Alkaptonuria

Overview

Plain-Language Overview

Alkaptonuria is a rare genetic disorder that affects the body's ability to break down certain amino acids, leading to a buildup of a substance called homogentisic acid. This acid can cause the urine to turn dark when exposed to air and may lead to dark pigmentation in connective tissues, a condition known as ochronosis. Over time, this buildup can cause joint pain and stiffness, especially in the spine and large joints. People with alkaptonuria may also experience heart problems and kidney stones due to the accumulation of this substance. The condition is present from birth but symptoms often appear in adulthood.

Clinical Definition

Alkaptonuria is an autosomal recessive metabolic disorder caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD), which is involved in the catabolic pathway of the amino acids phenylalanine and tyrosine. This enzymatic defect leads to the accumulation of homogentisic acid (HGA) in the body. Excess HGA is excreted in the urine, which darkens upon standing due to oxidation. Chronic deposition of HGA polymers in connective tissues results in ochronosis, characterized by bluish-black pigmentation of cartilage, skin, and sclera. Clinically, patients develop early-onset degenerative arthritis, particularly affecting the spine and large joints, as well as cardiac valvular disease and renal calculi. Diagnosis is confirmed by elevated HGA levels in urine and genetic testing for HGD mutations. The disease manifests in childhood with dark urine but typically presents with musculoskeletal symptoms in the third to fourth decade of life. There is no definitive cure, and management focuses on symptom relief and prevention of complications.

Inciting Event

There is no specific inciting event; disease manifestations result from lifelong accumulation of homogentisic acid.

Latency Period

Symptoms typically appear after decades of homogentisic acid accumulation in tissues.

Diagnostic Delay

Early symptoms such as dark urine may be overlooked or misattributed, delaying diagnosis.
Lack of awareness and rarity of the disease contribute to delayed recognition of ochronosis and arthritis.

Clinical Presentation

Signs & Symptoms

Darkening of urine in infancy or early childhood.
Progressive joint pain and stiffness, especially in the spine and large joints.
Bluish-black discoloration of sclera and ear cartilage.
Development of early-onset osteoarthritis.

History of Present Illness

Patients often report darkening of urine upon standing since infancy or childhood.
Progressive joint pain and stiffness, especially in the spine and large joints, typically begin in the third to fourth decade.
Some patients describe bluish-black discoloration of the ear cartilage and sclera.

Past Medical History

History of early-onset degenerative arthritis or joint replacements may be present.
No other systemic illnesses are typically associated.

Family History

Family history often reveals affected siblings due to autosomal recessive inheritance.
Consanguineous parents increase the risk of affected offspring.

Physical Exam Findings

Presence of bluish-black pigmentation on the sclera (scleral ochronosis).
Darkening of the ear cartilage and other connective tissues.
Restricted joint mobility with signs of early osteoarthritis.
Black discoloration of urine upon standing or exposure to air.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of alkaptonuria is established by detecting elevated levels of homogentisic acid in the urine, which darkens upon standing due to oxidation. Clinical features supporting diagnosis include ochronosis with bluish-black pigmentation of connective tissues and early-onset degenerative arthritis. Genetic testing confirming mutations in the HGD gene provides definitive diagnosis. Additional supportive findings include darkened ear cartilage and sclera, and radiographic evidence of joint degeneration.

Pathophysiology

Key Mechanisms

Alkaptonuria is caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase, leading to accumulation of homogentisic acid.
Accumulated homogentisic acid undergoes oxidation and polymerization, depositing as a pigmented polymer in connective tissues (ochronosis).
Ochronotic pigment deposition causes degeneration of cartilage and connective tissues, resulting in early-onset arthritis and tissue damage.

Involvement	Details
Organs	Heart valves may become calcified and dysfunctional due to pigment deposition.
	Kidneys can be affected by pigment accumulation leading to renal impairment.
	Sclera of the eyes show characteristic blue-black discoloration in alkaptonuria.
Tissues	Cartilage is damaged by ochronotic pigment deposition leading to early-onset arthritis.
Tissues	Connective tissue throughout the body accumulates pigment causing discoloration and structural damage.
Cells	Chondrocytes are involved in ochronotic pigment deposition leading to cartilage degeneration.
Cells	Osteoblasts participate in abnormal bone remodeling seen in ochronotic arthropathy.
Chemical Mediators	Homogentisic acid accumulates due to enzyme deficiency and deposits in connective tissues causing ochronosis.
Chemical Mediators	Reactive oxygen species may contribute to tissue damage in affected joints.

Treatment

Pharmacological Treatments

Nitisinone
- Mechanism: Inhibits 4-hydroxyphenylpyruvate dioxygenase, reducing homogentisic acid production
- Side effects: Elevated tyrosine levels, corneal deposits, headache
Analgesics
- Mechanism: Provide symptomatic relief of joint pain
- Side effects: Gastrointestinal upset, renal impairment with NSAIDs

Non-pharmacological Treatments

Low-protein diet to reduce phenylalanine and tyrosine intake and decrease homogentisic acid accumulation.
Physical therapy to maintain joint mobility and reduce stiffness.
Surgical joint replacement may be necessary in advanced ochronotic arthropathy.

Prevention

Pharmacological Prevention

Use of nitisinone to inhibit homogentisic acid production and slow disease progression.

Non-pharmacological Prevention

Low-protein diet restricting tyrosine and phenylalanine intake to reduce homogentisic acid.
Regular joint physiotherapy to maintain mobility and reduce stiffness.
Avoidance of activities that exacerbate joint stress.

Outcome & Complications

Complications

Severe arthropathy leading to joint deformities and disability.
Cardiac valve disease including aortic or mitral valve calcification.
Renal impairment secondary to stone formation or pigment deposition.
Spinal stenosis and neurological complications.

Short-term Sequelae	Long-term Sequelae
Intermittent joint pain and stiffness. Episodes of urine discoloration noticed by caregivers.	Chronic joint degeneration with loss of function. Progressive cardiac valve dysfunction. Chronic renal disease from ongoing pigment deposition.

Differential Diagnoses

Alkaptonuria versus Albinism

Alkaptonuria	Albinism
Normal pigmentation of skin and hair with characteristic blue-black discoloration of cartilage and sclera.	Congenital absence or reduction of melanin pigment leading to hypopigmented skin and hair.
Presence of homogentisic aciduria causing urine darkening on standing.	Normal urine color without darkening on standing.
Progressive arthropathy due to ochronotic pigment deposition.	Visual disturbances such as nystagmus and photophobia are common.

Alkaptonuria versus Hemochromatosis

Alkaptonuria	Hemochromatosis
Normal iron studies with elevated homogentisic acid in urine.	Elevated serum ferritin and transferrin saturation indicating iron overload.
Darkening of urine on standing due to homogentisic acid oxidation.	Bronze skin pigmentation due to iron deposition rather than ochronotic pigment.
Degenerative arthritis with ochronotic pigmentation of cartilage and connective tissue.	Commonly presents with hepatic dysfunction and diabetes mellitus.

Alkaptonuria versus Ochronosis secondary to exogenous causes

Alkaptonuria	Ochronosis secondary to exogenous causes
Autosomal recessive mutation causing deficiency of homogentisate 1,2-dioxygenase enzyme.	History of prolonged exposure to hydroquinone or other phenolic compounds.
Elevated homogentisic acid in urine causing darkening upon standing.	Absence of homogentisic acid accumulation in urine.
Systemic deposition of ochronotic pigment in connective tissues including cartilage and sclera.	Pigmentation localized to skin areas exposed to the exogenous agent.