Neonatal seizures and retardation in a girl with biochemical features of X-linked adrenoleukodystrophy: a possible new peroxisomal disease entity

Neonatal hypotonia, seizures beginning at 5 days, and severe retardation were noted in a girl with normal karyotype and biochemical evidence of impaired adrenal function. Postmortem examination at 14 months revealed malformative and destructive lesions of central gray and white matter, atrophy of adrenal cortex with striated adrenocortical cells, hepatic fibrosis, and PAS-positive macrophages in several organs. Pathologically and clinically, this patient most closely approximated neonatal adrenoleukodystrophy (ALD) and differed strikingly from X-linked childhood ALD. In contrast, biochemical changes resembled the abnormalities observed in X-linked ALD and differed from those in the neonatal form. The very-long-chain fatty acid accumulation characteristic of both disorders was demonstrated, but unlike neonatal ALD, the levels or metabolism of plasmalogens, pipecolic acid, phytanic acid, and bile acid intermediates were normal, and peroxisomes in a liver biopsy specimen were present in normal number and appeared enlarged. While the case resembles the recently reported entity of peroxisomal acyl-CoA oxidase deficiency, assignment to this category was excluded by immunoblot studies on postmortem liver, which revealed normal amounts of this enzyme. Correlation of clinical, morphologic, and biochemical data suggests that this case is an example of a so-far undescribed entity, and reinforces the concept that the phenotypic spectrum of peroxisomal disorders is wider than realized.     

Neonatal adrenoleukodystrophy.

Nine cases of neonatal adrenoleukodystrophy are described. All patients had abnormal facial features, moderate to severe hypotonia, hepatomegaly, and retinitis pigmentosa. The clinical course was rapidly progressive in six cases and more protracted in three others. Biological signs of adrenal insufficiency were present in five cases. CT scan showed a demyelinating process in four patients. Trilamellar inclusions were found in the liver of four cases and dark and complex lipidic inclusions in three other cases. In the three necropsied patients there was severe alteration of the white matter involving particularly the cerebellum in two cases. Gyral and cytoarchitectonic disturbances were absent in all three cases. Increased plasma levels of very long chain fatty acids (8/8), phytanic acid (7/8) and bile fluid trihydroxycoprostanic acid (2/4) confirmed the deficiency of multiple peroxisomal enzymes. Clinical, histopathological and biochemical findings of these nine cases are compared to those reported in other neonatal adrenoleukodystrophy cases and to those of other neonatal peroxisomal disorders, that is cerebro-hepato-renal syndrome of Zellweger and infantile Refsum's disease.     

Two siblings of Leber's congenital amaurosis with an increase in very long chain fatty acid in blood: relationship between peroxisomal disorders and Leber's congenital amaurosis

We reported two siblings of Leber's congenital amaurosis associated with increased level of very long chain fatty acid (VLCFA) in blood. Case 1, a 3 1/2-year-old boy had congenital blindness, severe psychomotor retardation, hepatomegaly, profound hypotonia, loss of deep tendon reflexes, muscular atrophy and weakness, and non-convulsive status epilepticus characterized by a sudden respiratory failure, and also showed a flat electroretinogram, non-pigmentary retinal degeneration, severe atrophy of the brain stem and cerebellum, hepatic fibrosis, decreased motor and sensory conduction velocities and atlanto-axial instability. Sural nerve biopsy revealed severely decreased number of total myelinated fibers without remarkable demyelination or remyelination. Case 2, an elder sister of case 1, with pigmentary retinal degeneration, hepatomegaly and pericarditis had died at 3 months. Autopsy revealed hypomyelination and heterotopy of the cerebral white matter, hepatic fibrosis, renal microcysts and normal adrenal cytoarchitecture. In case 1, the level of VLCFA was increased twofold and sevenfold of controls in serum and in red cell membrane, respectively. Phytanic or trihydroxycholestanoic acid was not detected in the serum and bile. Normal shaped peroxisomes were definitely recognized in biopsied liver by means of electronmicroscopic histochemistry. From the above findings, these patients was thought to be a new variant of peroxisomal disorders relating to degradation of VLCFA, other than Zellweger syndrome, infantile Refsum disease and infantile adrenoleukodystrophy. It was concluded that peroxisomal functions should be studied in cases of Leber's congenital amaurosis.     

Adrenomyeloneuropathy with bulbar palsy: A rare association

Adrenomyeloneuropathy (AMN) is a variant of adrenoleukodystrophy (ALD), an X-linked recessive peroxisomal disorder associated with accumulation of very long chain fatty acids (VLCFA). Mutations of this gene lead to abnormal peroxisomal β-oxidation, which results in the harmful accumulation of VLCFAs in affected cells. Neurological symptoms occur due to progressive demyelination and destruction of cerebral white matter and primary adrenal insufficiency. Bulbar palsy in a case of AMN is very unusual. We report a case of a 22-year-old male with AMN who developed adrenal insufficiency at the age of 4 years successfully treated by gluco- and mineralocorticoids followed by features of myeloneuropathy with bulbar palsy. AMN with prominent bulbar symptoms emphasizes the diverse clinical manifestation of this disease.     

Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy

The neuropathologic features of adrenomyeloneuropathy (AMN) are reviewed by supplementing those few previously published cases with 5 additional cases collected over the years. The endocrine involvement in AMN is briefly presented to serve as a pathogenetic backdrop and to emphasize that most of the lesions in AMN, as in adreno-leukodystrophy (ALD), are noninflammatory in the traditional sense of the word. The myeloneuropathy is emphasized, but the dysmyelinative/inflammatory demyelinative lesions also are presented. The preponderance of available data indicates that the myeloneuropathy of AMN is a central-peripheral distal (dying-back) axonopathy, as was originally proposed. The severity of the myeloneuropathy does not appear to correlate with the duration or severity of endocrine dysfunction. Microglia are the dominant participating cells in the noninflammatory myelopathy. Abnormalities in the ALD gene, which encodes a peroxisomal ABC half-transporter, do not correlate with clinical phenotypes. The relationship of the gene product, ALDP, to the peroxisomal very long chain fatty acid (VLCFA) synthetase, the activity of which is deficient in ALD/AMN, is unclear. An ALD-knockout mouse model has developed axonal degeneration, particularly in spinal cord, and is therefore more reminiscent of AMN than ALD. We continue to postulate that the fundamental defect in the myeloneuropathy of AMN is an axonal or neuronal membrane abnormality perhaps due to the incorporation of VLCFA-gangliosides, which perturbs the membrane's microenvironment and leads to dysfunction and atrophy.     

Neonatal seizures and severe hypotonia in a male infant suffering from a defect in peroxisomal beta-oxidation.

In this paper, we describe a baby male born to healthy non-consanguineous parents presenting at birth with hypotonia and seizures. Additional salient clinical features included the development of glaucoma, the absence of significant facial dysmorphism and the absence of liver enlargement or renal cysts. The patient died at the age of 3 months. At autopsy, liver fibrosis and kidney glomerulosclerosis were noted. Neuropathological findings included pachygyria of the olivary nuclei and cerebellar neuronal heterotopias. There was no evidence for a demyelinating process. Biochemically, the patient was found to have elevated plasma levels of very-long-chain fatty acids (VLCFA) and abnormal bile acid intermediates, whereas other indicators of peroxisomal function (plasmalogen biosynthesis and plasma pipecolic acid) were normal. Catalase staining of a liver biopsy specimen revealed peroxisomes to be present in normal numbers, although some were abnormally large. Trilamellar inclusions typical of a peroxisomal fatty acid oxidation defect were present in macrophages. Indeed, beta-oxidation of the very-long-chain fatty acid hexacosanoic acid (C26:0) was found to be strongly deficient. Fatty acyl-CoA oxidase activity in the patient's liver was normal, however. Furthermore immunocytochemical studies using antibodies against acyl-CoA oxidase, bifunctional protein and peroxisomal thiolase, revealed the normal localization of all three enzyme proteins within the peroxisomes. We suggest that our patient has a selective peroxisomal beta-oxidation defect, a recently identified heterogeneous group of early-onset peroxisomal disorders distinct from the Zellweger syndrome and other generalized peroxisomal disorders.     

Bilateral striopallidodentate calcification (Fahr's syndrome) and multiple system atrophy in a patient with longstanding hypoparathyroidism

Recently, a family with idiopathic brain calcification was reported, in which one family member was diagnosed with multiple system atrophy (MSA) at autopsy. We report here a case showing similar neuropathological features in a patient with longstanding hypoparathyroidism. Our female patient had a history of hypoparathyroidism with hypocalcaemia and tetany since the age of 9 years. In her 50s she developed dementia and parkinsonism. She died of myocardial infarction aged 65 years. Neuropathology showed severe brain calcifications of the Fahr type in the basal ganglia, thalami, cerebral and cerebellar white matter and dentate nuclei. Additionally, there was prominent alpha‐synucleinopathy of the multiple system atrophy type (MSA). The patient has a healthy identical twin and there is no family history of hypoparathyroidism or neurological disease. Data on alpha‐synuclein accumulation in various cases of Fahr's syndrome are needed to establish the correlation between alpha‐synucleinopathy and bilateral striopallidodentate calcification.     

Adult‐onset cerebello‐brainstem dominant form of X‐linked adrenoleukodystrophy presenting as multiple system atrophy: case report and literature review

X‐linked adrenoleukodystrophy (X‐ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello‐brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy‐confirmed cases exceedingly rare. We report a 69‐year‐old White man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X‐ALD or Addison's disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of MSA. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS‐positive, CD68‐positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting the optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft‐like trilamellar cytoplasmic inclusions in macrophages typical of X‐ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello‐brainstem dominant form of X‐ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult‐onset cerebello‐brainstem dominant form of X‐ALD. Although rare, X‐ALD should be considered in the differential diagnosis of MSA.     

Clinical approach to inherited peroxisomal disorders: A series of 27 patients

To illustrate the clinical and biochemical heterogeneity of peroxisomal disorders, we report our experience with 27 patients seen personally between 1982 and 1997. Twenty patients presented with a phenotype corresponding either to Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease, 3 of whom had a peroxisomal disorder due to a single enzyme defect. One patient had a mild form of rhizomelic chondrodysplasia punctata, 1 had classic Refsum disease. Finally, 5 patients presented with clinical manifestations that were either unusually mild or completely atypical, and initially did not arouse suspicion of a peroxisomal disorder. They showed multiple defects of peroxisomal functions with one or several functions remaining intact, suggesting a peroxisome biogenesis disorder. The defect in peroxisome biogenesis was further characterized by variable expression in different tissues and/or individual cells in 5 patients. Studies restricted to fibroblasts failed to identify abnormalities in this group. We demonstrate that clinical manifestations of peroxisomal disorders may be very mild or completely atypical, and therefore, peroxisomal disorders should be considered in a variety of clinical settings. Furthermore, we suggest performing extensive peroxisomal investigations in every patient suspected of suffering from a peroxisomal disorder, even when the clinical presentation is typical.     

Cortical cerebellar atrophy presenting with central type sleep apnea syndrome]

The patient was a 55-year-old man who had shown progressive dysarthria and unsteady gait since 48 years of age. Neurologically, pure cerebellar ataxia without either pyramidal or extrapyramidal signs was seen. He had been diagnosed as having cortical cerebellar atrophy (CCA) at age 53. Polysomnography was carried out at June 17th, 2003, because of snoring and sleep apnea had occurred since January 2003. The results showed central dominant sleep apnea with an apnea index (AI) of 16.6. Apnea occurred during shallow sleep, stages I and II, while the length of REM sleep was almost normal, occupying 17.7% of total sleep time. The rhythm of his sleep was well preserved. Brain MRI showed cerebellar atrophy without any brainstem abnormality. Except for the central type sleep apnea, no other autonomic symptoms were found. We considered that the diagnosis of CCA remained applicable to the patient because of the presence of pure cerebellar symptoms over a 7-year-course, and the absence of brainstem atrophy on MRI. Sleep apnea seen in the present patient was distinct from MSA in which central type sleep apnea dominated, and that the sleeping rhythm including REM was preserved.     

A novel form of familial congenital muscular dystrophy in two adolescents

We report on two brothers (the product of first-degree consanguineous marriage; aged 15 and 12 years) who presented with severe hypotonia at birth, proximal muscle weakness associated with delayed motor milestones but normal cognitive function. Investigations (at 4 years of age) revealed mildly elevated serum creatine kinase (CK) levels (300 and 824 IU/l; N < or = 210). Muscle biopsies showed minimal change myopathy, no neurogenic atrophy but remarkable type-1 fibre predominance (up to 85.5%) without fibre-type disproportion. Clinical examination at 12 and 9 years, respectively, showed mild facial weakness and high-arched palate in both patients. The younger sibling also had ptosis but otherwise normal external ocular muscles. They showed symmetric proximal muscle weakness and wasting associated with calf-muscle hypertrophy. They could walk independently. A repeat muscle biopsy showed advanced dystrophic changes in the younger patient at the age of 10 years. Virtually all the remaining fibres were type 1. Immunohistochemistry revealed normal expression of the dystrophin-glycoprotein complex (DGC), including dystrophin, beta-dystroglycan, alpha-(adhalin), beta-, gamma-, and delta-sarcoglycan, laminin-alpha2 chain (merosin) and syntrophin. Mild dystrophic features and type-1 fibre predominance (92.5%) were seen in the biopsy of the older patient, whereas immunohistochemistry showed normal expression of the DGC. Both cases also showed clear expression of integrin alpha7 at the muscle fibre surface and in the blood vessels. Three years later, they could still walk, but with difficulty, and the older brother showed enlargement of the tongue and echocardiographic features of left ventricular dilated cardiomyopathy.     

Mitochondrial encephalomyopathy with autosomal dominant inheritance: A clinical and genetic entity of mitochondrial diseases

We report a Japanese family with chronic progressive external ophthal-moplegia (CPEO) with autosomal dominant inheritance, and review 54 reported CPEO patients in seven families (including the present family) with autosomal dominant inheritance and mtDNA deletions in the skeletal muscle. Mean age at onset in the CPEO was 26 years, which is older than that in published solitary cases. In addition to blepharoptosis and external ophthalmoplegia, proximal muscle atrophy and weakness were found in 62%, hearing loss in 25%, and ataxia in 17% of the patients. Retinal degeneration was not found, and cardiac involvement was very rare. mtDNA deletions in the muscle were multiple and large scale, and all such deletions were located in the non–D-loop region. Autosomal dominant CPEO has unique clinical features which differ from those of solitary CPEO, and is associated with multiple large-scale mtDNA deletions. Thus, autosomal dominant CPEO can be considered a clinical and genetic entity of mitochondrial diseases. © 1995 John Wiley & Sons, Inc.     

Mannosidosis. New clinical presentation, enzyme studied, and carbohydrate analysis.

Mannosidosis is a rare inborn error of metabolism characterized by deficiency of the lysosomal enzyme alpha-mannosidase and widespread storage of complex carbohydrate, which is enriched in mannose. Two affected unrelated males, aged 6 and 26 years, are reported. Both had a nonprogressive encephalopathy with moderately severe mental retardation. The older patient showed several unique features, including massive gingival hyperplasia associated with histiocytes containing large amounts of a material with the staining characteristics of glycoprotein. The best determinant of mannose storage proved to be the ratio of mannose to other carbohydrates in urinary polysaccharides. The enzyme deficiency in this disease is most convincingly demonstrated at pH values below 4.0. The ability of zinc to activate the mutant enzyme in vitro offers a possible mode of therapy for this disease. Retarded individuals with a Hurler-like appearance and gum hyperplasia of unknown cause should be screened for alpha-mannosidase deficiency.     

Peripheral neuropathy associated with erythrophagocytic lymphohistiocytosis.

A 12 year old patient who developed clinical, biochemical and histological features of erythrophagocytic lymphohistiocytosis is described. In contrast to previously reported cases, the prominent neurological feature was a subacute sensorimotor polyneuropathy. Sural nerve biopsy showed a marked reduction of myelinated fibres and severe axonal lesions, absence of histiocyte infiltration and deposits of IgM along the epineurium. In addition to the hypertriglyceridaemia previously described in this condition, an elevation of plasma very long-chain fatty acids and phytanic acid was found which suggests a transient impairment of peroxisomal functions.     

A missense point mutation (Ser515Phe) in the adrenoleukodystrophy gene in a family with adrenomyeloneuropathy: a clinical, biochemical, and genetic study.

A 36 year old male patient with adrenomyeloneuropathy (AMN) developed progressive spastic paraparesis and sensory ataxia from the age of 18. Biochemical studies showed increased plasma concentrations of saturated very long chain fatty acids (VLCFAs), subclinical evidence of adrenal insufficiency, and primary hypogonadism. Three female family members had increased plasma concentrations of VLCFAs, suggesting carrier status of adrenoleukodystrophy (ALD). Molecular genetic analysis detected a missense point mutation (C1930T) in exon 6 within the ALD gene, which predicts substitution of an amino acid (Ser515Phe) that is conserved between the deduced amino acid sequence of the peroxisomal membrane protein PMP70 and ALD protein. Detection of this point mutation allows diagnosis of ALD or AMN, identification of heterozygotes, and prenatal diagnosis of ALD.     

Ataxic variant of adrenoleukodystrophy: MRI and CT findings

Summary A 28-year-old man developed slowly progressive dysarthria and gait disturbance over 7 years. Neurological examination revealed marked ataxia of articulation and gait, mild ataxia and spasticity of all four limbs without intellectual, visual, auditory, sensory or sphincter dysfunction. No physical signs of adrenal hypofunction were found. However, analysis of fatty acid of plasma sphingomyelin showed an increase in very long chain fatty acids, compatible with the diagnosis of adrenoleukodystrophy. Computed tomography disclosed marked atrophy of the cerebellum and pons, and bilateral low-density lesions in the deep while matter of the cerebellum. Magnetic resonance imaging showed these lesions more clearly, as well as other lesions in the middle and superior cerebellar peduncles, despite the absence of cerebral white matter involvement at the time of presentation. This is a rare case of adrenoleukodystrophy presenting as spinocerebellar degeneration and showing marked atrophy and several parenchymatous lesions of the cerebellum and brain stem.     

Unilateral hippocampal sclerosis with contralateral temporal scalp ictal onset

PURPOSE: To investigate the clinical characteristics and surgical outcomes in patients with unilateral hippocampal sclerosis whose scalp ictal EEG recordings localize to the opposite temporal lobe. METHODS: We retrospectively reviewed the data of all adult patients who had undergone depth electrode implantation for suspected temporal lobe epilepsy (TLE) at UCLA (1993-2000) or the Montreal Neurological Institute (1991-1998) to identify patients who had (a) unilateral hippocampal atrophy, and (b) surface ictal recordings in which the majority of seizures appeared to initiate in the opposite temporal lobe, with few or none that were concordant with the hippocampal atrophy. RESULTS: Of 109 patients with suspected TLE who underwent depth electrode study at the two centers, five patients met the aforementioned criteria. Four of these five had very severe hippocampal atrophy, whereas the fifth had mild atrophy but extensive signal change on magnetic resonance imaging (MRI). Depth electrode recordings in four of the five patients yielded clear ictal onset in the mesial temporal lobe ipsilateral to the imaging abnormality (contralateral to apparent scalp ictal onset). One patient had an unusual bitemporal onset pattern, which was nonetheless suggestive of onset in the sclerotic hippocampus. No patient had intracranial ictal onset contralateral to the imaging abnormality. All patients underwent resection of the structurally abnormal temporal lobe. After follow-up of > or = 2 years, four (80%) of five patients were seizure free, while the fifth showed lesser improvement (class III). CONCLUSIONS: Some patients with severe hippocampal sclerosis (sometimes called a "burned-out hippocampus") have atypical spread of ictal discharges, resulting in apparent gross discordance between imaging and scalp ictal recordings. These patients nonetheless have excellent surgical outcomes on the whole. Whether such patients may forego intracranial recordings requires further study.     

Cranial computed tomography in the diagnosis of multiple sclerosis.

A group of 202 patients with suspected, probable or definite multiple sclerosis was studied, using cranial computed tomography (CT). Atrophy alone, or in combination with white-matter and periventricular lucencies, and areas of contrast enhancement, were the main abnormal findings in 52% of patients. Atrophy was detected in 44% of patients, and its frequency and severity correlated with disease duration up to 10 years, age, and disease category. Atrophic changes in the brainstem and cerebellum could be correlated with clinical data more often than supratentorial atrophy could be correlated with features such as dementia or mood changes. Lucencies in the white matter, thought to represent areas of demyelination, were noted in 21% of patients, and only a proportion of these lesions could be correlated with clinical data, the others being clinically silent. Contrast enhancement was seen in a small proportion of white-matter lesions, and was independent of disease activity and steroid medication. Electrophysiological tests and cerebrospinal fluid analysis showed a higher yield of abnormality than CT scanning in cases with suspected or possible multiple sclerosis, though in such patients CT scanning excluded alternative cerebral atrophy. Modifications of the technique of CT scanning may improve the detection rate of white-matter lesions, thereby enhancing the value of CT as a diagnostic tool in the study of patients with multiple sclerosis.     

Peroxisomal functions in classical Refsum's disease: comparison with the infantile form of Refsum's disease

The infantile and classical forms of Refsum's disease are generally considered to belong to the newly recognized group of peroxisomal disorders. In this study we carried out a detailed investigation into different peroxisomal functions in classical Refsum's disease by analyses of plasma (very long chain fatty acids, di- and trihydroxycoprostanoic acid and pipecolic acid) and cultured skin fibroblasts from the patients (de novo plasmalogen biosynthesis, very long chain fatty acid oxidation and amount of particle-bound catalase). The results obtained indicate that, except for a deficient phytanic acid oxidation, peroxisomal functions were found to be normal in classical Refsum's disease in contrast with the findings in infantile Refsum's disease, in which there is a general impairment of peroxisomal functions. Based on these results it is concluded that peroxisomal biogenesis is normal in classical (but not in infantile) Refsum's disease and that the classical and infantile form of Refsum's disease hence represent distinct entities. Since available evidence suggests that phytanic acid is oxidized in mitochondria rather than in peroxisomes, at least in rat liver, it remains to be established whether classical Refsum's disease is a peroxisomal disorder or not.     

New approaches in peroxisomal disorders

The peroxisome is a subcellular organelle with important functions in plants and protozoa, which during the last decade has also been shown to have a role in mammalian lipid and amino acid metabolism. These functions include steps in the synthesis of ether lipids and bile acids and fatty acid beta-oxidation, particularly those of very long chain fatty acids. The proposition that the peroxisome carries out significant functions in man is highlighted by the fact that lack of this organelle is associated with severe abnormalities in many human organs. Human peroxisomal disorders are now grouped into three general categories. In the first group, peroxisomes are lacking or reduced in number. This group includes the Zellweger cerebro-hepato-renal syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease and hyperpipecolic acidemia. These patients lack the capacity to synthesize ether lipids and to oxidize very long chain fatty acids or phytanic acid, and they show abnormally high levels of pipecolic acid and bile acid intermediates. These patients rarely survive early childhood, have severe neurological deficits and multiple malformations. A second group includes the 'pseudo-Zellweger' syndrome and the rhizomelic form of chondrodysplasia punctata. Here the peroxisomal structure is intact, but there is deficient function of several peroxisomal enzymes. The third group includes X-linked adrenoleukodystrophy, acatalasemia and 'adult' Refsum's disease. The peroxisomal structure is intact, and the defect in each instance is thought to involve a mutation which affects a single peroxisomal enzyme. Peroxisomal disorders are of current interest because they occur more commonly than had been recognized and show phenotypic and genotypic heterogeneity. Their study provides the opportunity to learn more about the role of the peroxisome in normal brain function and development.