Alkaptonuria

Alkaptonuria – Treatment Options

Introduction
Alkaptonuria is a rare autosomal recessive metabolic disorder caused by deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD), leading to accumulation of homogentisic acid (HGA). Excess HGA is excreted in urine (which darkens on standing) and deposits in connective tissues, a process called ochronosis. Clinical features include bluish-black pigmentation of cartilage, sclera, and skin, progressive degenerative arthritis (especially of spine and large joints), and increased risk of cardiac valve disease, renal stones, and prostate stones. There is no definitive cure; treatment focuses on symptom management, slowing disease progression, and supportive care.

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1. Lifestyle and General Measures

• Low-protein diet (phenylalanine and tyrosine restriction): Limited benefit, but may reduce homogentisic acid production.

• Avoidance of excessive physical stress: To reduce joint damage.

• Hydration and urinary alkalinization: May help prevent kidney and prostate stone formation.

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2. Pharmacological Therapy

• Nitisinone (NTBC):

  • Inhibits 4-hydroxyphenylpyruvate dioxygenase, reducing HGA production.

  • Has been shown to dramatically lower HGA levels in urine and plasma.

  • Long-term studies are ongoing to assess its effect on slowing ochronosis and arthritis.

  • Monitoring required for elevated tyrosine levels (can cause corneal deposits and keratopathy).

• Vitamin C (ascorbic acid):

  • Antioxidant, proposed to reduce HGA oxidation and ochronosis.

  • Evidence of benefit is weak; used as supportive therapy.

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3. Orthopedic and Symptomatic Management

• Pain management: NSAIDs or analgesics for joint pain.

• Physical therapy: To maintain mobility and strengthen muscles.

• Joint replacement surgery: Often required in advanced ochronotic arthritis (hip, knee, or shoulder).

• Spine surgery: For severe spinal involvement or nerve compression.

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4. Cardiac and Renal Care

• Cardiac monitoring: Echocardiography for early detection of aortic or mitral valve calcification/stenosis.

• Urologic monitoring: Screening for kidney, bladder, or prostate stones; intervention as needed.

• Renal function monitoring: To detect nephropathy early.

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5. Genetic Counseling and Support

• Family counseling: Autosomal recessive inheritance → carrier testing for siblings and offspring.

• Patient support groups: Psychological support for chronic disease management.

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Prognosis

• Patients often have normal life expectancy, but experience progressive disability from arthritis, spinal stiffness, and cardiovascular complications.

• Early diagnosis, lifestyle adjustments, and emerging therapies (like nitisinone) improve long-term outcomes.