1. DEFINITION AND ETIOLOGY

Definition: An autosomal recessive disorder of tyrosine metabolism characterized by the accumulation of homogentisic acid (HGA) due to an enzyme deficiency.
Enzyme Defect: Deficiency of Homogentisate 1,2-dioxygenase (HGD).
Gene: HGD gene located on chromosome 3q13.
Inheritance: Autosomal Recessive.
Epidemiology: Rare (1:250,000); higher prevalence in Slovakia and Dominican Republic.

2. PATHOPHYSIOLOGY

Metabolic Block: Failure to convert Homogentisic Acid (HGA) to Maleylacetoacetic Acid in the tyrosine catabolic pathway.
Mechanism of Damage:
1. HGA Accumulation: HGA levels rise markedly in blood and urine.
2. Oxidation: HGA oxidizes to benzoquinone acetic acid, which polymerizes to form a dark pigment (Alkapton).
3. Deposition (Ochronosis): This pigment has a high affinity for connective tissue (cartilage, skin, sclera), leading to tissue weakness and degeneration.
Urine Change: HGA in urine oxidizes upon exposure to air or alkalization, turning the urine dark brown or black.

The disease evolves in three stages:

Dark Urine: The only early symptom.
- Urine turns black upon standing for hours or if alkalinized (e.g., washing diapers with soap).
- Often unrecognized ("staining of diapers") or misdiagnosed.
General: Asymptomatic otherwise; normal growth and development.

Ochronosis: Blue-black pigmentation of connective tissues (usually appears in 3rd–4th decade).
- Ears: Slate-blue discoloration of ear cartilage; earwax is black.
- Eyes: Brown/black pigment spots on the sclera (Osler's sign) midway between cornea and canthus.
- Skin: Axillary and inguinal pigmentation.

Ochronotic Arthropathy:
- Degenerative arthritis resembling osteoarthritis but occurring at a younger age.
- Spine: Affects large joints and spine first. Loss of lumbar lordosis, ankylosis, and severe back pain.
- Knees/Hips/Shoulders: Severe secondary osteoarthritis often requiring joint replacement.
Cardiovascular: Calcification and stenosis of the aortic or mitral valves; risk of coronary artery calcification.
Genitourinary: Black prostatic calculi.

Urine Tests:
- Visual: Urine turns black on standing or adding alkali (NaOH).
- Reducing Substances: Positive Benedict’s test (HGA is a reducing agent) but Negative Clinistix (Glucose oxidase).
- Ferric Chloride Test: Transient purple-black color.
Confirmatory:
- Gas Chromatography-Mass Spectrometry (GC-MS): Detects massive elevation of Homogentisic Acid (HGA) in urine.
Radiology:
- Spine X-ray: Calcification of intervertebral discs (pathognomonic sign). Narrowing of disc spaces and vertebral fusion (Bamboo spine appearance similar to Ankylosing Spondylitis).
Genetics: Molecular analysis of HGD gene.

Goal: Reduce HGA production and manage complications.

Nitisinone (NTBC):
- Mechanism: Inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase (upstream of the defect).
- Effect: Prevents the formation of HGA.
- Clinical Use: Shown to reduce HGA levels by 95% and slow the progression of ochronosis and cardiac pathology.
- Side Effect: Causes Hypertyrosinemia (requires dietary tyrosine/phenylalanine restriction to prevent corneal crystals).

Diet: Restriction of protein (phenylalanine and tyrosine) helps reduce HGA load (difficult to maintain long-term).
Vitamin C (Ascorbic Acid): High dose; prevents oxidation of HGA to pigment but does not reduce HGA levels. Clinical efficacy is doubtful.
Orthopedic: Physiotherapy, analgesia, and joint replacement surgery (hip/knee) for severe arthritis.
Cardiac: Valve replacement for severe aortic stenosis.

Life expectancy is generally normal.
Morbidity is high due to severe, crippling arthritis and cardiovascular disease in later life.