What is the diagnosis, treatment, and management of Alkaptonuria, a rare genetic disorder affecting amino acid breakdown, in patients presenting with darkening of the urine, ochronosis, and joint pain?

Alkaptonuria: Diagnosis, Treatment, and Management

Overview and Pathophysiology

Alkaptonuria is a rare autosomal recessive disorder of tyrosine metabolism caused by deficiency of homogentisate 1,2-dioxygenase (HGD), resulting in accumulation and excretion of gram quantities of homogentisic acid (HGA) in the urine, with progressive deposition of oxidized HGA polymers in connective tissues causing ochronosis and severe arthropathy. 1

• The enzymatic defect is caused by homozygous or compound heterozygous mutations in the HGD gene 1
• Prevalence is extremely low at 1:100,000-250,000 in most populations, with higher rates in Slovakia (1:19,000) and Dominican Republic 1
• HGD is the third enzyme in tyrosine catabolism; its deficiency does not cause hypertyrosinemia, unlike other tyrosine pathway disorders 2

Clinical Presentation

The disease manifests in three chronological stages:

Early Manifestation (Birth/Infancy)

• Darkening of urine upon standing or alkalinization is often the first sign, appearing at birth or in early infancy 1, 3
• Urine may appear normal when fresh but darkens to brown-black when exposed to air or alkaline conditions 1

Middle Age (Around 30 Years)

• Ochronosis develops: blue-black pigmentation of connective tissues, clinically visible in the ear cartilage and sclera 1, 3
• Cutaneous and cartilaginous pigmentation becomes apparent 4

Late Manifestation (Around 50 Years)

• Severe ochronotic arthropathy affecting spine and large joints (hips, knees, shoulders) 1, 5
• Progressive joint pain and stiffness, often debilitating 6, 5
• Cardiovascular complications, particularly aortic stenosis and valvular disease 4, 5
• Renal complications including urinary calculi 4, 5

Diagnosis

Laboratory Confirmation

The diagnosis is confirmed by detecting elevated urinary homogentisic acid, typically 4-8 grams per day (normal is negligible). 6

• Urine organic acid analysis by gas chromatography-mass spectrometry can identify HGA 2
• The presence of darkening urine with elevated urinary HGA is pathognomonic 1
• Genetic testing of the HGD gene confirms the diagnosis and enables family screening 1

Clinical Assessment

• Detailed family history for autosomal recessive inheritance pattern 5
• Physical examination for ochronotic pigmentation in ear cartilage, sclera, and skin 3
• Joint examination for arthropathy, particularly spine and large joints 5
• Cardiovascular evaluation including echocardiography to assess for valvular disease 4
• Renal imaging if urinary symptoms present 4

Treatment and Management

Pharmacological Therapy

Nitisinone is the primary disease-modifying treatment, effectively reducing urinary HGA excretion by inhibiting 4-hydroxyphenylpyruvate dioxygenase, the enzyme upstream of HGD in the tyrosine pathway. 6

Nitisinone Dosing and Efficacy

• Initial dose: 0.35 mg twice daily, escalating to 1.05 mg twice daily 6
• Reduces urinary HGA from average 4.0 g/day to 0.2 g/day (95% reduction) 6
• Six of seven patients reported decreased joint pain within weeks of treatment 6

Monitoring on Nitisinone

• Plasma tyrosine levels rise significantly (from ~68 μmol/L to ~760 μmol/L) due to upstream metabolite accumulation 6
• Weekly ophthalmologic examinations to monitor for corneal toxicity (keratitis risk from hypertyrosinemia) 2, 6
• Liver transaminase monitoring for hepatotoxicity 6
• Renal function monitoring (kidney stone risk reported) 6

Dietary Management with Nitisinone

• Protein-restricted diet (40 g/day) reduces plasma tyrosine levels from ~755 μmol/L to ~603 μmol/L while on nitisinone 6
• This dietary restriction helps mitigate hypertyrosinemia-related complications 6

Symptomatic Management

Arthropathy

• Pain management for ochronotic arthritis 6
• Orthopedic consultation for severe joint disease 5
• Joint replacement surgery may be necessary for end-stage arthropathy 5

Cardiovascular Complications

• Regular echocardiographic surveillance for valvular disease, particularly aortic stenosis 4
• Cardiology referral when valvular disease detected 4
• Valve replacement surgery may be required for severe aortic stenosis 4

Renal Complications

• Hydration to prevent urinary calculi 4
• Urological management of kidney stones as needed 4

Important Clinical Pitfalls

• Do not confuse with exogenous ochronosis (from hydroquinone use), which has similar pigmentation but different etiology 3
• Nitisinone causes significant hypertyrosinemia, requiring ophthalmologic monitoring to prevent keratitis, unlike the native disease which does not elevate tyrosine 2, 6
• Cardiovascular complications can be life-threatening: aortic stenosis may progress to severe disease requiring emergency valve replacement with high perioperative mortality 4
• The disease is progressive despite treatment: long-term efficacy of nitisinone in preventing arthropathy requires further study 6

Long-Term Considerations

• Multisystem involvement requires coordinated care across nephrology, rheumatology, cardiology, and ophthalmology 4, 5
• Genetic counseling for affected families given autosomal recessive inheritance 1
• Family screening in populations with high prevalence 5