INTRODUCTION

According to Bukhari et.al (2013) in the study Alkaptonuria, it is a rare disorder

of autosomal recessive inheritance. It is caused by a mutation in a gene that results in
the accumulation of homogentisic acid (HGA). Characteristically, the excess HGA
means sufferers pass dark urine, which upon standing turns black. This is a feature
present from birth. Over time patients develop other manifestations of AKU, due to
deposition of HGA in collagenous tissues, namely ochronosis and ochronotic
osteoarthropathy.

Overtime, it affects males and females in equal numbers, although symptoms

tend to develop sooner and become more severe in males. More than 1,000 affected
individuals have been reported in the medical literature. The exact incidence of
alkaptonuria is unknown. In the United States it is estimated to occur in 1 in 250,000-
1,000,000 live births. Alkaptonuria has been reported in all ethnic groups however the
areas with increased frequencies of the disorder have been identified in Slovakia, the
Dominican Republic and Germany.

Garrod’s use of AKU in the Croonian lectures brought the condition into the
spotlight in 1908. Yet many descriptions of the triad of features associated with AKU
date back long before this. The documentation of the condition began in the 16th and
17th centuries. The earliest clinical case of AKU was found in the Egyptian
mummy Harwa, which is believed to date back as far as 1500 BC. The name
Alkaptonuria is derived from the Arabic word “alkali” (meaning alkali) and the Greek
word meaning “to suck up oxygen greedily in alkali”. The name was created by
Boedeker in 1859 after he discovered unusual reducing properties in the urine of a
patient. On the other side, Ochronosis was first described and named by Virchow in
1866, because under microscopy the HGA pigment appeared to be ochre
(yellow/brown) in color. n 1891 HGA was identified as the causative component and
named so due to its close structural relationship with gentisic acid, a derivative of
benzoic acid. By 1995 the genetic defect was discovered, cloned, and mapped to
chromosome 3q21-q23.

Although this condition does not reduce life expectancy, it significantly affects quality of
life. The natural history of this condition is becoming better understood, despite gaps in
knowledge. Clinical assessment of the condition has also improved along with the
development of a potentially disease-modifying therapy. Furthermore, recent
developments in AKU research have led to new understanding of the disease, and
further study of the AKU arthropathy has the potential to influence therapy in the
management of osteoarthritis. With this, we performed a study to delineate the natural
history of alkaptonuria.

HISTORY

Deficiency in an enzyme called homogentisic, Genetics (defect in HGD gene) or

Inherited, Arthritis, Ankyloses

PHYSICAL FINDINGS

Darkening of fluids and pathological deposition in tissues, Discoloration of skin

and cartilage, dark spots on the sclera of the eye, black earwax, kidney stones, prostate
stones, organs affected (joints, kidney)

LABORATORY FINDINGS

Absence of homogentisate 1 and 2, dioxygenase and enzyme, deficient HGD

activity within liver that causes HGA level to rise, traces of homogentisic acid in your
urine through gas chromatography, presence of mutated HGD gene.

INITIAL APPROACH

- To determine the non-metabolic causes of symptoms such as infection in the

kidney or Urinary Tract Infection (UTI)
- Laboratory assessment prior to therapy:
  Urine: color, odor, pH, gas chromatography (to look for traces of
homogentisic acid in urine)
 Gene: DNA testing (to look for mutated HGD gene), analyzation of
homogentisate 1,2 -dioxygenase(HGD) gene (Invitae Alkaptonuria Test),
molecular
 Heart: chest x-rays (monitoring of aortic and mitral heart valves),
computed chromatography (determination of coronary artery disease)
 Bones and joints: discoloration (including connective tissues),
brittleness, synovial fluid examination, arthroscopy, flexibility of joints

FURTHER MANAGEMENT:

Dietary Restriction (low protein diet) various diets low in protein decreases
homogentisic acid excretion and to prevent the ochronotic pigmentation and arthritic
lesions. About 1g/kg per day and 3.5-5g/kg per day during 8 days. However it is age
dependent as observed, protein restriction to children younger than 12 years resulted to
the success of lowering homogenistic excretion, however, it is less effective on
adolescent and adult patients.

Medical Therapy (paracetamol, nonsteroidal inflammatory drugs) associated with

physiotherapy help to minimize pain and improve the range of joint motion. Older
individuals may require removal and fusion of lumbar disc.

Therapeutic strategies (HGA lowering treatment) Nitisinone inhibits p-hydroxy

phenyl pyruvate dioxgenase which is an enzyme leading to formation of HGA. It has
been found out to slow the rate of disease progression. However to test its long term
effectiveness, it still remains to be evaluated.

TREATMENT FOR ALKAPTONURIA

COFACTOR REPLACEMENT: It occurs when our body can’t produce enough of an
enzyme called homogentistic dioxygenase (HGD). This enzymes used to breakdown
the toxic substance and it is called homogentistic acid.

There is no cure for alkaptonuria but there is a treatment of this, however, the treatment
and therapy is no effective. According to our research the doctor recommended the
large doses of ascorbic acid to slow down the accumulation of homogentistic acid in the
cartilage. The other treatments for alkaptonuria are focused on the preventing the
possible complication such as: arthritis, heart disease, and kidney stones.

OUTCOME