Peroxisomal Acyl-CoA Oxidase Deficiency

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20.1 Clinical Features

and Laboratory Investigations A small number of patients has been described with isolated peroxisomal acyl-CoA oxidase deficiency.

This autosomal recessive disease has also been re- ferred to as pseudo-neonatal adrenoleukodystrophy (pseudo-NALD), because the clinical features are very similar to those of neonatal adrenoleukodystrophy.

The disease had its onset in the neonatal period with hypotonia and seizures. Neonatal reflexes may be absent. Craniofacial dysmorphism may be present and include hypertelorism, epicanthus, low nasal bridge, low-set ears, and polydactyly, but some children have normal features. Hepatomegaly is present in some but not all patients. Psychomotor development is retard- ed, but several motor milestones can be reached and children may achieve walking although delayed. They may learn to speak a few words. Subsequently, neurological deterioration sets in, usually at the age of 1–3 years, with regression of motor abilities. The hypotonia gradually changes into hypertonia with hy- perreflexia and positive Babinski signs. The epilepsy may become very severe with almost continuous epileptic seizures. Sensorineural hearing deficit be- comes apparent. Whereas ophthalmological examination initially reveals normal pupillary light responses and normal fundi, increasing abnormalities are subsequently noted with nystagmus, strabismus, optic atrophy, tapetoretinal degeneration, and absent pupillary light responses. After a few years a vegeta- tive state is reached, followed by death.

Neurophysiological investigations reveal increasing EEG abnormalities with epileptic discharges; the ERG may become flattened, and VEP may become almost entirely absent. Motor and sensory nerve con- duction velocities are normal. Skeletal X-ray examination and ultrasound of the kidneys are normal.

Laboratory investigations show signs of mild liver dysfunction. Serum cortisol level is low, with an increased ACTH value. In serum and fibroblasts, very- long-chain fatty acids (VLCFA) are elevated, but no increase is found in plasma levels of phytanic acid, pristanic acid, pipecolic acid, and bile acids like dihy- droxycholestanoic acid and trihydroxycholestanoic acid. In fibroblasts, VLCFA b-oxidation is seriously deficient, whereas de novo plasmalogen biosynthesis and other peroxisomal parameters are normal. The diagnosis is confirmed by measuring the activity of

acyl-CoA oxidase in fibroblasts. DNA confirmation by showing mutations in the acyl-CoA oxidase gene is possible. Prenatal diagnosis is possible using the same techniques.

20.2 Pathology

No postmortem examination of the brain has been performed in patients with pseudo-NALD. Liver tis- sue investigations show peroxisomes to be present in normal or increased numbers and to be increased in size.

20.3 Pathogenetic Considerations

The biochemical findings of an isolated accumulation of VLCFA in the absence of abnormal bile acid intermediates are consistent with an isolated deficiency of fatty acyl-CoA oxidase. Bile acid intermediates have their own CoA oxidase, whereas bifunctional protein and thiolase are active for all substances b-oxidized in peroxisomes. The gene encoding acyl-CoA oxidase or palmitoyl-CoA oxidase, ACOX1, is located on chro- mosome 17q25.

Two peroxisomal disorders, peroxisomal acyl-CoA oxidase deficiency (pseudo-NALD) and X-linked adrenoleukodystrophy, are characterized by an isolated accumulation of VLCFA. It is striking that both disorders may lead to demyelination with inflammation, as suggested by the contrast enhancement on neu- roimaging. There are, however, also important differences. Patients with acyl-CoA oxidase deficiency display clinical abnormalities from birth on, while the clinical symptoms start much later in X-linked adrenoleukodystrophy. In acyl-CoA oxidase deficien- cy, the b-oxidation of C22 unsaturated fatty acids by chain-shortening and the b-oxidation of dicarboxylic acids are deficient in addition to the oxidation of VLCFA, such as C24:0 and C26:0 fatty acids. In X-linked adrenoleukodystrophy only the b-oxidation of the VLCFA is deficient. These differences may be important in explaining the clinical differences.

Peroxisomal Acyl-CoA Oxidase Deficiency

Chapter 20

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20.4 Therapy

No specific treatment is available. Supportive care is important.

20.5 Magnetic Resonance Imaging

In several patients CT scan of the brain was performed at birth and found to be unremarkable. No evidence of cortical malformation was seen, although minor or mild abnormalities in gyration and hetero- topias can easily be missed on CT. Repeat CT after the onset of neurological deterioration reveals symmetri- cal white matter hypodensities in the centrum semio- vale and the occipital area with contrast enhancement of the border of the lesions. The CT findings are rem- iniscent of those reported in neonatal adrenoleukodystrophy.

MRI soon after the onset of neurological deterioration shows signal abnormalities in the cerebellar white matter, brain stem tracts, and middle cerebellar peduncles (Figs. 20.1 and 20.2). On follow-up, the pyramidal tracts at higher levels of the brain stem and the posterior limb of the internal capsule become abnormal in signal. Subsequently signal changes develop in the periventricular parieto-occipital white matter and the splenium of the corpus callosum (Figs. 20.2 and 20.3), spreading outward and forward, finally involving also the frontal white matter. If contrast is administered, enhancement is expected. No evidence of a migrational defect has been reported.

20.5 Magnetic Resonance Imaging 173

Fig. 20.1. A 3-year-old female patient with isolated peroxiso- mal acyl-CoA oxidase deficiency.Note the signal abnormalities in the corticospinal tracts in the brain stem and the cerebellar

white matter. The pyramidal tracts in the posterior limb of the internal capsule are affected. From Suzuki et al. (2002), with permission

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Fig. 20.2. The first two rows show the images of a male patient with peroxisomal acyl-CoA oxidase deficiency at the age of 3 years and 5 months. There are extensive signal abnormalities in brain stem tracts, middle cerebellar peduncles, and cerebellar white matter.There are incipient signal changes in the pari- eto-occipital white matter. The third row shows the images of

the same patient at the age of 7 years and 11 months.The posterior limb of the internal capsule, parieto-occipital white matter, and splenium of the corpus callosum now display promi- nent signal abnormalities. From Suzuki et al. (2002), with permission

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175 20.5 Magnetic Resonance Imaging

Fig. 20.3. Female patient with peroxisomal acyl-CoA oxidase deficiency at the age of 3 years and 3 months. Tracts in the brain stem (especially the corticospinal tracts), cerebellar white matter,hilus of the dentate nucleus,posterior limb of the internal capsule, thalamus, parieto-occipital white matter, and

splenium of the corpus callosum are affected. In addition, there is some generalized cerebral atrophy.The images resem- ble those of the cerebral form of X-linked adrenoleukodystrophy. From Suzuki et al. (2002), with permission