Garrod's tetrad

GARROD’S TETRAD

These are a collection of inborn errors of metabolism studied by Sir Archibald

Garrod. He was the first physician to exhibit interest in and carry out extensive

research into inborn errors of metabolism. The first diseases he studied were

Alkaptonuria, Cystinuria, Albinism and Pentosuria, all of which compose

Garrod’s Tetrad.

ALKAPTONURIA

1. It is an autosomal recessive condition that occurs due to mutations in

the HGD gene, which codes for Homogentisate Oxidase.

2. The enzyme Homogentisate Oxidase is needed for the metabolism of

Tyrosine and Phenylalanine.

3. It occurs in 1 in 250,000 births.

Biochemical Abnormality

The absence of Homogentisate Oxidase leads to accumulation of homogentisic

acid in the body. Homogentisic acid, which is excreted in urine, is oxidized by

polyphenol oxidase to give benzoquinone acetate. Polymerization of

benzoquinone acetate yields black coloured alkaptone bodies.

Clinical Manifestations:

Blackening of urine on standing due to formation of black coloured alkaptone

bodies. In some patients, in the 3 rd and 4 th decade of life, Ochronosis occurs.

Ochronosis is the deposition of alkaptone bodies in intervertebral discs,

cartilages of nose and ear pinna.

Diagnosis

1. Urine becomes black on standing.

2. Positive Ferric Chloride test answered by Homogentisic Acid in urine

3. Homogentisic Acid is also one of the non-sugar reducing substances that

answers Benedict’s test (along with glucuronides, salicylates and

ascorbic acid). Hence, Benedict’s test is positive.

ALBINISM

1. Albinism is an autosomal recessive disease with an incidence of 1 in

20,000 births.

2. It is due to absence or defect of tyrosinase, a copper-containing enzyme

involved in the production of melanin.

3. It is of two types: Ocular and Oculocutaneous.

4. The ocular fundus is hypopigmented and iris may be gray or red. There

will be associated photophobia, nystagmus and decreased visual acuity.

This is due to the dependence of the visual system on melanin for it’s

development

5. Skin is also prone to damage by UV radiation, which increases the risk of

Melanomas (skin cancers).

CYSTINURIA

1. It is an autosomal recessive disorder which is due to deficient transport

of amino acids. It occurs in 1 in 7,000 live births.

2. It leads to abnormal excretion of Cystine.

3. There is increased formation of cystine crystals and formation of calculi

in the urinary tract, which can lead to obstructive uropathy and as a

result, renal insufficiency.

4. Treatment is to increase urinary volume by increasing fluid intake.

PENTOSURIA

1. It is of 3 types: Essential pentosuria, Alimentary pentosuria and Drug-

induced pentosuria. The incidence is 1 in 2,500 births.

2. In this disorder, deficiency of L-Xylulose Reductase, which converts L-

Xylulose to D-Xylulose is observed. Xylitol Dehydrogenase can also lead

to pentosuria.

3. L-xylulose is excreted in urine and gives a positive Benedict’s test.

4. Barbiturates, aminopyrine, etc. will induce uronic acid pathway and will

increase Drug-induced Pentosuria in such patients.

5. This condition does not produce any harm; but it should be

differentiated from diabetes mellitus because both answer Benedict’s

test.

	GARROD’S TETRAD
1	Alkaptonuria
2	Cystinuria
3	Albinism
4	Pentosuria