Disorder Of amino Acid Metabolism Alkaptonuria (AKU)

 Alkaptonuria (AKU)

Alkaptonuria (PKU) is the first recognized inborn error of metabolism that follows classified principle of metabolism autosomal recessive inheritance. this means that both alleles  for the gene need to be mutated for the disease to show up. generally children are born to phenotypically normal carrier (heterozygous) parents .the first clinical description of this disease dates back 1584 when a school boy in good health excreted urine that turned black. it was named "black urine disease" and abnormal black pigment was called alkapton as it gets oxidized in presence of air and alkaline medium to an insoluble black pigment.

AKU arises due to a deficiency of homogentisate 1,2 dioxygenase (HGD) that converts homogentisic acid (HGD) to maleylacetoacetate, an intermediate in phenylalanine/tyrosine catabolism it is predominantly synthesized in the liver and kidney. the prevalence of the disease is low(1in 1,00,000-2,50,000) in most ethnic groups except Slovakia and Dominican  republic (1:19000)

Alkaptonuria is a progressive disease characterized by three classical stages that appears in the following chronology.

(a) darkening of urine : 

The lack of the enzyme homogentisate 1,2 dioxygenase leads to accumulation of homogentisic acid which is excreted in the urine ,resulting in homogentisic aciduria. this compound oxidizes on standing or on treatment with alkali to give the urine a characteristic dark color. it appears at birth and persists lifelong.

(b) ochronosis :

 Homogentisic acid is oxidized by a copper dependent polyphenol oxidase to highly reactive and labile, p-benzoquinone acetic acid (p-BAQ)which reacts with connective tissue proteins forming deposits of dark (ochre-colored) pigment. This condition is called ochronosis. para-BQA can also be polymerised to a melanin variant (HGA melanin). the most affected tissue are ears and eyes. the symptoms are clinically visible around 30 years of age.

(c)Arthritis:

The accumulated deposited further can lead to severe arthritis and painful enlarged joints , a condition called ochronotic osteoarthropathy. the symptoms generally develops around 50 years. not everyone with AKU develops arthritis.

The treatment for AKU is not very effective .commonly recommended strategies include dietary restriction of phenylalanine and tyrosine along with large doses of ascorbic acid (an antioxidant believed to reduce the oxidative conversion of HGA to BQA) which is effective particularly in children. which is effective particularly in children. the management of AKU remains palliative and involves physiotherapy, joint replacement surgery, and pain control. now a drug nitisinone is available which reduces HGA production by inhibiting hydroxy phenyl pyruvate dioxygenase. it arrests ochronosis and delays progression of AKU.