Peroxisomal D-Bifunctional Protein Deficiency

19.1 Clinical Features

and Laboratory Investigations A limited number of patients have been described with isolated D-bifunctional protein deficiency (BPD), a disease with an autosomal recessive mode of inheritance. The children show severe CNS involve- ment with profound hypotonia from birth onwards.

There are minimal spontaneous movements and the neonatal reflexes are depressed. Feeding problems are usually prominent. In most children dysmorphic features are present with high forehead, large open fontanel, flat nasal bridge, low-set ears, high-arched palate, and micrognathia, similar to the facial charac- teristics seen in patients with generalized peroxiso- mal dysfunction. Some infants have macrocephaly.

Joint contractures may be present. Most patients suffer from severe epilepsy from the beginning and seizures are often uncontrollable. Psychomotor de- velopment is severely delayed and most patients fail to acquire any significant developmental mile- stones. Some patients have ocular abnormalities, including glaucoma, optic atrophy, pigmentary reti- nal degeneration, and cataract. Auditory dysfunction is present in some. Hepatomegaly is found in some of the patients. Adrenocortical insufficiency is manifest in few children. Death occurs most often between 4 and 12 months of age, but some patients survive a few years.

EEG is severely abnormal with epileptic dis- charges. BAEP findings are often abnormal. Nerve conduction velocities are normal. Skeletal X-ray sur- vey is often normal, but calcific stippling of some joints may be seen. Renal ultrasound is normal.

Laboratory investigations reveal signs of adrenal insufficiency in some of the patients. In all patients very-long-chain fatty acids are elevated in plasma and fibroblasts. The plasma levels of bile acid intermedi- ates (dihydroxycholestanoic acid and trihydroxy- cholestanoic acid) and pristanic acid may also be elevated, but not in all patients.When pristanic acid is elevated, phytanic acid is usually also elevated, although much less seriously and with an increase in pristanic to phytanic acid ratio. Plasma pipecolic acid and the de novo plasmalogen synthesis in fibroblasts are normal. A D-bifunctional protein deficiency is

demonstrated and mutations are found in the D-BP gene. Prenatal diagnosis is possible by measuring D- bifunctional protein activity in chorionic villus sam- ples and, if the molecular defect has been resolved in the index patient, by DNA analysis.

19.2 Pathology

Postmortem examination of the brain reveals the brain to be relatively large. A combination of mal- formative and destructive abnormalities is usually found. Polymicrogyria is present in most but not all patients, in particular involving the lateral aspects of the brain in the area of the sylvian fissure. Scattered heterotopic neurons may be found in the centrum semiovale, the subcortical white matter, and cerebel- lar white matter. Mild dysplasia of the inferior olivary nucleus is noted. In addition, lack of stainable myelin is found in the cerebral and cerebellar white matter, probably partially related to a disturbance of myeli- nation, but there is also evidence of active demyelina- tion. The extent of both components also depends on the age at death. In infants of a few months the myelin content of the brain may be normal. In older infants, an evident deficiency of myelin is seen with relative sparing of the arcuate fibers. The active demyelina- tion is most prominent in the cerebellar and occipital white matter. In the areas of active demyelination, axons are relatively spared. Lipid-filled, foamy macro- phages, occasionally striated, and astrocytosis are seen in the areas of demyelination, cerebral cortex, and basal nuclei. The macrophages are located in the perivascular spaces. Cystic degeneration of the periventricular white matter has been observed. In the spinal cord the anterior and lateral corticospinal tracts and dorsal spinocerebellar tracts show loss of axons and myelin.

In liver, mild fibrosis is found. Electron microscopy of liver shows abundant peroxisomes. Additionally, adrenocortical atrophy is found with presence of lipid-containing, ballooned, striated cells. Electron microscopy reveals trilamellar lipid inclusions in these cells. Minute glomerular cysts may be seen in the kidney, but not in all cases.

Peroxisomal D-Bifunctional Protein Deficiency

19.3 Pathogenetic Considerations

D-bifunctional protein is involved in the b-oxida- tion process of both very-long-chain fatty acids, branched-chain fatty acids, like pristanic acid, and the oxidation of bile acid precursors. D-bifunctional pro- tein has two catalytic activities: enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activity. In some patients (group 2A), D-bifunctional protein is completely absent, which is associated with the loss of activity of both the enoyl-CoA hydratase and 3-hy- droxyacyl-CoA dehydrogenase components. In group 2B patients, enoyl-CoA hydratase activity is deficient, whereas in group 2C 3-hydroxyacyl-CoA dehydro- genase activity is deficient. Group A and group C patients accumulate very-long-chain fatty acids, branched-chain fatty acids, and abnormal bile acid intermediates. Group B patients have elevated very- long-chain fatty acids and branched-chain fatty acids, but bile intermediates are normal, due to the normal 3-hydroxyacyl-CoA dehydrogenase activity.

In patients with BPD, mutations have been found in the gene D-BP, located on chromosome 5q23.1. The patient formerly classified as a thiolase-deficient pa- tient (Goldfischer et al. 1986) also has a defect in the D-BP gene (Ferdinandusse et al. 2002).

It is striking that a disease caused by an isolated deficiency of one of the peroxisomal b-oxidation enzymes can have clinical symptomatology that is in- distinguishable from that of peroxisome biogenesis defects. This observation indicates the pathophysio- logical significance of accumulation of very-long- chain fatty acids and abnormal bile acid intermedi- ates. Evidently, the relationship between biochemical abnormalities and clinical symptomatology requires further elucidation.

19.4 Therapy

No specific treatment is possible. Supportive care is important.

19.5 Magnetic Resonance Imaging

A number of CT scans have been reported. Most were described as normal, some as showing white matter hypodensity and slight enlargement of the occipital horns of the ventricular system.

MRI shows a combination of polymicrogyria, especially over the lateral aspects of the brain in the area of the sylvian fissure, and white matter abnor- malities (Fig. 19.1). The white matter abnormalities consist of delayed and disturbed myelination (Fig. 19.2), while in particular in the older infants with more advanced myelination active demyelina- tion occurs (Figs. 19.3 and 19.4). The demyelination is most pronounced in brain stem tracts and occipital and cerebellar white matter (Fig. 19.4).

The combination of gyrational abnormalities and deficient myelination is also seen in Zellweger syn- drome. The combination of gyrational abnormalities and demyelination with predilection for the cerebel- lar and occipital white matter is also seen in neonatal adrenoleukodystrophy. In BPD no inflammatory reaction is seen in the area of active demyelination.

In conformity with this observation, no contrast en- hancement was found on the CT of the child who had active demyelination at autopsy, unlike the situation in neonatal adrenoleukodystrophy, where extensive contrast enhancement is seen.

Chapter 19 Peroxisomal D-Bifunctional Protein Deficiency 168

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Fig. 19.1. Baby boy, 3 weeks old, with BPD. The sagittal T

- weighted images show a germinolytic cyst in the thalamocau- date notch and polymicrogyria in the perisylvian region. The axial T

-weighted images confirm the perisylvian polymicro- gyria. There are possibly some small heterotopias around the

lateral ventricles. Myelination is compatible with a neonatal

stage. These images are indistinguishable from those seen in

Zellweger syndrome. Courtesy of Dr. D. Holder, Department of

Pediatric Neurology, Cincinnati Children’s Hospital, Cincinnati

Chapter 19 Peroxisomal D-Bifunctional Protein Deficiency 170

Fig. 19.2. Follow-up MRI of the same boy with BPD at the age of 6 months. The polymicrogyria in the perisylvian region is again visualized. The brain stem is now well myelinated, but there is little myelin in the supratentorial white matter. Note

the lesions in the hilus of the dentate nucleus. Courtesy of Dr. D. Holder, Department of Pediatric Neurology, Cincinnati Children’s Hospital, Cincinnati

Fig. 19.3. Follow-up MRI of the same boy with BPD at the age of 22 months. Demyelination has started in the pyramidal tracts of the brain stem. The cerebellar white matter is also

affected. Courtesy of Dr. D. Holder, Department of Pediatric Neurology, Cincinnati Children’s Hospital, Cincinnati

019_Valk_PeroxisomalD 08.04.2005 15:30 Uhr Seite 170

Fig. 19.4. Follow-up MRI of the same boy with BPD at the age of 26 months, shortly before he died. The process of demyeli- nation now involves the brain stem more extensively. The posterior limb of the internal capsule and posterior cerebral

white matter are also involved. Courtesy of Dr. D. Holder,

Department of Pediatric Neurology, Cincinnati Children’s Hos-

pital, Cincinnati