reported haplotypes associated with these mutations from other populations revealed that the R225H is a recurrent mutation in Turkey, whereas G270R most likely has a Slovak origin. Most interestingly, these analyses showed that the Turkish R58fs mutation shares an HGO haplotype with the R58fs mutation found in Finland, Slovakia and India, suggesting that R58fs is an old AKU mutation that probably originated in central Asia and spread throughout Europe and Anatolia during human migrations.

Adolescent↗

PubMed2003

Rapid detection methods for five HGO gene mutations causing alkaptonuria.

Alkaptonuria (AKU) is an autosomal recessive disorder caused by the deficiency of homogentisate 1,2 dioxygenase (HGO) activity. The disease is characterized by homogentisic aciduria, ochronosis and ochronotic arthritis. AKU shows a very low prevalence (1:250 000), in most ethnic groups. Altogether 43 HGO mutations have been identified in approximately 100 patients. In Slovakia, however, the incidence of this disorder rises up to 1:19 000, and 10 different AKU mutations have been identified in this relatively small country. Here, we report detection methods developed for rapid identification of five HGO mutations. PCR primers were designed enabling detection of mutations IVS5 + 1G-->A, R58fs, and V300G by restriction digestion of amplification-created restriction sites (ACRS). Mutation G152fs is readily identified by heteroduplex analysis, and G161R by amplification refractory mutation system (ARMS) PCR.

Alkaptonuria↗

PubMed1993

Homozygosity mapping of the gene for alkaptonuria to chromosome 3q2.

Alkaptonuria, the first human disorder recognized by Garrod as an inborn error of metabolism, is a rare recessive condition that darkens urine and causes a debilitating arthritis termed ochronosis. We have studied two families with consanguineous parents and four affected children in order to map the gene responsible for alkaptonuria. Coinheritance of either neonatal severe hyperparathyroidism or sucrase-isomaltase deficiency and alkaptonuria provided a candidate location for the mutated genes on chromosome 3. Homozygosity mapping with polymorphic loci identified a 16 centiMorgan region on chromosome 3q2 that contains the alkaptonuria gene. Analysis of two additional nonconsanguineous families supports linkage of alkaptonuria to this single locus (combined lod score = 4.3, theta = 0).

Adult↗

PubMed2003

Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.

BACKGROUND: The cosmetic use of bleaching products is considered a common practice in dark-skinned women from sub-Saharan Africa. However, there are few studies on this subject. OBJECTIVES: To increase the knowledge about the dermatological consequences of this practice in Dakar, the capital of Senegal. METHODS: A representative sample of 368 adult women presenting at our dermatological centre was selected. Each woman was questioned about her cosmetic use of bleaching products. Next, the following data were recorded in 425 women who used bleaching products: names and types of products used; modalities of the skin bleaching practice; skin diseases motivating the dermatological visit, with recording of their clinical features; and results of a full skin examination. The active substances of the bleaching products were determined mainly by reading the indications on their packages; with products of unknown composition, a pharmacological analysis of samples was done. A statistical analysis was performed. RESULTS: Of the 368 women questioned, 194 (52.7%) were current users of bleaching products. Concerning the 425 users enrolled, products were applied on the whole body in 92% of users, with a median duration of use of 4 years. The active principles used included hydroquinone (used by 89% of users), glucocorticoids (70%), mercury iodide (10%) and caustic agents (17%); 13% of users used products of unknown composition. In the samples that were analysed, hydroquinone was found at concentrations of between 4% and 8.7%. Concerning steroids, superpotent (class 1) glucocorticoids predominated. The main skin complaints in bleaching products users included dermatophyte infections (n = 105) and scabies (n = 69), both often unusually extensive and severe; acne (n = 42), often severe; eczema (n = 41); irritant dermatitis (n = 14); and dyschromia (n = 26, including 14 cases of exogenous ochronosis). The skin examination noted features apparently disregarded by users: striae (noticed in 39% of users), and macular hyperchromia involving the face, mainly the periocular area (33%). The statistical analysis showed that glucocorticoid use was associated with the presence and severity of infectious skin diseases, and of acne. CONCLUSIONS: More than half of the adult women presenting at our dermatology centre were using bleaching products. Most skin diseases observed in bleaching products users appeared to be induced, aggravated or modified by this practice. Superpotent topical glucocorticoids appeared to be the main agents responsible for the observed complications. The cosmetic use of bleaching products therefore has a major impact on our current dermatological practice.

Acne Vulgaris↗

PubMed2002

Natural history of alkaptonuria.

BACKGROUND: Alkaptonuria, caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. There is no effective therapy for this disorder, although nitisinone inhibits the enzyme that produces HGA. We performed a study to delineate the natural history of alkaptonuria. METHODS: We evaluated 58 patients with alkaptonuria (age range, 4 to 80 years), using clinical, radiographic, biochemical, and molecular methods. A radiographic scoring system was devised to assess the severity of spinal and joint damage. Two patients were treated with nitisinone for 10 and 9 days, respectively. RESULTS: Life-table analyses showed that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. Twenty-three new HGO mutations were identified. In a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone (7 days at a dose of 0.7 mg per day and 3 days at 2.8 mg per day). In a 59-year-old woman, urinary HGA fell from 6.4 g to 1.7 g per day after nine days of treatment with nitisinone (0.7 mg per day). Plasma tyrosine levels in these patients rose from approximately 1.1 mg per deciliter (60 micromol per liter) in both to approximately 12.8 mg per deciliter (700 micromol per liter) and 23.6 mg per deciliter (1300 micromol per liter), respectively, with no clinical signs or symptoms. CONCLUSIONS: The reported data on the natural history of alkaptonuria provide a basis for the evaluation of long-term therapies. Although nitisinone can reduce HGA production in humans with homogentisate 1,2-dioxygenase deficiency, the long-term safety and efficacy of this treatment require further evaluation.

4-Hydroxyphenylpyruvate Dioxygenase↗

PubMed1999

The toxicology of hydroquinone--relevance to occupational and environmental exposure.

Hydroquinone (HQ) is a high-volume commodity chemical used as a reducing agent, antioxidant, polymerization inhibitor, and chemical intermediate. It is also used in over-the-counter (OTC) drugs as an ingredient in skin lighteners and is a natural ingredient in many plant-derived products, including vegetables, fruits, grains, coffee, tea, beer, and wine. While there are few reports of adverse health effects associated with the production and use of HQ, a great deal of research has been conducted with HQ because it is a metabolite of benzene. Physicochemical differences between HQ and benzene play a significant role in altering the pharmacokinetics of directly administered when compared with benzene-derived HQ. HQ is only weakly positive in in vivo chromosomal assays when expected human exposure routes are used. Chromosomal effects are increased significantly when parenteral or in vitro assays are used. In cancer bioassays, HQ has reproducibly produced renal adenomas in male F344 rats. The mechanism of tumorigenesis is unclear but probably involves a species-, strain-, and sex-specific interaction between renal tubule toxicity and an interaction with the chronic progressive nephropathy that is characteristic of aged male rats. Mouse liver tumors (adenomas) and mononuclear cell leukemia (female F344 rat) have also been reported following HQ exposure, but their significance is uncertain. Various tumor initiation/promotion assays with HQ have shown generally negative results. Epidemiological studies with HQ have demonstrated lower death rates and reduced cancer rates in production workers when compared with both general and employed referent populations. Parenteral administration of HQ is associated with changes in several hematopoietic and immunologic endpoints. This toxicity is more severe when combined with parenteral administration of phenol. It is likely that oxidation of HQ within the bone marrow compartment to the semiquinone or p-benzoquinone (BQ), followed by covalent macromolecular binding, is critical to these effects. Bone marrow and hematologic effects are generally not characteristic of HQ exposures in animal studies employing routes of exposure other than parenteral. Myelotoxicity is also not associated with human exposure to HQ. These differences are likely due to significant route-dependent toxicokinetic factors. Fetotoxicity (growth retardation) accompanies repeated administration of HQ at maternally toxic dose levels in animal studies. HQ exposure has not been associated with other reproductive and developmental effects using current USEPA test guidelines. The skin pigment lightening properties of HQ appear to be due to inhibition of melanocyte tyrosinase. Adverse effects associated with OTC use of HQ in FDA-regulated products have been limited to a small number of cases of exogenous ochronosis, although higher incidences of this syndrome have been reported with inappropriate use of unregulated OTC products containing higher HQ concentrations. The most serious human health effect related to HQ is pigmentation of the eye and, in a small number of cases, permanent corneal damage. This effect has been observed in HQ production workers, but the relative contributions of HQ and BQ to this process have not been delineated. Corneal pigmentation and damage has not been reported at current exposure levels of <2 mg/m3. Current work with HQ is being focused on tissue-specific HQ-glutathione metabolites. These metabolites appear to play a critical role in the renal effects observed in F344 rats following HQ exposure and may also be responsible for bone marrow toxicity seen after parenteral exposure to HQ or benzene-derived HQ.

Animals↗

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↗

PubMed2000

Alkaptonuria with lumbar disc herniation: a report of two cases.

STUDY DESIGN: Two cases of lumbar disc herniation with alkaptonuria are presented. OBJECTIVES: To present a probable clinical course of lumbar disc herniation with alkaptonuria, a rare metabolic disease. SUMMARY OF BACKGROUND DATA: Although lumbar disc disease is a common clinical occurrence in alkaptonuria, lumbar disc surgery is needed rarely in this disease. A patient with alkaptonuria without ochronotic signs is also rarely seen. METHODS: The cause, clinical presentation, diagnostic techniques and treatment of alkaptonuria with lumbar disc disease are reviewed. RESULTS: The symptoms of the patients disappeared after surgery, and there were no symptoms on follow-up. CONCLUSION: Alkaptonuria frequently occurs in association with lumbar disc disease. In patients with no other signs of alkaptonuria or ochronosis, early detection of the disease is important to treat involvement of other systems (e.g., cardiovascular and urinary).

Adult↗

PubMed2003

Reconstruction of combined defects of the Achilles tendon and the overlying soft tissue with a fascia lata graft and a free fasciocutaneous lateral arm flap.

A new approach to reconstruction of the Achilles tendon and overlying soft tissue is presented. A fascia lata graft is used to reconstruct the tendon and is enwrapped by the fascia that is included in a fasciocutaneous lateral arm flap. Five patients were treated with this technique; three of them after surgical Achilles tendon repair, rerupture, and consecutive infection, one after a full-thickness burn with loss of the tendon and one with a history of ochronosis and necrosis of the whole tendon and overlying soft tissue. There were no anastomotic complications and all flaps healed primarily. Functional evaluation with the Cybex II dynamometer was done at least 49 months after reconstruction. A good functional and cosmetic result was obtained in all patients and donor site morbidity was acceptable. These results are well within the results of other surgical treatment options reported in the literature.

Achilles Tendon↗

PubMed1991

Regional dermatoses in the African. Part I. Facial hypermelanosis.

Acquired facial hyperpigmentation is a common problem among African patients, particularly women, where the causes of the dermatoses are identified largely from circumstantial evidence of exposure to known agents. These include hydroquinone-induced exogenous ochronosis from skin-bleaching creams, mercury deposits from mercury-containing skin-lightening soaps and creams, sulfonamide-related drugs, antimalarials, fixed drug eruptions, clofazimine, and photosensitizing herbal concoctions. The differential diagnosis includes melasma and facial erythema ab igne (local cooks).

Africa↗

PubMed1991

The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream.

The efficacy of 20% azelaic acid cream and 4% hydroquinone cream, both used in conjunction with a broad-spectrum sunscreen, against melasma was investigated in a 24-week, double-blind study with 329 women. Over the treatment period the azelaic acid cream yielded 65% good or excellent results; no significant treatment differences were observed with regard to overall rating, reduction in lesion size, and pigmentary intensity. Severe side effects such as allergic sensitization or exogenous ochronosis were not observed with azelaic acid.

Administration, Cutaneous↗

PubMed2005

Hydroquinone and its analogues in dermatology - a potential health risk.

Hydroquinone has been used for decades as a skin lightening agent. Since January 1, 2001, its use in cosmetics has been banned. This ban is as a result of mid-term effects such as leukoderma-en-confetti/occupational vitiligo and exogenous ochronosis. However, a recent literature search on hydroquinone as a skin lightening agent suggests that possible long-term effects such as carcinogenesis may be expected as well. Metabolites of hydroquinone formed in the liver, e.g., p-benzoquinone and glutathione conjugates of hydroquinone, are mainly responsible for this. In the bone marrow, hydroquinone is oxidized into p-benzoquinone because of the high myeloperoxidase activity. Topically applied hydroquinone-containing creams may give rise to accumulation of these compounds, which can cause DNA damage and mutations. They also have the capability to disrupt protective mechanisms, whereby they facilitate further development of cancer. In the bone marrow, long-term effects such as aplastic anemia and acute myeloid leukemias may occur. Most of the evidence stems from research on benzene toxicity, which appears to arise via its metabolite hydroquinone. There is no report yet demonstrating carcinogenesis resulting from the application of hydroquinone-containing creams. However doctors should be aware of these potential health risks which were up until now disregarded.

Journal Article↗

PubMed1997

Histopathological findings in chronic tendon disorders.

Tendon injuries and other tendon disorders represent a common diagnostic and therapeutic challenge in sports medicine, resulting in chronic and long-lasting problems. Tissue degeneration is a common finding in many sports-related tendon complaints. In the great majority of spontaneous tendon ruptures, chronic degenerative changes are seen at the rupture site of the tendon (1). Systemic diseases and diseases specifically deteriorating the normal structure of the tendon (i.e. foreign bodies, and metabolic, inherited and infectious tendon diseases) are only rarely the cause of tendon pathology. Inherited diseases, such as various hereditary diseases with disturbed collagen metabolism and characteristic pathological structural alterations (Ehlers-Danlos syndrome, Marfani syndrome, homocystinuria (ochronosis)), represent approximately 1% of the causes of chronic tendon complaints (2), whereas foreign bodies are somewhat more common and are found in less than 10% of all chronic tendon problems (1). Rheumatoid arthritis and sarcoidosis are typical systemic diseases that cause chronic inflammation in tendon and peritendinous tissues. Altogether, these 'specific' disorders represented less than 2% of the pathological alterations found in the histological analysis of more than 1000 spontaneously ruptured tendons (1, 3, 4). In this material, degenerative changes were seen in a great majority of the tendons, indicating that a spontaneous tendon rupture is a typical clinical end-state manifestation of a degenerative process in the tendon tissue. The role of overuse in the pathogenesis of chronic tendon injuries and disorders is not completely understood. It has been speculated that when tendon is overused it becomes fatigued and loses its basal reparative ability, the repetitive microtraumatic processes thus overwhelming the ability of the tendon cells to repair the fiber damage. The intensive repetitive activity, which often is eccentric by nature, may lead to cumulative microtrauma which further weakens the collagen cross-linking, non-collagenous matrix, and vascular elements of the tendon. Overuse has also been speculated to cause chronic tendon problems, by disturbing the micro- and macrovasculature of the tendon and resulting in insufficiency in the local blood circulation. Decreased blood flow simultaneous with an increased activity may result in local tissue hypoxia, impaired nutrition and energy metabolism, and together these factors are likely to play an important role in the sequence of events leading to tendon degeneration (4). A sedentary lifestyle has been proposed as a main reason for poor basal circulation of the tendon, and presumably is at least partly responsible for the high number of tendon problems in people with a sedentary lifestyle who occasionally take part in high physical activity sports events.

Humans↗