LabMed

Alkaptonuria

At a Glance

Alkaptonuria is an inherited disorder of metabolism of the tyrosine due to a defect in the enzyme homogentisate dioxygenase (HGD). Alkaptonuria was the first inborn error of metabolism described by Sir Archibald Garrod in 1902.

Alkaptonuria is inherited in an autosomal recessive manner, meaning the individual has inherited two abnormal copies of the HGD gene (i.e., each gene contains a mutation). Both parents of an individual with alkaptonuria are carriers and do not manifest any symptoms of disease.

Because of the enzyme defect, individuals accumulate homogentistic acid and typically present in their 30s and 40s with back and joint pain similar to osteoarthritis. As homogentistic acid accumulates in the cartilage and connective tissue of the large joints, ear cartilage, skin, and sclera, these tissues in these individuals develop a grayish/black color (called onchronosis). Urine turns black when exposed to air or when alkalinized. Individuals develop joint pain, effusions, and synovitis as calcification progresses. Scoliosis and back pain progress as vertebral disks are calcified and vertebral fusion occurs. Coronary artery disease, as well as aortic and mitral valve calcification and regurgitation, may be present. Renal stones have also been reported.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Diagnosis can be made through demonstration of elevated homogentistic acid in urine organic acid analysis. Suspected individuals should have an eye exam; skeletal survey, including the spine and large joints; renal ultrasound or CT; echocardiogram; electrocardiogram; and coronary CT.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Homogentistic acid is not seen in other disorders. Elevations of 4-hydroxyphenyllactic acid and 4-hydroxyphenylpyruvic acid may be additionally seen reflecting treatment with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC).

What Lab Results Are Absolutely Confirmatory?

Confirmation of alkaptonuria is usually sufficient with urine organic acid analysis but, in certain individuals, should include DNA sequencing of the HGD gene. Targeted sequencing is available for common mutations seen in individuals of Slovak ancestry. Full sequence analysis picks up more than 90% of mutations.

Enzyme activity analysis is generally not needed.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Following diagnosis, affected individuals should be closely followed for progressive disease. Treatment is typically focused on the management of symptoms of disease. Regular physical and occupational therapy are important to maintain normal activities of daily living, but often joint replacement of the knee, hip, and shoulders is needed. Dietary restriction of tyrosine will decrease levels of homogentistic acid, but this is difficult to maintain. Treatment with nitisinone (Orfadin®, 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione, NTBC), which blocks parahydroxyphenylpyruvic acid dioxygenase, the second step in the tyrosine degradation pathway, will also decrease homogenetisate but requires dietary tyrosine restriction and is currently in long-term clinical trials. Vitamin C supplementation has also been shown to have some benefit.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Failure to demonstrate homogentistic acid effectively will rule out alkaptonuria. Other causes of onchronosis and arthritis/osteoarthritis should be considered.

Other causes of dark brown or black urine may include disorders of porphyrin metabolism, elevations of bilirubin, melanin, methemoglobin, or iron. Several drugs, such as chloroquine, hydroquinone, quinine, metronidazole, levodopa, resorcinol, or nitrofurantoin, may also cause dark urine. Dark brown or reddish urine should also prompt evaluation for rhabdomyolysis by checking a plasma creatine kinase and urine myoglobin (urine may be heme positive on urinalysis).

If clinically suspected, the Biochemical Genetics Laboratory director should be contacted to review the urine organic acid chromatogram for homogentistic acid, although levels are typically markedly elevated.

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