Biochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy

O’Brien, William M.; Du, Bert N. La; Bunim, Joseph J.

doi:10.1016/0002-9343(63)90089-5

Cited by 289 publications

(208 citation statements)

References 138 publications

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“…For the same reason disc prolapse is unusual in ochranosis, 5 although cervical disc ruptures have been reported. 14 The cardiovascular lesions of ochranosis, include discolouration of the heart valves, endocardium and intima of the aorta. There is an increased incidence of generalised atherosclerosis, and myocardial infarction is the frequent cause of death.…”

Section: Discussionmentioning

confidence: 99%

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

Reddy

Prasad

1998

Spinal Cord

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Alkaptonuria is a rare genetic disorder caused by de®ciency of the enzyme homogentisic acid oxidase, resulting in accumulation of homogentisic acid in various body tissues; 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¯exibility and ankylosis of the thoracic and lumbar segments. 1 The clinical presentation with spondylosis and canal stenosis is common after the third and fourth decades, 2 but intervertebral disc prolapse is unusual in ochranosis.Keywords: alkaptonuria; ochranosis; disc prolapse; spine Case reportA 22 year old male presented with backache and left sided sciatica of 6 weeks duration. Conservative treatment from his general practitioner failed to relieve the pain and he developed paraesthesiae in left lower limb. There was marked restriction of straight leg raising on the left side; weakness of the left ankle dorsi¯exors and of the extensor hallucis longus; and decreased sensation over the medical aspect of left foot.A clinical diagnosis of prolapsed intervertebral disc at L4/L5 on the left side was made, and he was investigated. Plain radiographs of the lumbar spine were unremarkable; magnetic resonance image tomography revealed a prolapse of the L4/5 intervertebral disc (Figure 1). At operation, there was marked hypertrophy of the facet joints with encroachment onto the canal, and there was severe pressure on the L5 left nerve root due to the underlying bulging disc.

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Section: Discussionmentioning

confidence: 99%

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

Reddy

Prasad

1998

Spinal Cord

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“…The pigment is deposited in connective tissue, especially in cartilage, a process called ochronosis (Zannoni et al 1969). This leads to early onset arthritis of the spine and synovial joints and other debilitating symptoms (O'Brien et al 1963;Ranganath et al 2013). There is currently no approved pharmacological treatment for AKU.…”

Section: Introductionmentioning

confidence: 99%

Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria

et al. 2015

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Background: Alkaptonuria (AKU) is a serious genetic disease due to a defect in tyrosine metabolism, leading to increased serum levels of homogentisic acid (HGA). Nitisinone decreases HGA in AKU, but the concentration-response relationship has not been previously reported.Objectives: To determine the relationship between serum concentrations of nitisinone and the effect on both HGA and tyrosine; secondly to determine steady-state pharmacokinetics of nitisinone in AKU patients.Method: Thirty-two patients with AKU received either 1, 2, 4, or 8 mg nitisinone daily. Urine and serum HGA and serum tyrosine and nitisinone were measured during 24 h at baseline (before first dose) and after 4 weeks of treatment.Results: Nitisinone pharmacokinetics (area under the curve [AUC] and maximum concentrations [C max ]) were dose proportional. The median oral clearance determined in all patients, irrespective of dose, was 3.18 mL/hÁkg (range 1.6-6.7).Nitisinone decreased urinary excretion of HGA in a concentration-dependent manner, with a maximum effect seen at average nitisinone concentrations of 3 mmol/L. The association between nitisinone and tyrosine concentrations was less pronounced. Serum levels of HGA at Week 4 were below the limit of quantitation in 65% of samples, which prevented determination of the relationship with nitisinone concentrations.Conclusion: Nitisinone exhibits dose-proportional pharmacokinetics in the studied dosage interval. Urinary excretion of HGA decreases in a concentration-dependent manner, while the increase in tyrosine is less clearly related to nitisinone concentrations.

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“…This process takes many years and is known as ochronosis (Zannoni et al 1969). The damaging effects of ochronosis include arthritis (especially in the spine and large weight bearing joints), stones (renal, prostatic, gall bladder and salivary), cardiac valve disease especially aortic (Goodfellow et al 2005), ruptures (muscle, tendons and ligaments), osteopenia and fractures (O'Brien et al 1963). Virtually all connective tissue is affected.…”

Section: Introductionmentioning

confidence: 99%

Reversible Keratopathy Due to Hypertyrosinaemia Following Intermittent Low-Dose Nitisinone in Alkaptonuria: A Case Report

et al. 2014

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We describe a patient with ultra-rare disease, alkaptonuria, who developed tyrosine keratopathy following nitisinone therapy of 2 mg on alternate days. His vision became impaired approximately 7 weeks following the commencement of nitisinone and ophthalmological examination at week nine showed characteristic dendritic keratopathy associated with tyrosinaemia. The corneal lesion as well as his visual symptoms normalized completely following discontinuation of nitisinone. This is the first documented report of keratopathy due to acquired tyrosinaemia due to very low-dose nitisinone.

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Biochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy

Cited by 289 publications

References 138 publications

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

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

Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria

Reversible Keratopathy Due to Hypertyrosinaemia Following Intermittent Low-Dose Nitisinone in Alkaptonuria: A Case Report

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