Alkaptonuria (AKU)

 

Alkaptonuria (AKU)

Alkaptonuria is a rare autosomal recessive metabolic disorder caused by deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD) in the tyrosine degradation pathway. The disease results in accumulation of homogentisic acid (HGA), which is excreted in urine and deposited in connective tissues.

Definition

• Inborn error of metabolism involving tyrosine and phenylalanine catabolism.

• First metabolic disorder described by Sir Archibald Garrod (1902) as an inborn error of metabolism.

Biochemical basis

Normal pathway:

Phenylalanine → Tyrosine → p-Hydroxyphenylpyruvate → Homogentisic acid → (HGD enzyme) → Maleylacetoacetate

In alkaptonuria:

• HGD deficiency blocks conversion of homogentisic acid.

• Homogentisic acid accumulates in blood and tissues.

• Oxidation of HGA forms dark polymers that deposit in connective tissue (ochronosis).

Genetics

Inheritance

Autosomal recessive

Gene

HGD

Chromosome

3q13.33

Defective enzyme

Homogentisate 1,2-dioxygenase

Accumulated metabolite

Homogentisic acid (HGA)

Pathophysiology

Excess homogentisic acid causes:

• Darkening of urine on standing (oxidation of HGA)

• Ochronosis (blue-black pigmentation of connective tissues)

• Progressive degenerative arthritis

• Calcification of cartilage and intervertebral discs

Clinical features

Early finding

• Urine turns brown or black after exposure to air.

Ochronosis

• Pigmentation of:

  • Ear cartilage

  • Sclera (especially at the limbus)

  • Nose

  • Skin over cartilage

Musculoskeletal

• Chronic back pain

• Stiffness of spine

• Osteoarthritis of knees, hips, and shoulders

• Reduced joint mobility

Cardiovascular

• Aortic or mitral valve calcification

• Aortic stenosis

• Coronary artery involvement (less common)

Renal and urological

• Kidney stones

• Prostatic calculi

Diagnosis

Urine examination

• Urine darkens on standing.

• Increased urinary homogentisic acid.

Laboratory tests

• Gas chromatography-mass spectrometry (GC-MS)

• High-performance liquid chromatography (HPLC)

Genetic testing

• Identification of HGD gene mutations.

Imaging

• Calcified intervertebral discs

• Degenerative joint disease

Differential diagnosis

• Hematuria

• Melanuria

• Porphyria

• Phenol poisoning

Treatment

There is no definitive cure, but progression can be reduced.

Medical management

• Nitisinone (reduces HGA production by inhibiting 4-hydroxyphenylpyruvate dioxygenase)

• Pain management

• Physiotherapy

Dietary measures

• Moderate restriction of phenylalanine and tyrosine intake (especially in selected patients).

Surgical treatment

• Joint replacement for severe arthritis

• Valve replacement if significant valvular disease develops

Prognosis

• Life expectancy is often near normal.

• Progressive joint disease and cardiovascular complications are major causes of morbidity.

Important examination points

• Inheritance: Autosomal recessive

• Enzyme deficiency: Homogentisate 1,2-dioxygenase

• Accumulated metabolite: Homogentisic acid

• Classical triad:

  • Black urine

  • Ochronosis

  • Arthritis

• Drug of choice: Nitisinone

Mnemonic

“BLACK HGA”

• Black urine

• Large joints affected

• Autosomal recessive

• Cartilage pigmentation (ochronosis)

• Kidney stones

HGA

• Homogentisic acid accumulation

• Gene = HGD

• Arthritis

Academic references

1. Garrod AE. The Incidence of Alkaptonuria: A Study in Chemical Individuality. Lancet. 1902.

2. Phornphutkul C, Introne WJ, Perry MB, et al. Natural history of alkaptonuria. New England Journal of Medicine. 2002;347(26):2111-2121.

3. Ranganath LR, Jarvis JC, Gallagher JA. Recent advances in management of alkaptonuria (invited review). Journal of Clinical Pathology. 2013;66:367-373.

4. National Organization for Rare Disorders (NORD). Alkaptonuria. NORD Rare Disease Database.

5. Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 8th ed. W.H. Freeman.