Biochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: Review of world literature (1584–1962)

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

The American Journal of Medicine

Volume 34, Issue 6, June 1963, Pages 813-838

https://doi.org/10.1016/0002-9343(63)90089-5 Get rights and content

Abstract

The biomedical literature on alcaptonuria, ochronosis and ochronotic joint disease, including 604 cases reported from thirty-five countries, is reviewed. The history of the development of our knowledge concerning this hereditary metabolic disorder, from 1584 to 1962, is recapitulated. The nature of the biochemical defect, a deficiency of homogentisic acid oxidase, in alcaptonuria is described and the pattern of genetic transmission traced. The geographic and racial distribution, and the multisystemic clinical manifestations of ochronosis are summarized. The diagnostic features and differential diagnostic considerations are presented. The gross, histopathologic and electron microscopic changes as well as pathogenesis are discussed. The various types of treatment attempted, without success, are mentioned.

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Cited by (231)

Alkaptonuria – Past, present and future
2023, Advances in Clinical Chemistry
Alkaptonuria (AKU) is an ultra-rare inherited inborn error of metabolism that afflicts the tyrosine metabolic pathway, resulting in the accumulation of homogentisic acid (HGA) in the circulation, and significant excretion in urine. Clinical manifestations, typically observed from the third decade of life, are lifelong and significantly affect the quality of life. This review provides a comprehensive overview of the natural history of AKU, including clinical, biochemical and genetic perspectives. An update on the major advances on studies in murine models and human subjects, providing mechanistic insight into the molecular and biochemical processes that underlie pathophysiology and its response to treatment are presented. The impact of treatment with nitisinone is also presented with a specific emphasis on hypertyrosinemia, as uncertainty on this topic remains. Future perspectives are explored, such as novel approaches to treat hypertyrosinemia including the use of binding agents and amino acid transporter inhibitors, as well as advanced potentially curative gene and cell therapy initiatives.
Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria
2022, Molecular Genetics and Metabolism Reports
Although changes in the tyrosine pathway during nitisinone therapy are known, a complete characterization of the induced tyrosinaemia is lacking to improve disease management.
Our research aims were addressed by 24-h blood sampling. 40 patients with alkaptonuria (AKU), treated with 0, 1, 2, 4 and 8 mg nitisinone daily (n = 8), were studied over four weeks. Serum homogentisic acid (sHGA), tyrosine (sTYR), phenylalanine (sPHE), hydroxyphenylpyruvate (sHPPA), hydroxyphenyllactate (sHPLA) and nitisinone (sNIT) were measured at baseline and after four weeks.
sNIT showed a clear dose-proportional response. sTYR increased markedly but with less clear-cut dose responses after nitisinone. Fasting and average 24-h (C_av) sTYR responses were similar. Individual patient sTYR 24-h profiles showed significant fluctuations during nitisinone therapy. At week 4, sTYR, sHPPA and sHPPL all showed dose-related increases compared to V0, with the greatest difference between 1 and 8 mg nitisinone seen for HPLA, while there was no change from V0 in sPHE. sHGA decreased to values around the lower limit of quantitation.
There was sustained tyrosinaemia after four weeks of nitisinone therapy with significant fluctuations over the day in individual patients. Diet and degree of conversion of HPPA to HPLA may determine extent of nitisinone-induced tyrosinaemia.
A fasting blood sample is recommended to monitor sTYR during nitisinone therapy Adaptations in HPPA metabolites as well as the inhibition of tyrosine aminotransferase could be contributing factors generating tyrosinaemia during nitisinone therapy.
Temporal adaptations in the phenylalanine/tyrosine pathway and related factors during nitisinone-induced tyrosinaemia in alkaptonuria
2022, Molecular Genetics and Metabolism
Adaptations within the phenylalanine (PHE)/tyrosine (TYR) pathway during nitisinone (NIT) are not fully understood.
To characterise the temporal changes in metabolic features in NIT-treated patients with alkaptonuria.
Serum (s) and 24-urine (u) homogentisic acid (sHGA, uHGA₂₄), TYR (sTYR, uTYR₂₄), PHE (sPHE, uPHE₂₄), hydroxyphenylpyruvate (sHPPA, uHPPA₂₄), hydroxyphenyllactate (sHPLA, uHPLA₂₄) and sNIT were measured at baseline (V1) and until month 48 (V6) in 69 NIT-treated patients, recommended to reduce protein intake. The 24-h urine urea (uUREA₂₄), creatinine (uCREAT₂₄) and body weight were also measured. Amounts of tyrosine metabolites in total body water (TBW) were derived by multiplying the serum concentrations by 60% body weight, and sum of TBW and urine metabolites resulted in combined values (c).
uUREA₂₄ and uCREAT₂₄ decreased between V1 and V6 during NIT, whereas body weight and sNIT increased. Linear regression coefficient between uUREA₂₄ and uCREAT₂₄ was extremely strong (R = 0.84). sPHE, TBWPHE and cPHE24 increased gradually from V1 to V6. A decrease in cTYR₂₄/cPHE_24, sTYR/sPHE and TBWTYR/TBWPHE was seen from V2 to V6. Serum, 24-urine and combined TYR, HPPA and HPLA either remained stable or decreased from V2 to V6.
The gradual increase in PHE suggests adaptation to increasing TYR during NIT therapy. The decrease in protein intake resulted in decreased muscle mass and increased weight gain.
Progressive adaptation by decreasing PHE conversion to TYR occurs over time during NIT therapy. A low protein diet results in loss of muscle mass but also weight gain suggesting an increase in fat mass.
Treatment of osteoporotic fractures in alkaptonuria by teriparatide stimulates bone formation and decreases fracture rate – A report of two cases
2021, Bone Reports
Two cases of advanced alkaptonuria (AKU) with co-existing osteoporosis are described. Case 1 developed multiple non-vertebral fragility fractures, while Case 2 developed vertebral fragility fractures, both refractory to bisphosphonates. Difficulties in diagnosing osteoporosis in AKU complicated by extensive calcifying and ossifying spondylosis are discussed. Both patients continued to fracture despite nitisinone therapy for metabolic control of AKU, as well as bisphosphonate antiresorptive therapy for osteoporosis. Subsequently the patients were treated with teriparatide 20 μg subcutaneous injections daily for two years, leading to reduction in fractures soon after commencing therapy in both cases. Markers of bone remodelling P1NP and CTX were stimulated. No complications due hypercalcaemia or calcification were encountered in either case. We conclude that teriparatide is an effective adjunct in the treatment of AKU when bisphosphonates prove ineffective.
Evaluating the aortic stenosis phenotype before and after the effect of homogentisic acid lowering therapy: Analysis of a large cohort of eighty-one alkaptonuria patients
2021, Molecular Genetics and Metabolism
A large alkaptonuria (AKU) cohort was studied to better characterise the poorly understood phenotype of aortic stenosis of rare disease AKU.
Eighty-one patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Nine only attended once. Fifty-one attended more than once and received nitisinone 2 mg daily. Twenty-one attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, standard transthoracic echocardiography, as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Blood and urine samples were collected for chemical measurement.
The prevalence of aortic stenosis and aortic valve replacement were 22.2 and 6.2% in the current group. Aortic maximum velocity (Vmax) was directly related to varying degrees to age (R = 0.58, p < 0.001), systolic blood pressure (R = 0.32, p < 0.05), serum homogentisic acid (sHGA) (R = 0.28, p < 0.05), ochronosis scores (R = 0.72, p < 0.001), and alkaptonuria severity score index (AKUSSI) (R = 0.58, p < 0.001) on linear regression analysis. Age and ochronosis scores were significantly related to Vmax on multiple regression analysis (p < 0.005). Nitisinone decreased sHGA, 24-h urine HGA (uHGA₂₄₎, ochronosis scores and AKUSSI significantly at all visits post-nitisinone. Nitisinone decreased Vmax change scores at final visit comparison, with a similar pattern at earlier visits.
Aortic valve disease is highly prevalent in this NAC cohort, and strongly associated with ochronosis and disease severity. Nitisinone decreases ochronosis and had a similar significant effect on Vmax.
A case report of pregnancy in untreated alkaptonuria – Focus on urinary tissue remodelling markers
2021, Molecular Genetics and Metabolism Reports
A 34-year old woman with alkaptonuria had an elective pregnancy, during which she collected urine samples over the duration of her pregnancy until parturition. She had been attending the National Alkaptonuria Centre from the age of 31 years and continued to attend after delivery for a further three annual visits. Data from her NAC visits as well as urine samples collected during pregnancy were analysed. Urine CTX-1/urine creatinine, urine αCTX-I/ urine creatinine, urine CTX-II/ urine creatinine, and urine C3M/urine creatinine all showed a rapid increase early in pregnancy, returning to baseline before increasing in late pregnancy, indicating significant remodelling of bone, subchondral bone, cartilage and other organs and connective tissue rich in collagens I, II and III. The pattern of tissue remodelling in AKU pregnancy has been described for the very first time. Further research is needed to understand pregnancy in AKU.

View all citing articles on Scopus

¹: From the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Maryland.

View full text

ReviewBiochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: Review of world literature (1584–1962)

Abstract

J. Biol. Chem.

Lancet

Lancet

J. Biol. Chem.

Am. J. Med.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Complete roentgen and ophthalmologic examination for ochronosis in two alcaptonuric children

Virginia M. Month.

Thirteen cases of alkaptonuria from one family tree with special reference to osteo-arthrosis alkaptonurica

J. Bone & Joint Surg.

Untersuchen über den Eiweisstoffwechsel, ausgeführt an einem Alkaptonuriker

Hoppe-Seyler Ztschr. Physiol. Chem.

Über Alkaptonurie

Biochem. Ztschr.

Ueber Ochronose

Ztschr. Heilk.

Beitrag zur Alkaptonurie in Kindesalter

Arch. Kinderh.

Ocular findings in hereditary ochronosis

Arch. Ophth.

Osteoartrosi alcaptonurica

Minerva med.

Corneal and conjunctival pigmentation among workers engaged in manufacture of hydroquinone

Arch. Ophth.

Una eccezionale associazione morbosa congenita: rene policistico ed alcaptonuria con ochronose

Arch. ital. pediat.

“Alkapton” in urine

Dublin J. M. Sc.

A case of alkaptonuria ochronosis from the medical service of the U.S.A. General Hospital, at the Presidio of San Francisco, California

Mil. Surgeon

Ein Fall von Alkaptonurie

Wien. med. Wchnschr.

Troubles familiaux du métabolisme des acides aminés (alcaptonurie, oligophrénie phénylpyruvique, cataracte congénitale dans une même famille)

Schweiz. med. Wchrschr.

Alkaptonuria

New England J. Med.

Metabolic study of an alkaptonuric infant

Arch. Dis. Childhood

Alkaptonuric arthritis; report of a case in a Bantu

Central African J. Med.

A case of alkaptonuria

Am. J. M. Sc.

Alcaptonuria; primer caso en la República Argentina?

Día Méd.

Über das Verhalten paraalkylierter Phenole gegen das Carosches Reagens

Beitr. deutsch. chem. Gesellsch.

Zwei Fälle von Alkaptonurie

München. med. Wchnschr.

Espondilosis ocronótica

Rev. españ. reum.

Alcaptonuria, with a report of an additional case

M. J. Australia

Zur Kenntnis der Knochen-und Gelenksveränderungen bei Alkaptonurie. Osteoarthrosis alcaptonurica (ochronotica)

Fortschr. Geb. Röntgenstrahlen.

Ueber Steinbildungen in den Harnwegen bei Ochronose (Lithiasis ochronotica)

Mitt. Grenzgeb. Med. Chir.

Ueber das Vorkommen von Brenzcatechin im Harn

Arch. ges. Physiol.

Genetic control of biochemical reactions in neurospora

Ochronosis associated with carboluria

Quart. J. Med.

A further note on ochronosis associated with carboluria

Quart. J. Med.

A case of alkaptonuria associated with ochronosis and purp ric rashes

Indian M. Gaz.

Ochronosis; report of a case

J. Louisiana M. Soc.

A case of alkaptonuria in an infant

Am. J. Dis. Child.

Alcaptonuria and ochronosis: report of five cases occurring in an American family

Arch. Int. Med.

Tyrosinosis: a search for additional cases

Review
Biochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: Review of world literature (1584–1962)