Editing Alkaptonuria

{{Infobox medical condition (new)
| name            = Alkaptonuria
| synonyms        = Black urine disease, black bone disease, alcaptonuria
| image           = OCHRONOSIS.jpg
| caption         = Pigmentation of the face in alkaptonuria
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'''Alkaptonuria''' is a rare inherited genetic disease which is caused by a [[mutation]] in the ''HGD'' [[gene]] for the [[enzyme]] [[homogentisate 1,2-dioxygenase]] ({{EC number|1.13.11.5}}); if a person inherits an abnormal copy from both parents (it is a [[dominance relationship|recessive condition]]), the body accumulates an intermediate substance called [[homogentisic acid]] in the blood and tissues. Homogentisic acid and its [[oxide|oxidized form]] ''alkapton'' are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to [[cartilage]] ([[ochronosis]], leading to [[osteoarthritis]]) and [[heart valve]]s, as well as precipitating as [[kidney stone]]s and stones in other organs. Symptoms usually develop in people over 30 years old, although the dark discoloration of the urine is present from birth.

Apart from treatment of the complications (such as [[analgesia|pain relief]] and [[Arthroplasty|joint replacement]] for the cartilage damage), the drug [[nitisinone]] has been found to suppress homogentisic acid production, and research is ongoing as to whether it can improve symptoms. Alkaptonuria is a [[rare disease]]; it occurs in one in 250,000 people, but is more common in [[Slovakia]] and the [[Dominican Republic]].

==Signs and symptoms==
[[File:Ochronosis, Intervertebral discs Calcification. ZB.jpg|thumb|Intervertebral discs calcification due to ochronosis]]
Patients with alkaptonuria are [[asymptomatic]] as children or young adults, but their urine may turn brown or even inky black if collected and left exposed to open air.<ref name=Ranganath>{{cite journal |vauthors=Ranganath LR, Jarvis JC, Gallagher JA |title=Recent advances in management of alkaptonuria (invited review; best practice article) |journal=J. Clin. Pathol. |volume=66 |issue=5 |pages=367–73 |date=May 2013  |pmid=23486607 |doi=10.1136/jclinpath-2012-200877|s2cid=24860734 }}</ref> Pigmentation may be noted in the cartilage of the ear and other cartilage,<ref name=Ranganath/><ref name=Speeckaert>{{cite journal |vauthors=Speeckaert R, Van Gele M, Speeckaert MM, Lambert J, van Geel N |title=The biology of hyperpigmentation syndromes |journal=Pigment Cell Melanoma Res |volume=27 |issue=4 |pages=512–24 |date=July 2014  |pmid=24612852 |doi=10.1111/pcmr.12235 |doi-access=free }}</ref> and the [[sclera]] and [[corneal limbus]] of the eye.<ref>{{Cite journal|title = On the ocular findings in ochronosis: a systematic review of literature|journal = BMC Ophthalmology|date = 2014-01-30|issn = 1471-2415|pmc = 3915032|pmid = 24479547|pages = 12|volume = 14|issue = 1|doi = 10.1186/1471-2415-14-12|language = en|first1 = Moritz|last1 = Lindner|first2 = Thomas|last2 = Bertelmann | doi-access=free }}</ref>

After the age of 30, people begin to develop pain in the weight-bearing joints of the spine, hips, and knees. The pain can be severe to the point that interferes with activities of daily living and may affect the ability to work. Joint-replacement surgery (hip and shoulder) is often necessary at a relatively young age.<ref name=Ranganath/> In the longer term, the involvement of the spinal joints leads to reduced movement of the rib cage and can affect breathing.<ref name=Ranganath/> [[Bone mineral density]] may be affected, increasing the risk of [[bone fracture]]s, and rupture of tendons and muscles may occur.<ref name=Ranganath/>

[[Valvular heart disease]], mainly calcification and regurgitation of the [[aortic valve|aortic]] and [[mitral valve]]s, may occur, and in severe and progressive cases, [[valve replacement]] may be necessary. [[Cardiac arrhythmia|Irregularities in the heart rhythm]] and [[heart failure]] affect a significant proportion of people with alkaptonuria (40% and 10%, respectively).<ref name=Ranganath/> Hearing loss affects 40% of people. Also, a propensity to developing [[kidney stone]]s exists, and eventually also [[gallstone]]s and stones in the [[prostate]] and [[salivary gland]]s ([[sialolithiasis]]) can occur.<ref name=Ranganath/>

==Pathophysiology==
[[File:Homogentisic acid.svg|thumb|right|Chemical [[skeletal formula]] of homogentisic acid, which accumulates in the body fluids of people with alkaptonuria.]]
All people carry in their DNA two copies (one received from each parent) of the gene ''HGD'', which contains the genetic information to produce the enzyme [[homogentisate 1,2-dioxygenase]] (HGD) which can normally be found in numerous tissues in the body (liver, kidney, small intestine, colon, and prostate). In people with alkaptonuria, both copies of the gene contain abnormalities that mean that the body cannot produce an adequately functioning enzyme.<ref name=Zatkova2011>{{cite journal |author =Zatkova A |title=An update on molecular genetics of Alkaptonuria (AKU) |journal=J. Inherit. Metab. Dis. |volume=34 |issue=6 |pages=1127–36 |date=December 2011  |pmid=21720873 |doi=10.1007/s10545-011-9363-z |s2cid=32395461 }}</ref> ''HGD'' mutations are generally found in certain parts ([[exon]]s 6, 8, 10, and 13), but a total of over 100 abnormalities has been described throughout the gene.<ref name=Zatkova2011/> The normal HGD enzyme is a hexamer (it has six subunits) that are organized in two groups of three (two trimers) and contains an [[Ferrous|iron atom]]. Different mutations may affect the structure, function, or solubility of the enzyme.<ref name=Zatkova2011/> Very occasionally, the disease appears to be transmitted in an autosomal-dominant fashion, where a single abnormal copy of ''HGD'' from a single parent is associated with alkaptonuria;  other mechanisms or defects in other genes possibly are responsible in those cases.<ref name=Zatkova2011/>

[[File:Inborn errors of metabolism of phenylalanine and tyrosine.svg|800px|centre|thumb|Pathophysiology of alkaptonuria (AKU) is due to the absence of functional homogentisate dioxygenase (HGD) in the liver.]]
The HGD enzyme is involved in the metabolism (chemical processing) of the [[aromatic amino acids]] [[phenylalanine]] and [[tyrosine]]. Normally, these enter the bloodstream through protein-containing food and the natural turnover of protein in the body. Tyrosine is specifically required for a number of functions, such as [[hormone]]s (e.g. [[thyroxine]], the thyroid hormone), [[melanin]] (the dark pigment in the skin and hair), and certain proteins, but the vast majority (over 95%) is unused and is metabolized through a [[Tyrosine#Degradation|group of enzymes]] that eventually generate [[acetoacetate]] and [[malate]].<ref name=Ranganath/> In alkaptonuria, the HGD enzyme cannot metabolize the homogentisic acid (generated from tyrosine) into [[4-maleylacetoacetate]], and homogentisic acid levels in the blood are 100-fold higher than would normally be expected, despite the fact that a substantial amount is eliminated into the urine by the kidneys.<ref name=Ranganath/>

The homogentisic acid is converted to the related substance benzoquinone acetic acid  which forms [[polymer]]s that resemble the skin pigment melanin. These are deposited in the [[collagen]], a connective tissue protein, of particular tissues such as cartilage. This process is called ochronosis (as the tissue looks [[ochre]]); ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage.<ref name=Ranganath/>

==Diagnosis==
[[File:Alkaptonuria.jpg|thumb|right|Urine of a 4-month-old baby with dark urine (on the left) after 10% ammonia and 3% silver nitrate were added. The tube in the middle is a normal control. Color change on alkalinization is not a specific test, and confirmatory investigations are needed.<ref name=Ranganath/>]]

If the diagnosis of alkaptonuria is suspected, it can be confirmed or excluded by collecting urine for 24 hours and determining the amount of homogentisic acid by means of [[chromatography]]. No assay of HGA in blood has been validated.<ref name=Ranganath/> The Genetic Testing Registry  is used for maintaining information about the genetic test for alkaptonuria.<ref>{{cite web|author=Anonymous | url=https://rarediseases.info.nih.gov/diseases/5775/alkaptonuria|date=18 March 2016| access-date=17 April 2018 | title=Alkaptonuria}}</ref>

The severity of the symptoms and response to treatment can be quantified through a validated questionnaire titled the AKU Severity Score Index. This  assigns scores to the presence of particular symptoms and features, such as the presence of eye and skin pigmentation, joint pain, heart problems, and organ stones.<ref name=Ranganath/>

==Treatment==
In 2012 the  AKU Society formed a consortium called  DevelopAKUre to prove that [[nitisinone]], a drug already approved for treating another rare disease,  hereditary tyrosinaemia type-1, could be repurposed to treat AKU.{{cn|date=October 2024}}

The DevelopAKUre trials concluded in 2019 and successfully illustrated that nitisinone lowered levels of [[Homogentisic acid|homogentisic acid (HGA)]], the acid that causes the damage in AKU, by 99% which effectively halts the progression of the disease. In 2020, the [[European Medicines Agency]] and the [[European Commission]] approved the use of nitisinone for treating AKU making the treatment available to patients across the Europe and the UK.{{cn|date=October 2024}}

Nitisinone has revolutionised the treatment of AKU, however it can lead to a condition known as hypertyrosinaemia<ref>{{cite web | url=https://pubmed.ncbi.nlm.nih.gov/35201733 | pmid=35201733 | year=2023 | last1=Adnan | first1=M. | last2=Puranik | first2=S. | title=Hypertyrosinemia | publisher=StatPearls }}</ref> caused by elevated levels of the amino acid [[tyrosine]]. Hypertyrosinaemia can lead to serious symptoms including corneal keratopathy,<ref>{{cite journal | pmc=6122027 | year=2017 | last1=White | first1=A. | last2=c. Tchan | first2=M. | title=Nitisinone-Induced Keratopathy in Alkaptonuria: A Challenging Diagnosis Despite Clinical Suspicion | journal=Jimd Reports | volume=40 | pages=7–9 | doi=10.1007/8904_2017_56 | pmid=28879639 | isbn=978-3-662-57879-7 }}</ref> dermal toxicity,<ref>{{cite journal | pmc=4241204 | year=2014 | last1=Stewart | first1=R. M. | last2=Briggs | first2=M. C. | last3=Jarvis | first3=J. C. | last4=Gallagher | first4=J. A. | last5=Ranganath | first5=L. | title=Reversible Keratopathy Due to Hypertyrosinaemia Following Intermittent Low-Dose Nitisinone in Alkaptonuria: A Case Report | journal=Jimd Reports | volume=17 | pages=1–6 | doi=10.1007/8904_2014_307 | pmid=24997710 | isbn=978-3-662-44577-8 }}</ref>  neurodevelopment delay issues in children,<ref>{{cite journal | pmc=6488549 | year=2019 | last1=Davison | first1=A. S. | last2=Strittmatter | first2=N. | last3=Sutherland | first3=H. | last4=Hughes | first4=A. T. | last5=Hughes | first5=J. | last6=Bou-Gharios | first6=G. | last7=Milan | first7=A. M. | last8=Goodwin | first8=R. J. | last9=Ranganath | first9=L. R. | last10=Gallagher | first10=J. A. | title=Assessing the effect of nitisinone induced hypertyrosinaemia on monoamine neurotransmitters in brain tissue from a murine model of alkaptonuria using mass spectrometry imaging | journal=Metabolomics | volume=15 | issue=5 | page=68 | doi=10.1007/s11306-019-1531-4 | pmid=31037385 }}</ref> and alterations of wider metabolism.<ref>{{cite journal | pmc=9170613 | year=2021 | last1=Norman | first1=B. P. | last2=Davison | first2=A. S. | last3=Hughes | first3=J. H. | last4=Sutherland | first4=H. | last5=Wilson | first5=P. J. | last6=Berry | first6=N. G. | last7=Hughes | first7=A. T. | last8=Milan | first8=A. M. | last9=Jarvis | first9=J. C. | last10=Roberts | first10=N. B. | last11=Ranganath | first11=L. R. | last12=Bou-Gharios | first12=G. | last13=Gallagher | first13=J. A. | title=Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism | journal=Genes & Diseases | volume=9 | issue=4 | pages=1129–1142 | doi=10.1016/j.gendis.2021.02.007 | pmid=35685462 }}</ref> There is currently no effective treatment for hypertyrosinaemia other than limiting protein intake. Due to the potential side-effects of nitisinone treatment it is currently only prescribed to children aged 16 and above in Europe and patients will then have to follow a protein restricted diet and closely manage their tyrosine levels through frequent monitoring.{{cn|date=October 2024}}

==Prognosis==
Alkaptonuria does not appear to affect life expectancy, although the latest study on the topic is from 1985.<ref name=Ranganath/> The main impact is on quality of life; many people with alkaptonuria have disabling symptoms such as pain, poor sleep, and breathing symptoms. These generally start in the fourth decade. The typical age at requiring joint replacement surgery is 50–55 years.<ref name=Ranganath/>

==Epidemiology==
In most ethnic groups, the prevalence of alkaptonuria is between 1:100,000 and 1:250,000.<ref name=Zatkova2011/> In Slovakia and the Dominican Republic, the disease is much more common, with prevalence estimated at 1:19,000 people.<ref name=Zatkova2011/> As for Slovakia, this is not the result of a single mutation, but due to a group of 12 mutations in specific "hot spots" of the ''HGD'' gene.<ref name=Zatkova2011/> The Slovakian clustering probably arose in a small area in the northwest of the country and spread after the 1950s due to migration.<ref name=Zatkova2011/>

==History==
Alkaptonuria was one of the four diseases described by [[Archibald Edward Garrod]], as being the result of the accumulation of intermediates due to metabolic deficiencies. He linked [[ochronosis]] with the accumulation of alkaptans in 1902,<ref name=Zatkova2011/><ref>{{cite journal|author =Garrod AE|year=1902|title=The incidence of alkaptonuria: a study in clinical individuality|journal=Lancet|volume=2|pages=1616–20|doi=10.1016/S0140-6736(01)41972-6|pmid=8784780|issue=4137|pmc=2230159}} Reproduced in {{cite journal | author=Garrod AE| title=The incidence of alkaptonuria: a study in chemical individuality. 1902 classical article|journal=Yale Journal of Biology and Medicine | volume=75 | pages=221–31 |year=2002| pmid=12784973 | issue=4 | pmc=2588790}}</ref> and his views on the subject, including its mode of heritance, were summarized in a 1908 [[Croonian Lecture]] at the [[Royal College of Physicians]].<ref name=Zatkova2011/><ref>{{cite journal|author =Garrod AE|year=1908|title=The Croonian lectures on inborn errors of metabolism: lecture II: alkaptonuria|journal=Lancet|volume=2|issue= 4428|pages=73–79|doi=10.1016/s0140-6736(01)78041-5 |url=https://zenodo.org/record/1576909}}</ref><ref>{{cite book | author=Garrod AE | title=Inborn errors of metabolism | publisher=Oxford University Press | date=1909| ol=7116744M}}</ref> The genetics of it was also studied by [[William Bateson]] in 1902.<ref>{{cite book |last1=Kean |first1=Sam |title=The Violinist's thumb |pages=57–58}}</ref>

The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in 1958.<ref name=Zatkova2011/><ref>{{cite journal |vauthors=La Du BN, Zannoni VG, Laster L, Seegmiller JE |title=The nature of the defect in tyrosine metabolism in alcaptonuria |journal=Journal of Biological Chemistry |volume=230 |issue=1 |pages=251–60 |date=1 January 1958 |doi=10.1016/S0021-9258(18)70560-7 |pmid=13502394 |doi-access=free }}</ref> The genetic basis was elucidated in 1996, when'' HGD'' mutations were demonstrated.<ref name=Zatkova2011/><ref>{{cite journal |vauthors=Fernández-Cañón JM, Granadino B, Beltrán-Valero de Bernabé D |title=The molecular basis of alkaptonuria |journal=Nature Genetics |volume=14 |issue=1 |pages=19–24 |year=1996 |pmid=8782815 |doi=10.1038/ng0996-19|s2cid=7809387 }}</ref>

A 1977 study showed that an ochronotic Egyptian [[mummy]] had probably suffered from alkaptonuria.<ref>{{cite journal |vauthors=Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A |title=Biochemical identification of homogentisic acid pigment in an ochronotic egyptian mummy |journal=Science |volume=197 |issue=4303 |pages=566–68 |year=1977 |pmid=327549 |doi= 10.1126/science.327549|bibcode=1977Sci...197..566S }}</ref><ref>{{Cite journal  | last1 = Lee | first1 = SL. | last2 = Stenn | first2 = FF. | title = Characterization of mummy bone ochronotic pigment. | journal = JAMA | volume = 240 | issue = 2 | pages = 136–38 |date=Jul 1978  | pmid = 351220 |doi=10.1001/jama.1978.03290020058024}}</ref>

==Society and culture==
The [https://akusociety.org/ AKU Society] is a charity which support all people affected by AKU. Based in the UK, the charity can be [https://akusociety.org/find-us/ contacted here]. It has a number of [https://akusociety.org/information-and-support/information-for-international-patients/ international AKU sister societies] who provide support across the world.{{cn|date=October 2024}}

The AKU Society works to provide information, education, support, and helps people to access treatment for their condition. A number of support resources are [https://akusociety.org/information-and-support/aku-downloadable-resources/ available here] and they have also been  translated into all major languages here{{cn|date=October 2024}}

As part of the [https://akusociety.org/aku-clinical-trials/ DevelopAKUre] consortium, the AKU Society successfully proved the effectiveness of [[nitisinone]] to treat AKU, leading to the drug receiving approval from the [[European Medicines Agency]] in 2020. The AKU Society continues to drive research into developing potential treatments and cures for AKU working closely with a number of universities across the world.{{cn|date=October 2024}}

==Research directions==
Research collaborations by several national centres have been established to find a more definitive treatment for alkaptonuria. This has included studies on the use of nitisinone and investigations into antioxidants to inhibit ochronosis.<ref name=Zatkova2011/> The ideal treatment would replace HGD enzyme function without accumulating other substances.<ref name=Ranganath/>

== See also ==
* [[List of cutaneous conditions]]
* [[List of radiographic findings associated with cutaneous conditions]]

==References==
{{Reflist}}

== External links ==
{{Medical resources
| DiseasesDB      = 409
| ICD10           = {{ICD10|E|70|2|e|70}} ([[ILDS]] E70.210)
| ICD9            = {{ICD9|270.2}}
| OMIM            = 203500
| MedlinePlus     = 001200
| eMedicineSubj   = ped
| eMedicineTopic  = 64
| MeshID          = D000474
| GeneReviewsNBK  = NBK1454
| GeneReviewsName = Alkaptonuria
| Orphanet        = 56
}}

{{Amino acid metabolic pathology}}

[[Category:Amino acid metabolism disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Skin conditions resulting from errors in metabolism]]
[[Category:Rare diseases]]