Homogentisate 1,2-Dioxygenase (HGD) Deficiency

Homogentisate 1,2-dioxygenase (HGD) deficiency is a rare, inherited condition in which the body cannot fully break down the amino acids tyrosine and phenylalanine. Because the HGD enzyme does not work well, a substance called homogentisic acid (HGA) builds up. Over years, HGA turns into a dark pigment that settles in cartilage, tendons, heart valves, and other tissues. This pigment is called ochronosis. The buildup slowly damages joints (leading to spine, hip, knee, and shoulder arthritis), can stiffen heart valves, and can promote kidney, bladder, and prostate stones. Many people also notice that their urine gets dark or almost black after standing in air. Life expectancy is usually near normal, but disability from joint and spine disease can be significant without good care. Genetic Diseases Information Center+3NCBI+3NCBI+3

Homogentisate 1,2-dioxygenase (HGD) deficiency is a rare, inherited metabolic disease. It happens when the HGD enzyme, which lives mainly in the liver and kidneys, does not work enough or does not work at all. This enzyme is needed to break down a natural amino-acid pathway (the tyrosine/phenylalanine pathway). When HGD is weak or absent, a chemical called homogentisic acid (HGA) builds up in the body. Extra HGA leaks into urine (which can turn dark on standing), and over many years it oxidizes and turns into pigment that settles in cartilage, tendons, and other connective tissues. This pigment is called “ochronotic” pigment. It makes tissues stiff, fragile, and dark colored. With time, people develop early, severe osteoarthritis (especially in the spine, hips, knees), tendon problems, and sometimes heart valve and kidney stone disease. The condition is lifelong and is passed down in an autosomal recessive way (both copies of the HGD gene are changed).

Other names

• Alkaptonuria (AKU)

• Hereditary ochronosis / endogenous ochronosis

• Homogentisic aciduria

• HGD deficiency

• Black urine disease

• Alkaptonuric ochronosis

All of these names refer to the same disease process: excess HGA due to HGD enzyme deficiency leading to pigment build-up and tissue damage.

What is happening inside the body

Proteins contain amino acids. Two of them, phenylalanine and tyrosine, are normally broken down step by step. HGD works in the middle of that pathway. If HGD is missing, the pathway gets stuck and homogentisic acid (HGA) rises in blood and tissues. HGA is a strong reducing agent; when exposed to air or alkaline conditions, it oxidizes to benzoquinone acetic polymers (the ochronotic pigment). This pigment binds to collagen in cartilage, ligaments, intervertebral discs, and other tissues, making them dark, brittle, and prone to degeneration and calcification. Over years, this causes early arthritis, spine stiffness, tendon tears, and valve and stone problems. Urine may appear normal when fresh but turns brown-black after standing or with alkali.

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Types

Because the genetic cause is the same (changes in the HGD gene), doctors often classify “types” by how the disease shows up and how severe it is:

1. Classic alkaptonuria (typical course).
   Normal childhood, darkening of urine may be noticed early, joint and spine symptoms start in the 3rd–4th decade, and progress.

2. Early-onset musculoskeletal type.
   Same genetic cause, but joint and tendon problems appear earlier (for example in the 20s) and progress faster.

3. Predominantly axial (spine-dominant) type.
   Back pain, reduced spine motion, and disc calcification are the main features, with hips/knees involved later.

4. Predominantly peripheral joint type.
   Knees, hips, and shoulders are the leading problems before the spine becomes very stiff.

5. Cardio-renal prominent type.
   Along with joint disease, people show more kidney stones/prostate stones and valve calcification.

6. Genotype-severity spectrum.
   Some people have “null” variants (no enzyme activity) and others have “hypomorphic” variants (low activity). Lower activity generally means faster pigment build-up and earlier symptoms.

These “types” are not separate diseases. They are useful patterns that help plan monitoring and care.

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Causes

Strictly speaking, there is one root cause: a pathogenic variant in both copies of the HGD gene (autosomal recessive). The items below explain the forms and contributors that cause the disease to appear and to get worse over life.

1. Autosomal recessive inheritance.
   You get one faulty HGD gene from each parent who is a healthy carrier.

2. Missense variants in HGD.
   A single amino-acid change alters the enzyme shape and lowers activity.

3. Nonsense variants.
   A “stop” signal shortens the enzyme so it cannot work.

4. Frameshift variants.
   Small insertions/deletions shift the code and make a nonfunctional enzyme.

5. Splice-site variants.
   Errors at exon–intron boundaries create faulty mRNA and a weak enzyme.

6. Large deletions/duplications.
   Big pieces of the HGD gene are missing or repeated and the enzyme is lost.

7. Promoter/regulatory variants.
   Gene “on/off” control is impaired, lowering HGD production.

8. Compound heterozygosity.
   Two different variants, one on each gene copy, together cause deficiency.

9. Consanguinity.
   Parents who are related are more likely to carry the same rare variant.

10. Founder effects in certain regions.
    In some populations specific HGD variants are more common, raising risk.

11. Very low residual HGD activity.
    Less leftover activity means more HGA build-up and earlier disease.

12. High dietary phenylalanine/tyrosine load.
    Large protein intake can increase HGA production and pigmentation over time.

13. Aging.
    Pigment accumulates slowly; with age, damage becomes visible.

14. Mechanical joint stress.
    Heavy physical strain speeds cartilage wear once pigment has bound.

15. Oxidative conditions.
    Oxidation of HGA to pigment is favored in alkaline or oxidative settings.

16. Dehydration/low urine volume.
    Concentrated urine increases visible darkening and may promote stones.

17. Chronic inflammation in joints.
    Inflamed cartilage is more vulnerable to pigment-related damage.

18. Calcification tendency.
    Once tissues are stiff and pigmented, calcium deposits more easily.

19. Coexisting kidney stone risk.
    Stone history can worsen pain and urinary symptoms linked to AKU.

20. Delayed diagnosis and lack of monitoring.
    Unrecognized disease allows pigment to build unchecked for decades.

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Common symptoms

1. Dark urine after standing.
   Fresh urine may look normal but turns brown-black in minutes to hours, especially in alkaline containers.

2. Dark earwax or ear cartilage discoloration.
   Earwax looks brown-black; the rim of the ear can become blue-black and stiff.

3. Brown-gray spots on the whites of the eyes (sclera).
   “Osler’s sign”–like scleral pigmentation near the cornea, often at 3 and 9 o’clock.

4. Skin discoloration in sweat areas.
   Axillae, face lines, and genital/inguinal folds may look darker over time.

5. Early-onset back pain and stiffness.
   Degeneration of intervertebral discs causes morning stiffness and limited bending.

6. Reduced spine flexibility.
   Difficulty touching toes; Schober test is often reduced; posture may become stooped.

7. Large-joint pain (hips, knees, shoulders).
   Pigment-stiffened cartilage wears down, causing osteoarthritis in mid-life.

8. Crepitus and swelling.
   Grinding sensations and intermittent effusions, especially in the knees.

9. Tendon or ligament pain.
   Achilles, patellar, or biceps tendinopathy due to pigment and calcification.

10. Tendon tears/ruptures (sometimes sudden).
    Weak, pigment-laden tendons can fail with minor trauma.

11. Kidney stones.
    Flank pain, blood in urine, or urinary infections from stones.

12. Prostate stones or enlargement in males.
    Urinary hesitancy or infections due to calcified deposits.

13. Heart valve problems (especially aortic).
    Calcification makes valves stiff, causing a murmur, breathlessness, or chest discomfort on exertion.

14. Reduced height or stooped posture with age.
    Disc narrowing and spinal calcification shorten stature and alter posture.

15. Fatigue and activity limitation.
    Chronic pain and stiffness reduce daily function and exercise tolerance.

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Diagnostic tests

A) Physical-exam–based tests

1. General inspection for pigment.
   The doctor looks for blue-black color in ear cartilage, dark earwax, and brown-gray scleral spots. These are classic external clues.

2. Skin exam in sweat and crease areas.
   Subtle brown or slate-gray patches in axilla, face lines, and groin suggest ochronosis.

3. Spine mobility assessment (e.g., Schober test).
   Measures forward bending of the lower back. Reduced increase indicates stiff lumbar spine from disc degeneration/calcification.

4. Joint range-of-motion testing.
   Limited, painful movement in hips, knees, and shoulders points to early osteoarthritis typical of HGD deficiency.

B) Simple “manual” or bedside tests

5. Urine darkening on standing/with alkali.
   Collect fresh urine and observe color change at room temperature or after adding a mild alkali (e.g., sodium bicarbonate). Darkening suggests excess HGA.

6. Ferric chloride spot test (historical).
   Adding ferric chloride can produce a transient green/black color with HGA. It is not specific but can support suspicion in the right context.

7. Reducing substance screen (older bedside chemistry).
   HGA can act as a reducing agent and give a positive reaction; this is supportive only and must be confirmed by modern lab testing.

C) Laboratory and pathological tests

8. Quantitative urine HGA (GC-MS or HPLC).
   This is the key test. Very high HGA in urine confirms the biochemical diagnosis.

9. Plasma HGA concentration.
   Elevated blood HGA supports the diagnosis and helps research/monitoring.

10. Genetic testing of the HGD gene.
    Finding pathogenic variants in both HGD copies provides definitive, molecular confirmation and helps with family counseling.

11. Urine organic acid profile.
    A broader panel that shows a striking HGA peak and screens for other metabolic disorders if needed.

12. Histology of pigmented tissue (if obtained).
    Cartilage or disc tissue may show brown ochronotic deposits that stain like melanin-like polymers. This is rarely needed but is characteristic.

13. Renal function and urinalysis.
    Checks for blood, crystals, or infection and monitors kidney impact of stones.

D) Electrodiagnostic and physiologic tests

14. Electrocardiogram (ECG).
    Screens for rhythm or strain changes in patients with suspected aortic stenosis due to valve calcification.

15. Holter monitoring or event recorder (if symptoms).
    Looks for intermittent arrhythmias in those with palpitations or syncope related to valve disease.

16. Spirometry (lung function) in severe kyphosis.
    Long-standing spinal rigidity can cause a restrictive breathing pattern; spirometry quantifies this effect.

E) Imaging tests

17. Spine radiographs (X-rays).
    Show calcified, narrowed intervertebral discs, vacuum phenomena, and bridging osteophytes consistent with ochronotic spondyloarthropathy.

18. Large-joint X-rays (hips/knees/shoulders).
    Reveal joint-space loss, osteophytes, and calcified cartilage typical of early osteoarthritis in AKU.

19. Transthoracic echocardiography (heart ultrasound).
    Evaluates aortic/mitral valve thickening and calcification, and measures stenosis or regurgitation severity.

20. Renal and prostate ultrasound (and CT if needed).
    Detects kidney and prostate stones, hydronephrosis, or calcifications linked to long-term pigment effects.

Non-pharmacological treatments (therapies & other measures)

Each item includes: description, purpose, mechanism in plain words.

1. Education & care plan
   Description: Understand AKU, how it progresses, and how treatments work.
   Purpose: Empower day-to-day choices, spot problems early.
   Mechanism: Informed self-care improves adherence to exercise, diet, and monitoring; early action prevents damage.

2. Regular physiotherapy (PT)
   Description: Guided exercises for mobility, strength, and posture.
   Purpose: Reduce pain and stiffness; keep joints working longer.
   Mechanism: Strong muscles unload damaged cartilage; mobility reduces secondary muscle spasm and stiffness—extrapolated from osteoarthritis care, which fits AKU’s arthritis pattern. NCBI

3. Aquatic therapy
   Description: Exercise in warm water.
   Purpose: Move more with less pain and impact.
   Mechanism: Buoyancy reduces joint load; warmth relaxes muscles.

4. Core and back-extensor training
   Description: Focused spine conditioning.
   Purpose: Support the spine and improve posture.
   Mechanism: Strong core/back muscles stabilize segments stressed by ochronosis-related disc and facet wear. NCBI

5. Low-impact aerobic exercise
   Description: Walking, cycling, elliptical.
   Purpose: Pain control, heart health, weight management.
   Mechanism: Improves circulation and anti-inflammatory tone without pounding joints.

6. Flexibility & range-of-motion work
   Description: Daily gentle stretching of spine, hips, knees, shoulders.
   Purpose: Preserve motion; reduce stiffness in pigmented cartilage.
   Mechanism: Maintains capsular and muscle length; reduces guarding.

7. Weight management
   Description: Reach and keep a healthy weight.
   Purpose: Slow joint wear; lower surgical risk.
   Mechanism: Less mechanical load on hips/knees/spine; lower systemic inflammation.

8. Heat and cold therapy
   Description: Heating pads or ice packs to painful areas.
   Purpose: Short-term pain relief.
   Mechanism: Heat relaxes muscles; cold reduces local inflammation.

9. Occupational therapy (OT)
   Description: Task and tool adaptation for daily living and work.
   Purpose: Protect joints; maintain independence.
   Mechanism: Joint-protection techniques and assistive devices reduce strain.

10. Assistive devices
    Description: Braces, canes, walkers, ergonomic chairs.
    Purpose: Pain relief and safer mobility.
    Mechanism: Off-loads painful joints; improves balance to prevent falls.

11. Posture and ergonomics
    Description: Optimize desk/bed/car setup; teach neutral spine habits.
    Purpose: Lower spine stress and pain flares.
    Mechanism: Reduces shearing/pressure on worn discs and facets.

12. Fall-prevention program
    Description: Balance training; home hazard review.
    Purpose: Avoid fractures or tendon tears.
    Mechanism: Better balance and safer environment cut risk.

13. Stone-prevention hydration
    Description: Aim for pale-yellow urine all day.
    Purpose: Reduce kidney/bladder/prostate stone formation.
    Mechanism: Dilutes stone-forming compounds (including pigment and oxalate). nhs.uk+1

14. Citrate from foods (e.g., lemon/lime)
    Description: Add citrus to water (if teeth are protected).
    Purpose: Support stone prevention.
    Mechanism: Urinary citrate binds calcium and discourages crystal growth (general kidney-stone principle). Genetic Diseases Information Center

15. Heart-healthy lifestyle
    Description: Cardio exercise as tolerated, stop smoking, manage blood pressure and lipids, sleep well.
    Purpose: Protect vessels and heart valves affected by ochronosis.
    Mechanism: Lowers cardiovascular strain; supports surgical fitness. nhs.uk

16. Skin and ear care
    Description: Moisturizers; protect areas with pigment.
    Purpose: Comfort and appearance; prevent cracking.
    Mechanism: Hydration keeps pigmented cartilage/skin supple (cosmetic but helpful). DermNet®

17. Dental and jaw care
    Description: Bite guards if bruxism; gentle jaw range exercises.
    Purpose: Reduce TMJ load in ochronotic cartilage.
    Mechanism: Minimizes repetitive joint stress (pragmatic arthritis care).

18. Pain-coping skills / CBT
    Description: Simple psychological strategies for chronic pain.
    Purpose: Reduce distress; improve activity.
    Mechanism: Reframes pain signals; lowers central sensitization.

19. Workplace accommodations
    Description: Breaks to move/stretch; lifting aids.
    Purpose: Prevent flares; maintain employment.
    Mechanism: Cuts repeated micro-trauma to joints and spine.

20. Structured, periodic specialist review
    Description: Regular follow-up with metabolic, rheumatology, cardiology/urology/orthopedic teams as needed.
    Purpose: Detect complications early; plan timely surgery.
    Mechanism: Surveillance finds valve disease or stones before crises. NCBI+1

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Drug treatments

Important context: The only therapy shown to lower HGA and slow disease progression is nitisinone (off-label in AKU). Most other drugs are for symptom control or complication prevention (extrapolated from osteoarthritis/stone care). PubMed+1

1. Nitisinone (HPPD inhibitor; disease-modifying)
   Class: Tyrosine-catabolism inhibitor (blocks p-hydroxyphenylpyruvate dioxygenase upstream of HGA).
   Dose/time: Common adult AKU dose: 10 mg once daily; long-term use studied over 4 years in SONIA-2.
   Purpose: Markedly lowers HGA and slows clinical progression.
   Mechanism: Prevents formation of HGA, cutting HGA in urine by ~95–99% and reducing progression on the cAKUSSI clinical score.
   Key safety: Raises tyrosine levels → risk of corneal keratopathy/photophobia; needs regular serum tyrosine checks and eye exams; often pair with tyrosine/phenylalanine-restricted diet to control hypertyrosinemia. Karger+3PubMed+3PMC+3

2. Acetaminophen (paracetamol)
   Class: Analgesic/antipyretic.
   Dose: 325–1000 mg per dose; typical max 3,000 mg/day (some guidelines 4,000 mg/day if supervised).
   Purpose: First-line pain relief for joint pain.
   Mechanism: Central COX inhibition; safer for stomach than NSAIDs.

3. Ibuprofen
   Class: NSAID.
   Dose: 200–400 mg every 6–8 h (Rx max 3200 mg/day).
   Purpose: Pain and inflammation in AKU-related arthritis.
   Risk: Stomach, kidney, CV risks; add gastroprotection if needed.

4. Naproxen
   Class: NSAID.
   Dose: 250–500 mg twice daily.
   Purpose/mechanism: As above; often preferred for steady anti-inflammatory effect.

5. Topical diclofenac 1% gel
   Class: Topical NSAID.
   Dose: 2–4 g to affected joint up to 4×/day.
   Purpose: Local pain control with lower systemic risk.

6. Proton-pump inhibitor (e.g., omeprazole 20 mg daily)
   Class: Acid suppression.
   Purpose: Protect stomach in people who must use NSAIDs.
   Mechanism: Reduces gastric acid, lowers ulcer risk.

7. H2 blocker (e.g., famotidine 20 mg twice daily)
   Class: Acid suppression alternative.
   Purpose: GI protection if PPI not tolerated.

8. Duloxetine
   Class: SNRI antidepressant for chronic musculoskeletal pain.
   Dose: 30 mg daily → 60 mg daily.
   Purpose: Help persistent pain when NSAIDs/acetaminophen are not enough.
   Mechanism: Modulates central pain pathways.

9. Tramadol
   Class: Atypical opioid.
   Dose: 25–50 mg q6h PRN (max 400 mg/day; lower in older adults).
   Purpose: Short-term rescue for severe flares.
   Caution: Dependence, sedation, serotonin syndrome with SSRIs—use sparingly and under supervision.

10. Intra-articular corticosteroid (e.g., triamcinolone 20–40 mg for knee)
    Class: Glucocorticoid injection.
    Purpose: Reduce severe joint inflammation during flares.
    Mechanism: Local anti-inflammatory effect; temporary relief; limit frequency.

11. Hyaluronic acid intra-articular injection
    Class: Viscosupplement.
    Purpose: Pain relief in some knee OA patterns; may help select AKU knees.
    Evidence: Mixed; discuss case-by-case.

12. Topical capsaicin 0.025–0.075%
    Class: Counter-irritant/neuromodulator.
    Purpose: Adjunct for chronic knee/hand pain.
    Mechanism: Depletes substance P in peripheral nerves.

13. Gabapentin or pregabalin
    Class: Neuropathic pain agents.
    Purpose: If nerve pain or radicular pain from spine degeneration.
    Mechanism: Calcium-channel modulation in dorsal horn.

14. Potassium citrate
    Class: Urinary alkalinizer.
    Dose: Commonly 10–20 mEq 2–3×/day (individualize).
    Purpose: Prevent stone formation or help pass small stones.
    Mechanism: Raises urinary citrate and pH to reduce crystal formation (general stone care). Genetic Diseases Information Center

15. Tamsulosin 0.4 mg nightly
    Class: Alpha-blocker.
    Purpose: Facilitate passage of distal ureteral stones; relieve prostate symptoms if present (AKU can cause prostate stones). Genetic Diseases Information Center

16. Lubricating eye drops
    Class: Artificial tears.
    Purpose: Soothe eye irritation/photophobia if tyrosine rises on nitisinone; does not treat the cause.
    Mechanism: Surface comfort while diet/levels are adjusted. Karger

17. Vitamin D (cholecalciferol) repletion
    Class: Hormone/vitamin.
    Purpose: Treat deficiency to support bone health before/after joint surgery; dose based on labs.

18. Bisphosphonates (case-by-case)
    Class: Anti-resorptives for osteoporosis when indicated.
    Purpose: Bone protection if DEXA shows low bone mass; not a disease-modifier for AKU arthritis itself.

19. Topical lidocaine patches
    Class: Local anesthetic.
    Purpose: Focal pain relief (back or joint area) without systemic effects.

20. Short peri-operative antibiotic prophylaxis (when indicated)
    Class: Antibacterial.
    Purpose: Standard infection prevention around joint/valve surgery (not AKU-specific but commonly needed in advanced disease requiring procedures).

Key evidence note: The disease-modifying role belongs to nitisinone (10 mg daily shown to reduce HGA massively and slow progression over 4 years), but it must be balanced with dietary Tyr/Phe restriction and monitoring due to hypertyrosinemia-related corneal issues. Karger+3PubMed+3PMC+3

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Dietary molecular supplements

Supplements are optional and do not replace nitisinone or medical care. Always review interactions with your clinician.

1. Vitamin C (ascorbic acid) 250–1000 mg/day
   Function: Antioxidant; historically proposed to slow pigment formation.
   Mechanism: May reduce oxidation/polymerization of HGA in tissues; evidence is mixed, and it does not lower HGA excretion. Use modest doses and avoid mega-doses. Nature+1

2. Omega-3 fatty acids (fish oil) 1–2 g EPA+DHA/day
   Function: Anti-inflammatory support for joint pain.
   Mechanism: Competes with arachidonic acid pathways to lower inflammatory mediators.

3. Turmeric/curcumin extract standardized (e.g., 500–1000 mg curcuminoids/day)
   Function: Adjunct pain relief.
   Mechanism: NF-κB and COX-2 modulation; variable bioavailability.

4. Glucosamine sulfate 1500 mg/day
   Function: Symptom relief in some osteoarthritis patients.
   Mechanism: Cartilage matrix substrate; mixed evidence.

5. Chondroitin sulfate 800–1200 mg/day
   Function/Mechanism: As above; sometimes combined with glucosamine; evidence mixed.

6. Collagen peptides 5–10 g/day
   Function: Potential symptom benefit in joint pain.
   Mechanism: Provides amino acids for collagen turnover; evidence modest.

7. Magnesium citrate per label (often 200–400 mg elemental Mg/day)
   Function: Bowel regularity; may support stone prevention when part of citrate strategy.
   Mechanism: Citrate component can help bind urinary calcium (general stone science). Genetic Diseases Information Center

8. Citrate from lemon juice (dietary, not a pill)
   Function: Stone prevention aid.
   Mechanism: Increases urinary citrate; see hydration/citrate notes above. Genetic Diseases Information Center

9. Vitamin D3 dose per deficiency (e.g., 1000–2000 IU/day or targeted repletion)
   Function: Bone health, especially with limited mobility or pre-surgery.
   Mechanism: Optimizes calcium absorption and bone remodeling.

10. Coenzyme Q10 100–200 mg/day
    Function: General mitochondrial support reported for fatigue in chronic disorders; evidence limited.

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Immunity booster / regenerative / stem-cell drugs

Honest, safety-first answer: There are no proven “immunity-booster,” regenerative, or stem-cell drugs that treat AKU or reverse ochronosis. Stem-cell or regenerative injections have not shown reliable benefit in AKU and are not recommended outside clinical trials. What is evidence-based is preventing infections before surgeries and keeping nutrition/vaccination up to date. Here are six safer, practical medical measures often used around AKU care:

1. Seasonal influenza vaccination (annual, standard adult dose).

2. Pneumococcal vaccination per age/risk schedules (e.g., PCV then PPSV, per local guidelines).

3. COVID-19 vaccination/boosters per current guidance.

4. Vitamin D repletion to normal range (dose guided by labs).

5. Protein-adequate diet (not high-protein) to maintain muscle for joint protection.

6. Peri-operative optimization (treat dental infections, skin issues; smoking cessation) to reduce surgical complications.

If you are offered stem-cell or PRP injections for AKU, ask for published, peer-reviewed evidence in AKU specifically; at present, none show disease-modifying benefit comparable to nitisinone. PubMed+1

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Surgeries

1. Total joint replacement (hip/knee/shoulder)
   Why: Advanced ochronotic arthritis with severe pain and loss of function.
   Goal: Restore mobility and relieve pain; outcomes are similar to osteoarthritis surgery when done at the right time. DermNet®

2. Spine surgery (decompression ± fusion)
   Why: Nerve compression, severe spinal stenosis, or instability from ochronotic disc and facet degeneration.
   Goal: Relieve nerve pain/weakness; stabilize segments. NCBI

3. Aortic valve replacement (or repair)
   Why: Ochronosis can stiffen and calcify the aortic valve, causing stenosis or regurgitation.
   Goal: Treat heart failure symptoms, protect heart function. nhs.uk

4. Tendon repair
   Why: Ochronotic tendons can rupture (e.g., Achilles, biceps).
   Goal: Restore function after acute tears. NCBI

5. Stone procedures (e.g., ureteroscopy, lithotripsy; occasionally prostate surgery)
   Why: Recurrent kidney/bladder/prostate stones with pain, infection, or obstruction.
   Goal: Clear stones; prevent complications. nhs.uk

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Prevention tips

1. Hydrate all day (aim for pale-yellow urine) to reduce stone risk. Genetic Diseases Information Center

2. Keep weight in a healthy range to unload joints.

3. Prefer low-impact exercise (walk, cycle, swim) over high-impact running/jumping.

4. Use joint-protection and ergonomic habits at work/home.

5. Do regular PT/OT to maintain posture, strength, and flexibility.

6. Stop smoking and manage blood pressure/lipids (heart/valve protection). nhs.uk

7. Dental/skin/foot care to reduce infection risk before surgeries.

8. Vaccinations up to date (flu, pneumococcal, COVID-19) before major procedures.

9. If on nitisinone: follow tyrosine/phenylalanine-restricted diet, get regular eye exams and blood tyrosine tests to avoid corneal issues. Karger

10. Plan periodic specialist reviews (metabolic, cardiology, urology, orthopedics) to catch problems early. NCBI

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When to see a doctor (red flags & routine)

• Immediately / urgently: sudden severe joint pain after a pop (possible tendon rupture), chest pain or new shortness of breath (possible valve issue), fever with back/urinary pain, inability to pass urine, or severe eye pain/photophobia if you’re on nitisinone (possible tyrosine-related keratopathy). NCBI+2nhs.uk+2

• Soon (within days): new kidney-stone symptoms (colicky flank pain, blood in urine), rapid swelling of a joint, or new nerve signs (weakness, numbness, foot drop). NCBI

• Routine: at least annual review with your metabolic or AKU clinic, and more often if on nitisinone (for labs and eye checks). PubMed+1

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What to eat and what to avoid

If you are on nitisinone:

• Eat: A controlled-protein diet that limits tyrosine and phenylalanine (often by moderating animal proteins and certain legumes) under a dietitian’s guidance. Include plenty of vegetables, fruits, whole grains, and healthy fats.

• Avoid/limit: Very high-tyrosine foods (large portions of aged cheeses, soy products, some protein supplements) and very high-phenylalanine foods (large servings of meat/fish/eggs) because nitisinone raises blood tyrosine, and diet helps keep levels safe for the eyes. Karger

If you are not on nitisinone:

• No strict protein restriction is routinely required in adults, but a balanced, not high-protein, diet is reasonable. Focus on anti-inflammatory patterns (vegetables, fruit, legumes, whole grains, olive oil, nuts) and adequate hydration for stone prevention. Genetic Diseases Information Center

General tips (both groups):

• Spread protein across meals; don’t “protein-load.”

• Use lemon/lime water periodically for dietary citrate (protect teeth from acid).

• Limit ultra-processed foods and added sugars (helps weight and inflammation).

• If trying vitamin C, keep to modest doses (see notes above). Nature

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Frequently Asked Questions

1. Is AKU curable?
   No cure yet. The main disease-modifier is nitisinone, which lowers HGA and slows progression. Symptom care, exercise, and surgeries address complications. PubMed+1

2. Does nitisinone really help?
   Yes—10 mg daily cut HGA dramatically and slowed clinical progression over 4 years in a large randomized study. It requires eye and blood monitoring because it raises tyrosine. PubMed+1

3. Will vitamin C stop the disease?
   No. It may slightly affect pigment chemistry but does not reduce HGA output; evidence is mixed. Nature

4. Why does my urine turn dark?
   HGA in urine oxidizes on contact with air and darkens. Genetic Diseases Information Center

5. Which joints are usually hit first?
   Spine (especially lumbar/thoracic), then hips, knees, and shoulders. MedlinePlus

6. Can AKU affect the heart?
   Yes. Ochronosis can stiffen the aortic valve and blood vessels; some people need valve surgery. nhs.uk

7. Why are stones common?
   Pigment and other factors promote kidney, bladder, and prostate stones; hydration helps. Genetic Diseases Information Center

8. Is life expectancy normal?
   Often near normal, but quality of life can be limited by joint/spine disease without proper management. DermNet®

9. Is AKU common in any region?
   It’s rare worldwide but more frequent in a few populations due to founder mutations. (Overall prevalence <1 in 100,000). NCBI

10. Can children be treated?
    Management is individualized; nitisinone in children requires expert monitoring because of growth and tyrosine issues. Work with a metabolic specialist. NCBI

11. Will exercise make it worse?
    High-impact activities can hurt. Low-impact exercise and PT are helpful and recommended. NCBI

12. Do I need a special doctor?
    Ideally a metabolic (inherited disorders) clinic plus rheumatology/orthopedics, and cardiology/urology if those organs are involved. NCBI

13. How often should I be checked if I take nitisinone?
    Regular tyrosine blood tests and eye exams; your clinic will set the exact schedule. Karger

14. Are there research trials?
    Yes—ask your clinic about AKU trials or registries; key trials like SONIA-2 informed dosing and monitoring. PubMed

15. Can diet alone treat AKU?
    No. Diet helps with stone risk and, if you take nitisinone, diet helps keep tyrosine safe—but diet alone does not stop HGA buildup. Karger+1

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The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: September 12, 2025.

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