Alkaptonuria

Question 1

A 45-year-old man presents with chronic joint pain and stiffness, particularly in the knees and lower back. He mentions that his urine often darkens to a black color if left standing for several hours. On examination, there is bluish-black pigmentation of the sclera and ear cartilage. Which of the following is the most likely underlying enzymatic defect?

A) Phenylalanine hydroxylase
B) Tyrosinase
C) Homogentisic acid dioxygenase
D) Tyrosine aminotransferase
E) Fumarylacetoacetate hydrolase

Answer 1

Answer: Homogentisic acid dioxygenase

Explanation: Alkaptonuria is caused by a deficiency of homogentisate oxidase, an enzyme involved in the degradation pathway of tyrosine to fumarate. This deficiency leads to the accumulation of homogentisic acid, which deposits in connective tissues, causing ochronosis (bluish-black pigmentation of cartilage and sclera) and darkening of urine upon exposure to air. Long-term complications include debilitating arthralgias due to homogentisic acid’s toxicity to cartilage.

Incorrect Answers:

A) Phenylalanine hydroxylase deficiency causes phenylketonuria (PKU), characterized by intellectual disability and musty body odor, not ochronosis or black urine.
B) Tyrosinase deficiency leads to albinism, presenting with hypopigmented skin and hair, not ochronosis or joint pain.
D) Tyrosine aminotransferase deficiency causes tyrosinemia type II, presenting with eye pain, photophobia, and skin lesions, not ochronosis or black urine.
E) Fumarylacetoacetate hydrolase deficiency causes tyrosinemia type I, presenting with liver failure and a cabbage-like body odor, not ochronosis or black urine.

Question 2

What is the genetic inheritance pattern of Alkaptonuria?

Answer 2

Autosomal recessive.

mutation in the HGD gene.

Question 3

What enzyme deficiency causes Alkaptonuria?

Answer 3

Deficiency of homogentisate oxidase in the tyrosine degradation pathway

Question 4

What metabolite accumulates in Alkaptonuria, and why is it toxic?

Answer 4

Accumulation of homogentisic acid, which is toxic to cartilage and leads to ochronosis (black pigmentation)

Question 5

What are the hallmark clinical findings in Alkaptonuria?

Answer 5

Bluish-black connective tissue, ear cartilage, sclera (ochronosis), and black urine on exposure to air

Question 6

What happens to the urine of patients with Alkaptonuria upon prolonged exposure to air?

Answer 6

Urine turns black on prolonged exposure to air due to oxidation of homogentisic acid

Question 7

What complications can arise from Alkaptonuria?

Answer 7

Homogentisic acid deposition in cartilage leads to:

• Debilitating arthralgias and degeneration in the spine
• Mitral valve stenosis
• nephrolithiasis
• black lesion in ear and sclera

Question 8

What is the main treatment strategy for Alkaptonuria?

Answer 8

Supportive care, dietary restriction of phenylalanine and tyrosine, and symptomatic management of arthritis