Abstract
Objective: To report late onset cerebral white matter disease as a distinctive phenotype in peroxisome biogenesis disorder (PBD).
Background: There is phenotypic and genetic overlap among the PBD known as Zellweger syndrome (ZS), infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NALD). Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy. In a structured follow-up cohort of 25 patients with PBD, not including ZS, three patients had an unusual pattern of cerebral white matter disease with onset past the age of 1, not conforming to any of the classic PBD phenotypes.
Methods: Clinical phenotyping and follow-up, peroxisomal biochemical determinations in body fluids and fibroblasts, identification of affected PEX gene by genetic complementation in fibroblasts, and MRI studies.
Results: Two unrelated patients with PBD without distinctive external features had normal neurodevelopmental milestones during their first year, followed by rapid deterioration including severe hypotonic pareses, seizures, retinopathy, and deafness. A third patient initially diagnosed with IRD developed cerebral white matter degeneration in the third year of life, complicating the original diagnosis. MRI in all three patients showed cerebral demyelination with sparing of subcortical fibers and pronounced central cerebellar demyelination.
Conclusions: Late-onset cerebral white matter disease may occur in PBD, either following IRD or following normal early development and in the absence of distinctive external features. Peroxisome biogenesis disorder should be included in the differential diagnosis of post-infantile onset of cerebral white matter disease.
Inherited disorders of peroxisomal function can arise principally in two ways: by absence of a specific peroxisomal enzyme or by a failure to form peroxisomes resulting in a generalized or multiple deficiency of peroxisomal enzymes. The latter group is known as peroxisome biogenesis disorders (PBD).1,2⇓ The peroxisome, an ubiquitous organelle in nucleated cells, incorporates a set of substrate-specific metabolic pathways. Most of these pathways have a role in the formation and functioning of the brain, and to some extent also the peripheral nervous system. These pathways include peroxisomal β-oxidation required for chain-shortening of saturated and mono-unsaturated very long-chain fatty acids (VLCFA), peroxisomal α- and β-oxidation of long branched chain fatty acids (foremost phytanic acid), the formation of polyunsaturated fatty acids (PUFA), the synthesis of etherphospholipids (plasmalogens), and the synthesis of bile acids. Peroxisomal enzymes are synthesized on free ribosomes. Failure to import the enzymes into the peroxisome results in peroxisome biogenesis disorders. Table 1 presents two defined classes of peroxisomal disorders.3,4⇓ A subset of PBD, known as generalized peroxisomal disorders, has a varied symptomatology with at least three phenotypes commonly described: Zellweger syndrome (ZS), infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NALD).1 Common to all three are liver disease, variable neurodevelopmental delay, retinopathy, and perceptive deafness with onset in the first months of life. In addition, patients with ZS are severely hypotonic and weak from birth and have distinct facial features, periarticular calcifications, severe brain dysfunction associated with neuronal migration disorder, and die before 1 year of age. Patients with NALD have hypotonia and seizures, may have polymicrogyria, have progressive white matter disease, and usually die in late infancy. Patients with IRD have external features reminiscent of ZS, no neuronal migration disorder, and no progressive white matter disease. Their cognitive and motor development varies between severe global handicap and moderate learning disorder with deafness and visual impairment due to retinopathy. Their survival is variable. Most patients with IRD reach childhood and some even reach adulthood. Clinical distinction between PBD phenotypes, however, is not well defined. At present, at least 10 PEX (“peroxin”) genes have been identified. Nine of these are associated with a generalized peroxisomal disorder (ZS, IRD, NALD). Of the known PEX genes, until now, seven have become associated with more than one phenotype,3 indicating that these disorders represent a spectrum rather than well separated entities. Categorization within this spectrum is difficult in some cases with an atypical course. Recently we identified three children with a PBD who had rapid neurologic regression associated with cerebral white matter involvement after their first year. We describe and discuss their phenotypes, extending the spectrum of generalized peroxisomal disorders.
Peroxisomal disorders with nervous system involvement and their classification into two groups
Patients and methods.
The patients belonged to a group of 25 patients with a PBD and prolonged survival after the first year (not including ZS) whose follow-up is an ongoing study to define phenotype/genotype relations in patients with a generalized peroxisomal disorder. Peroxisomal investigations in body fluids and fibroblasts and complementation analysis for PEX gene identification were done according to standard procedures developed in our laboratory.5-11⇓⇓⇓⇓⇓⇓
MRI was performed on a 1.5-T unit and included axial T1-weighted spin echo MR images (repetition time [TR]/echo time [TE]/number of acquisitions 570/14/2, 23 × 23 cm field of view [FOV], 192 × 256 matrix) and axial fast spin-echo T2-weighted MR images (TR/TE/number of acquisitions 3500/22–90/1, 23 × 23 cm FOV, 192 × 256 matrix).
Results.
The clinical findings of the three patients are listed in table 2. Patients 1 and 2 had no distinctive external features. Their development was normal during the first year followed by general loss of cerebral functions, retinopathy, deafness, and ultimate death. Patient 3 had mild distinctive external features (figure 1), delayed closure of the fontanel, and moderate developmental delay during the first 2 years before precipitous and fatal regression set in during the third year. Her external features, early onset retinopathy, deafness, and moderate delay in development during the first year are in line with the initial diagnosis of IRD. Patients 1 and 3 were the offspring of consanguineous marriages.
Clinical findings
Figure 1. Patient 3 at 14 months. A and B highlight facial features of infantile Refsum disease, which include high forehead, epicanthal folds, and hypoplastic earlobules, reminiscent of but less prominent than the much more severe Zellweger syndrome phenotype.
Cerebral MR studies in the three patients revealed white matter involvement in all three, with relative sparing of the subcortical fibers, and striking involvement of the central cerebellar white matter (figures 2 through 4⇓⇓).
Figure 2. Patient 1 at age 3.5 years. Axial fast T2-weighted spin echo MRI (3500/90/1). (A) Cerebral hemisphere with demyelination affecting the central white matter, splenium of corpus callosum, external capsule, posterior internal capsule, posterior thalamus, and globus pallidus. (B) Posterior fossa with demyelination of central parts of cerebellar hemispheres. Symmetric involvement of medulla oblongata includes corpus restiforme and olivo-cerebellar fibers and pyramidal tracts.
Figure 3. Patient 2 at 1.5 years. Axial fast T2-weighted spin echo MRI (3500/90/1). (A) Supraventricular part of cerebral hemispheres showing demyelination of central white matter with sparing of U-fibers. (B) Involvement of central cerebellar white matter.
Figure 4. Patient 3 at 2 years. Axial fast T2-weighted spin echo MRI (3500/90/1). (A) Supraventricular part of cerebral hemispheres with demyelination of central white matter. (B) Severe involvement of central cerebellar white matter.
The biochemical findings of the three patients are listed in table 3. The results show that in all three patients plasma VLCFA, pristanic acid, phytanic acid, erythrocyte docosahexaenoic acid, and plasma di- and trihydroxycholestanic acid were abnormal except for normal phytanic acid and pristanic acid in Patient 3, a finding that may be related to dietary phytanic acid restriction. Fibroblast studies confirmed that β-oxidation of C26:0 and pristanic acid and α-oxidation of phytanic acid were essentially abnormal in all three patients. With respect to plasmalogen synthesis, results were different in the three patients. In Patient 3 all findings pointed to severe impairment of plasmalogen metabolism. In Patient 1 plasmalogen metabolism was moderately impaired. In Patient 2 results of plasmalogen studies were normal except for mildly decreased dihydroxyacetonephosphate acyltransferase activity in fibroblasts. Catalase positive particles (peroxisomes) were absent in Patients 2 and 3, and diminished in Patient 1.
Biochemical findings and PEX gene
Screening for other inherited metabolic diseases was negative, including urinary organic acids, determinations of lactate and pyruvate in plasma, and muscle studies to exclude respiratory chain disease in Patient 2. Motor nerve conduction velocities were normal in all three patients. Complementation studies revealed that Patient 3 belonged to the PEX5 group12 and Patient 2 to the newly discovered PEX13 group.13 Patient 1 could not be assigned to a known complementation group but could be excluded from PEX1, PEX5, PEX6, PEX13, and complementation Group 8 (CG8).
Discussion.
Patients 1 and 2 in this report share important features with NALD: biochemical findings of PBD, absence of distinguishing external features, retinopathy, sensory deafness, and progressive white matter disease. Atypical for NALD are normal development in the first year and the precipitous onset of neurologic regression after the age of 1 year. In Patient 3 the initial diagnosis was IRD because of PBD with mild external distinguishing features (figure 1), retinopathy, sensory deafness, and onset of moderate delay in mental and motor development in the first months of life. She differed, however, from “classic” IRD by her precipitous neurologic regression in late infancy with associated cerebral white matter disease. In all three patients cerebral demyelination was found in the supratentorial white matter sparing the U-fibers. Typical in all three cases was involvement of the central cerebellar white matter. Brainstem white matter involvement was seen in one.
Previously reported autopsies in NALD describe cerebral, cerebellar, and brainstem white matter degeneration14,15⇓ with associated mononuclear perivascular cuffing.14 Whereas the large majority of patients in earlier NALD series present neonatal or early infantile onset,14,15⇓ exceptions are on record. One patient15 was neurologically normal until the end of the first year when he developed leukodystrophy with cerebral and cerebellar demyelination confirmed by autopsy at 7 years. In a series comprising 93 patients with generalized peroxisomal disorder2 the course in one patient, assigned to complementation Group 7 (present PEX10), was similar to our Patients 1 and 2, manifesting at age 22 months with spastic diplegia, MRI findings of cerebral demyelination, and death at 4.7 years. A female patient in this series assigned to complementation Group 1 (now PEX1 gene) had severe hearing impairment and retinopathy with onset in early childhood, normal intelligence, mental regression, and behavioral disturbance in her thirties with MR evidence of leukodystrophy at 37. Late regression may complicate IRD but white matter involvement is not a typical component of this phenotype. Two autopsy reports of patients classified as IRD emphasize the absence of overt demyelination.16,17⇓ Cerebral and cerebellar demyelination was discovered by MRI in two patients with “generalized peroxisomal disorder and peroxisomal mosaicism,” failure to thrive in infancy, and neurologic regression during childhood.18,19⇓
Attempts at treatment in the patients presented here included the usual dietary measures such as phytanic acid restriction, treatment of deficiencies of fat soluble vitamins, especially vitamins E and K, and the correction of docosahexaenoic acid (DHA) deficiency by oral supplements. Patients 1 and 2 were given DHA after onset of regression. Patient 3 had her DHA deficiency corrected prior to onset of leukodystrophy as indicated by levels in plasma and erythrocyte membranes. In Patient 3, visceral complications—i.e., pneumonitis and renal stones—complicated the course. A search for possible causes of the latter revealed moderately increased excretion of oxalate, but normal excretion of glycol, and decreased phosphate reabsorption with normal parathyroid function. Alanine glyoxylate aminotransferase is a peroxisomal enzyme, which becomes cytosolic in the case of a generalized peroxisomal disorder but this does not usually lead to hyperoxaluria.20 Two cases of a generalized disorder with hyperoxaluria and renal stones have been described previously, although the mechanism of this exceptional behavior has not been explained despite extensive investigations.21
The reason for the late onset of regressive white matter disease in generalized peroxisomal disorders is unknown. Typical storage of VLCFA in the brain of children with NALD in some respects resembles childhood onset X-linked adrenoleukodystrophy including macrophages with trilaminar inclusions.14,15⇓ Diminished turnover of VLCFA in myelin leads to storage in brain macrophages and subsequent cytokine related inflammatory response.22 A similar situation may exist in generalized peroxisomal disorders because the essential biochemical abnormality of X-linked adrenoleukodystrophy (XALD) is the impairment of the peroxisomal β-oxidation of VLCFA, a situation that also forms part of generalized peroxisomal disorders. The pattern of white matter involvement in the current disorder is different from that encountered in XALD. Early cerebellar white matter involvement is not seen in XALD, but appears characteristic for the patients in this report. Also, signs of cavitation, a usual feature in late XALD, were not found. The frequency of the abnormality we described appears low. The patients described in this study belong to a group of 25 patients with generalized peroxisomal disorders enrolled in a multicenter study for detailed analysis of their genetic and phenotypic features. No other patients with a similar course are known to us. In two published series, one with 93 patients with PBD2 and one with 19 patients with PBD,23 only the former included a patient with a course similar to the patients described above, underlining the rarity of the current phenotype. One possible pitfall in diagnosis should be mentioned. Males with childhood onset of white matter disease and increased VLCFA in plasma will be diagnosed routinely with X-linked adrenoleukodystrophy. However, in the case of clinical onset before 4 years of age or in case of atypical MR findings such as central cerebellar involvement, additional peroxisomal investigations will be necessary to differentiate between XALD and PBD-linked white matter disease.
Acknowledgments
Supported by Prinses Beatrix Fonds, grant 98-0202.
- Received April 30, 2001.
- Accepted August 30, 2001.
References
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