WBR0987

Author	[[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry
Sub Category	SubCategory::General Principles
Prompt	[[Prompt::A biology student collects 50 urine samples for pH measurement and microscopic analysis. The samples are obtained from 21-year-old healthy individuals and stored in sterile cups pending analysis. The student forgets to close one cup and leaves the cup open overnight. The next day, the student returns to his bench and notices that the urine color in the open cup turned bluish/black. The student inquires about his finding and eventually discovers that the sample was collected from a subject with a genetic disorder characterized by a deficiency of an enzyme involved in tyrosine breakdown. Which of the following is a long-term complication of this genetic disorder?]]
Answer A	AnswerA::Blindness
Answer A Explanation	[[AnswerAExp::Alkaptonuria is associated with bluish/black pigmented sclerae. However, it is not associated with blindness.]]
Answer B	AnswerB::Cancer
Answer B Explanation	[[AnswerBExp::Alkaptonuria is a benign condition that is not associated with the development of cancer.]]
Answer C	AnswerC::Arthralgia
Answer C Explanation	[[AnswerCExp::Alkaptonuria is associated with arthralgia due to the excessive homogentisic acid deposition (ochronosis).]]
Answer D	AnswerD::Hearing loss
Answer D Explanation	[[AnswerDExp::Alkaptonuria is associated with pigmented ears, concha, and cerumen. However, it is not associated with hearing loss.]]
Answer E	AnswerE::Seizures
Answer E Explanation	[[AnswerEExp::Alkaptonuria is not associated with development of seizures.]]
Right Answer	RightAnswer::C
Explanation	[[Explanation::Alkaptonuria is an autosomal recessive genetic disorder characterized by deficiency of homogentisate 1,2-dioxygenase enzyme, which is involved in tyrosine breakdown to fumarate. The enzyme normally converts homogentisic acid (HGA) to maleylacetoacetic acid. In alkaptonuria, the blood and urinary concentrations of homogentisic acid (HGA) and its oxide (benzoquinone acetic acid) gradually increase and cause early ochronosis (HGA deposition) by the age of 30. Excessive ochronosis typically manifests with arthritis with lumbar spine calcification, disc flattening, and osteophyte formation. In addition, alkaptonuria results in HGA deposition that occurs in the skin, tendons, urine, eyes, and ears (resulting in bluish/black pigmentation in skin, sweat, urine, cerumen, sclera, conjunctiva, and concha due to HGA oxidation to melanin-like compounds) and valvular calcification or regurgitation, recurrent nephrolithasis, and prostate stones. The diagnosis is often made upon detection of high concentration of urinary HGA. Genetic testing confirms the diagnosis, demonstrating a mutation in the HGD gene. Management of alkaptonuria is directed towards management of manifestations and includes physical therapy and surgical interventions when needed. Educational Objective: Alkaptonuria is an autosomal recessive genetic disorder characterized by deficiency of homogentisate 1,2-dioxygenase enzyme, which is involved in tyrosine breakdown and normally converts homogentisic acid (HGA) to maleylacetoacetic acid. Excessive ochronosis (HGA deposition) typically manifests with arthritis with lumbar spine calcification, disc flattening, and osteophyte formation. In addition, alkaptonuria results in HGA deposition that occurs in the skin, tendons, urine, eyes, and ears. References: Introne WJ, Gahl WA. Alkaptonuria. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2003. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1454/ Menon IA, Persad SD, Haberman HF, et al. Characterization of the pigment from homogentisic acid and urine and tissue from an alkaptonuria patient. Biochem Cell Biol. 1991;69(4):269-73. First Aid 2014 page 111.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Alkaptonuria, WBRKeyword::Arthralgia, WBRKeyword::HGA, WBRKeyword::Complication, WBRKeyword::Urine, WBRKeyword::Dark color, WBRKeyword::Homogentisate 1, WBRKeyword::2-dioxygenase, WBRKeyword::Autosomal recessive, WBRKeyword::Genetic disorder, WBRKeyword::Ochronosis, WBRKeyword::Pigment, WBRKeyword::Pigmentation, WBRKeyword::Melanin, WBRKeyword::Tyrosine breakdown, WBRKeyword::Homogentisic acid, WBRKeyword::Fumarate, WBRKeyword::Benzoquinone acetic acid
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