AUTHOR INFORMATION

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Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Edited by James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Karl S Roth, MD
Editor's Email:	James Bowman, MD

eMedicine Journal, July 2 2005, VOLUME 6, Number 7

INTRODUCTION

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Background: Alkaptonuria is one of 4 disorders originally defined as an inborn error of metabolism by Archibald Garrod in his Croonian Lectures of 1902. The hallmark of the disease is passage of urine that becomes black when left standing. Garrod identified a familial pattern of inheritance and concluded that an inherited biochemical abnormality must result in the passage of an abnormal intermediate in the urine. That Garrod conceived of an intermediate is remarkable given that virtually nothing was known of serial biochemical reactions in the metabolic disposal of nutrient substances at that time.

Pathophysiology: The defect lies in the catabolic pathway of tyrosine, which contains a parahydroxylated ring structure. In a poorly understood complex reaction, the enzyme phenylpyruvic acid oxidase is thought simultaneously to move the pyruvic acid side chain, to decarboxylate it, and to add an additional hydroxyl group to the ring. The product, homogentisic acid, is actually ortho-meta-dihydroxyphenylacetic acid. A deficiency of the hepatic enzyme homogentisate 1,2-dioxygenase(HGO)forces the accumulation of homogentisic acid, which is rapidly cleared in the kidney and excreted.

Upon contact with air, homogentisic acid is oxidized to form a pigmentlike polymeric material responsible for the black color of standing urine. Although homogentisic acid blood levels are kept very low through rapid kidney clearance, over time homogentisic acid is deposited in cartilage throughout the body and is converted to the pigmentlike polymer through an enzyme-mediated reaction that occurs chiefly in collagenous tissues. As the polymer accumulates within cartilage, a process that takes many years, the normally transparent tissues become slate blue, an effect ordinarily not seen until adulthood.

The earliest sign of the disorder is the tendency for diapers to stain black. Throughout childhood and most of early adulthood, an asymptomatic, slowly progressive deposition of pigmentlike polymer material into collagenous tissues occurs.

In the fourth decade of life, external signs of pigment deposition, called ochronosis, begin to appear. The slate blue, gray, or black discoloration of sclerae and ear cartilage is indicative of widespread staining of the body tissues, particularly cartilage. The hips, knees, and intervertebral joints are affected most commonly and show clinical symptoms resembling rheumatoid arthritis. Because of calcifications that occur in these sites, however, the radiologic picture is more consistent with osteoarthritis.

Despite many speculations that this polymer deposition is associated with cardiac pathology, no reports of mortality directly related to the homozygous state for alkaptonuria exist. Reports exist of calcification and stenosis of the aortic annulus leading to coronary artery disease, and the risk of myocardial infarction is higher than normal in older patients with ochronosis.

Molecular analysis of the HGO gene shows a wide spectrum of mutation. Although no correlation has so far been made between the molecular nature of the HGO mutation and its clinical phenotype, the wide variability of mutational phenomena could certainly help explain the clinical variability in this disease. Approximately 70 separate mutations have thus far been reported.

Frequency:

• In the US: As Garrod suggested, alkaptonuria is an autosomal recessive genetic trait. The true frequency of alkaptonuria cannot be given with certainty for a number of reasons. These include the fact that newborn screening for alkaptonuria is much less widely practiced than that for phenylketonuria and the fact that some carriers express 50% or more of normal enzyme activity and do not manifest abnormal findings even with tyrosine loading. To further complicate this picture, reports in the literature indicate wide variability in incidence, particularly where gene pools are highly restricted. In certain areas, an incidence rate as high as 1 in every 25,000 live births has been reported; worldwide it is certainly far lower.

Mortality/Morbidity: Life expectancy is normal; however, associated morbidity can be significant. Early involvement of the intervertebral discs at the thoracic and lumbar levels is very common, occurring in approximately 50% of affected individuals. Typically, significant back pain begins from age 30 years. The large joints (knee, shoulder and hip) are very frequently involved; at least half of all patients undergo joint replacement by their mid 50s. Achilles tendon involvement is also common and may result in tearing. Involvement of the aortic and/or mitral valve leaflets is common, and calcifications of the coronary arteries occurs in half of all patients prior to age 60.

Sex:

• The distribution of this disease is equal in males and females because it is an autosomal recessive trait.

• Males tend to have an earlier onset of arthritic symptoms with a greater degree of severity than females, although the reason for this difference is unclear.

Age:

• Because it is a genetic disorder, the deficiency of the homogentisate 1,2-dioxygenase enzyme is present from conception.

• Clinical symptoms, aside from dark-stained diapers, are generally present only after the third decade of life.

CLINICAL

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History:

• Since alkaptonuria is autosomal recessive, a family pedigree, in all likelihood, would reveal no other affected individuals. However, since many individuals are asymptomatic, it could be argued that the low frequency of affected family members may be because of lack of ascertainment.



• Despite the intrinsic biochemical defect and the expectation that all affected individuals should excrete urine that becomes black when left standing, a significant number of people with alkaptonuria do not present with this clinical finding.



• The most common history is one of arthritic symptoms confined chiefly to the spine, hips, and knees. Virtually all people with alkaptonuria eventually experience arthritis. Onset of thoracic and/or lumbar back pain around age thirty is frequent.

Physical:

• Slate blue or gray discoloration may be found in the sclerae or ear cartilage.



• Calcifications may be palpable in the discolored areas, particularly in the cartilage of the ear.



• Joint mobility diminishes, as in osteoarthritis. Ankylosis may be present. Spontaneous fusion of one or more discs may occur, with consequent diminished spinal flexion. Joint effusions, particularly in the knee are common and range of motion may be significantly diminished.



• Signs of aortic or mitral valvulitis may be present.

Causes:

• Inability to convert homogentisic acid to maleylacetoacetic acid results in accumulation of the former. Homogentisic acid is subsequently converted to benzoquinone acetic acid and spontaneously polymerized. Deposition of the polymer in association with cartilage is the initiating pathophysiologic cause of the arthritis.



• Although unproven, the deposition of polymer is assumed to also cause an inflammatory response that results in calcium deposition in affected joints.



• Exogenous agents including quinacrine (Atabrine), carbolic acid, and hydroquinone have been reported to cause an ochronotic picture without the joint disease. All have been reversible.

DIFFERENTIALS

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Mitral Valve Insufficiency
Porphyria, Acute

Other Problems to be Considered:

Aortic stenosis, rheumatic
Osteoarthritis
Mitral stenosis, rheumatic

WORKUP

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Lab Studies:

• Homogentisic acid can be identified in urine using gas chromatography—mass spectroscopy. Spectrophotometric quantitation shows two orders of magnitude elevations above normal.



• Since many patients present without dark urine, looking for homogentisate in all patients with radiographic evidence of osteoarthritis may be advisable.



• After DNA extraction from whole blood, screening for mutations can be performed with PCR technique.

Imaging Studies:

• Radiographs


• • A spinal radiograph reveals disk degeneration combined with dense calcification, particularly in the lumbar area.
  
  
  
  • A chest radiograph is advised to assess for possible involvement of aortic or mitral valves.
  
  
  
  • In affected individuals over 55, CT scanning may provide evidence of coronary artery calcifications.
  
  
  

Other Tests:

• Electrocardiography may be advisable, with particular attention directed at any signs of myocardial insufficiency.

Procedures:

• Other studies and procedures should be directed at the joint disease itself. Joint replacements may become necessary in severely affected larger joints.

TREATMENT

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Medical Care:

• In infancy, a history of dark-stained diapers should alert the physician.



• Infants, young children, and asymptomatic young adults can be evaluated with simple urine testing on an outpatient basis.



• Medical therapy is used to ameliorate the rate of pigment deposition. This minimizes articular and cardiovascular complications in later life.



• Reduction of phenylalanine and tyrosine has reportedly reduced homogentisic acid excretion. Whether a mild dietary restriction from early in life would avoid or minimize later complications is not known, but such an approach is reasonable.



• Vitamin C, up to 1 g/d, is recommended for older children and adults. The mild antioxidant nature of ascorbic acid helps to retard the process of conversion of homogentisate to the polymeric material that is deposited in cartilaginous tissues.



• Limited use of nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, which mediates formation of homogentisic acid, has been reported. Urinary homogentisate excretion was markedly reduced, but safety of prolonged use is still an open question.

Surgical Care:

• Older individuals may require removal of lumbar discs with fusion.



• Hip, shoulder, or knee joint replacement may be necessary.

Consultations:

• Biochemical geneticist



• Neurosurgeon



• Orthopedist



• Cardiologist for older individuals

Diet:

• Reduction of phenylalanine and tyrosine reportedly reduced homogentisic acid excretion in the urine of a child. In an adult, a similar restriction reportedly had no effect on excretion of the abnormal metabolite. Whether a mild dietary restriction from early in life would avoid or minimize later complications is not known, but such an approach is reasonable.



• Vitamin C, up to 1 g/d, is recommended for older children and adults.

MEDICATION

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No medications are known to be useful in managing alkaptonuria. Vitamin C, up to 1 g/d, is recommended for older children and adults.

Drug Category: Vitamins -- Organic substances required by the body in small amounts for various metabolic processes.

Drug Name	Ascorbic acid (Cecon, Cevalin, Cevi-Bid, Ce-Vi-Sol) -- The mild antioxidant nature of ascorbic acid helps to retard the process of conversion of homogentisate to the polymeric material that is deposited in cartilaginous tissues.
Adult Dose	1 g/d PO
Pediatric Dose	Older children: 1 g/d PO
Contraindications	Pregnancy, if large doses administered
Interactions	Decreases effects of warfarin and fluphenazine; increases aspirin levels
Pregnancy	A - Safe in pregnancy
Precautions	Pregnancy category C with prolonged use of doses greater than RDA for pregnancy (ie, >80-85 mg/d), the fetus adapts to high vitamin C levels resulting in scorbutic condition following birth; prolonged high doses may cause renal calculi, especially in people with diabetes; patient on sodium restrictive diet or taking anticoagulants should not take large doses (ie, > 1 g) for prolonged periods

Drug Category: Enzyme inhibitors

Drug Name	Nitisinone (Orfadin) -- This compound has seen very restricted use in experimental treatment. It is an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, which mediates formation of homogentisic acid.
Adult Dose	0.35 mg twice a day PO
Pediatric Dose	N/A
Contraindications	Hypersensitivity
Interactions	N/A
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Elevated serum tyrosine; corneal toxicity

FOLLOW-UP

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Further Inpatient Care:

• If treatment is successful, the patient does not need to be admitted.

Further Outpatient Care:

• Carefully monitor diet with periodic measurement of plasma amino acid levels to avoid phenylalanine deficiency.

In/Out Patient Meds:

• Medications are not needed, although large doses of supplemental vitamin C may be beneficial.

Transfer:

• Transfer is not required if appropriate outpatient consultation and follow-up are obtained.

Deterrence/Prevention:

• High-protein diets should be avoided.



• No exercise restriction is necessary in the absence of cardiovascular disease.

Complications:

• Calcification of the ear cartilage



• Calcified lumbar discs



• Severe arthritis



• Ankylosis



• Aortic or mitral valvulitis

Prognosis:

• Life expectancy is normal.



• Risk of myocardial infarction later in life is increased.

Patient Education:

• Family members should be referred for genetic counseling.



• The need for rigorous follow-up with a biochemical geneticist should be emphasized.



• For excellent patient education resources, visit eMedicine’s Arthritis Center.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Patients have been misdiagnosed with acute intermittent porphyria.

Special Concerns:

• Many affected individuals are asymptomatic. Therefore, all siblings of a newly diagnosed patient should be biochemically screened.



• Patients treated with dietary phenylalanine and tyrosine restrictions must be biochemically monitored.

TEST QUESTIONS

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CME Question 1: Which of the following is not a complication of alkaptonuria?

A: Aortic valvular stenosis
B: Hypertension
C: Calcification of the ear cartilage
D: Calcified lumbar discs
E: Ankylosis

The correct answer is B: Hypertension is not a known complication, although its presence could significantly add to the risk of myocardial infarction due to coronary artery calcification, which is typically seen in alkaptonuria before age 60.

CME Question 2: Which of the following is the preferred management of alkaptonuria?

A: Elimination of phenylalanine
B: Large doses of vitamin B-6
C: Restriction of phenylalanine and tyrosine
D: Vitamin C 1 g/d
E: Restriction of phenylalanine and tyrosine plus vitamin C 1 g/d

The correct answer is E: Reduction of phenylalanine and tyrosine reportedly reduced homogentisic acid excretion in the urine of a child. In an adult, a similar restriction reportedly had no effect on excretion of the abnormal metabolite. Whether a mild dietary restriction from early in life would avoid or minimize later complications is not known, but such an approach is reasonable. Administration of vitamin C, up to 1 g/d, is recommended for older children and adults.

Pearl Question 1 (T/F): A frequent early sign of alkaptonuria is darkened cartilage of the ear.

The correct answer is False: The earliest sign of the disorder is the tendency for diapers to stain black when left standing. Throughout childhood and most of early adulthood, an asymptomatic, slowly progressive deposition of polymer pigment material into collagenous tissues is observed.

Pearl Question 2 (T/F): In alkaptonuria, the typical and highly suggestive radiograph finding in the lumbar spine is kyphoscoliosis.

The correct answer is False: Spinal radiographs of patients with alkaptonuria reveal disk degeneration combined with dense calcification, particularly in the lumbar area.

Pearl Question 3 (T/F): The only useful therapeutic agent in alkaptonuria is vitamin C.

The correct answer is False: Administration of vitamin C, up to 1 g/d, is recommended for older children and adults. No other known medications are useful in treating patients with alkaptonuria, although experimental trials of an enzyme inhibitor(nitisinone) to reduce production of homogentisic acid are ongoing.

Pearl Question 4 (T/F): The most serious potential long-term consequence of alkaptonuria is arthritic joint disease.

The correct answer is False: Aortic stenosis secondary to ochronosis of the aortic valve is the most serious potential complication of alkaptonuria. A further consequence, as for aortic stenosis of any etiology, is the potential for coronary artery insufficiency. However, most patients eventually require major joint replacements.

BIBLIOGRAPHY

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• de Haas V, Carbasius Weber EC, de Klerk JB, et al: The success of dietary protein restriction in alkaptonuria patients is age-dependent. J Inherit Metab Dis 1998 Dec; 21(8): 791-8[Medline].
• Fisher AA, Davis MW: Alkaptonuric ochronosis with aortic valve and joint replacements and femoral fracture: A case report and literature review. Clin Med Res 2004; 2: 209-215.
• Garrod AE: The incidence of alkaptonuria: a study in chemical individuality. Lancet II 1902; 1616-20.
• Keller JM, Macaulay W, Nercessian OA: New developments in ochronosis: review of the literature. Rheumatol Int 2005; 25: 81-85.
• Levine HD, Parisi AF, Holdsworth DE, Cohn LH: Aortic valve replacement for ochronosis of the aortic valve. Chest 1978 Oct; 74(4): 466-7[Medline].
• Lorenzini S, Mannoni A, Selvi E: Alkaptonuria. N Engl J Med 2003 Apr 3; 348(14): 1408; author reply 1408[Medline].
• Mayatepek E, Kallas K, Anninos A, Muller E: Effects of ascorbic acid and low-protein diet in alkaptonuria. Eur J Pediatr 1998 Oct; 157(10): 867-8[Medline].
• O'Brien W, La Du BN, Bunim JJ: Biochemical, pathological and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: review of the world literature (1584-1962). Am J Med 1963; 34: 813-38.
• Phornphutkul C, Introne WJ, Perry MB: Natural history of alkaptonuria. N Engl J Med 2002; 347: 2111-2121.
• Suwannarat P, O'Brien K, Perry MB: Use of ntitisonone in patients with alkaptonuria. Metabolism 2005; 54: 719-728.
• Vavuranakis M, Triantafillidi H, Stefanadis C, Toutouzas P: Aortic stenosis and coronary artery disease caused by alkaptonuria, a rare genetic metabolic syndrome. Cardiology 1998; 90(4): 302-4[Medline].
• Wolff JA, Barshop B, Nyhan WL, et al: Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr Res 1989 Aug; 26(2): 140-4[Medline].

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