Biology of Disease

are rapidly degraded leading to a severe peroxisomal deficiency. Individuals

have severe abnormalities in their brain, liver and kidneys and die soon

after birth. Refsum’s disease or hereditary motor sensory neuropathy type IV,

heredopathia atactica polyneuritiformis, was first recognized in the 1940s by

Refsum, who observed markedly increased concentrations of phytanic acid,

a major constituent of dairy foods, in certain patients. The clinical features

include the accumulation of phytanic acid in plasma and lipid-containing tis-

sues, retinitis pigmentosa, blindness, anosmia (loss of sense of smell), deaf-

ness, sensory neuropathy and ataxia.

Refsum’s disease is an autosomal recessive disorder that affects the A-oxidation

of phytanic acid. In contrast to Zellweger syndrome, Refsum’s disease is due

to a reduced enzyme activity. Two enzymes, @-phytanoyl-CoA hydroxylase

(PAHX) and A-hydroxyphytanoyl-CoA lyase, found in peroxisomes, are

necessary for the oxidation of phytanic acid (Figure 16.11). Mutant forms of

PAHX have been shown to be responsible for some cases of Refsum’s disease.

An infantile form of Refsum’s disease also leads to an accumulation of phytanic

acid but resembles Zellweger syndrome in that it is due to general defects in

the transport of appropriate peroxisomal enzymes into the organelle. It is

relatively less severe than Zellweger syndrome because the enzymes in the

cytosol are thought to have a longer half-life.

Diagnosis and Treatment of Peroxisomal Disorders

The diagnosis of peroxisomal disorders usually involves biochemical

tests, such as determining the concentrations of VLCFAs in the plasma.

Observations of deficient secretions of aldosterone and cortisol (Chapter 7)

by the adrenal cortex can imply ALD. Prenatal diagnoses are available using

cultured amniocytes and chorionic villus cells (Chapter 15).

The treatment of patients with peroxisomal defects is problematic since many,

especially those with Zellweger syndrome, have significant brain damage at

birth so a full recovery is not possible even with postnatal therapy. Patients

with some of the relatively milder conditions can live into their second decade.

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Figure 16.11 Outline of the catabolism of

phytanic acid.

Margin Note 16.2 Lorenzo’s oil

Lorenzo’s oil gained considerable

publicity due to the 1992 film

of the same name. The film is

based on the story of Augusto

and Michaela Odone’s efforts to

save the life of their son, Lorenzo,

who was diagnosed with incurable

adrenoleukodystrophy (ALD) in 1984.

His parents were, however, unwilling

to give up the struggle to save him

and after participating in several

failed therapies, began to investigate

the disease themselves. This resulted

in the treatment of Lorenzo with

a mixture glyceryltrioleate (C18:1)

and glyceryltrierucate (C22:1) hence

‘Lorenzo’s oil’, in the hope it would

reduce the concentration of longer

chain fatty acids in the body and also

reduce demyelination and clinical

progression.

It would appear that Lorenzo’s oil

rapidly reduces very long chain fatty

acids in plasma to normal or near

normal levels. Unfortunately, in

patients with neurological symptoms,

its use does not alleviate symptoms

nor delay the progression of the

disease. Postmortem studies show

that very long chain fatty acids in

brain are apparently unaffected.

i

X]VeiZg&+/ MEMBRANE, ORGANELLE AND CYTOSKELETAL DISORDERS

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COSCoA

COO-

CO 2

3 CH 3 CH 2 COO- + CH 3 COO- +

Phytanoyl-CoA

Ahydroxyphytanoyl-CoA

Pristanate

A–phytanoyl-CoA hydroxylase

A–hydroxyphytanoyl-CoA lyase

Aoxidation

Successive

Boxidations

CH COO-

H 3 C

H 3 C

COSCoA

OH

CHO