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Background: Plasmalogens are ether phospholipids required for normal mammalian developmental, physiological, and cognitive functions. They have been proposed to act as membrane antioxidants and reservoirs of polyunsaturated fatty acids as well as influence intracellular signaling and membrane dynamics. Plasmalogens are particularly enriched in cells and tissues of the human nervous, immune, and cardiovascular systems. Humans with severely reduced plasmalogen levels have reduced life spans, abnormal neurological development, skeletal dysplasia, impaired respiration, and cataracts. Plasmalogen deficiency is also found in the brain tissue of individuals with Alzheimer disease., Results: In a human and great ape cohort, we measured the red blood cell (RBC) levels of the most abundant types of plasmalogens. Total RBC plasmalogen levels were lower in humans than bonobos, chimpanzees, and gorillas, but higher than orangutans. There were especially pronounced cross-species differences in the levels of plasmalogens with a C16:0 moiety at the sn-1 position. Humans on Western or vegan diets had comparable total RBC plasmalogen levels, but the latter group showed moderately higher levels of plasmalogens with a C18:1 moiety at the sn-1 position. We did not find robust sex-specific differences in human or chimpanzee RBC plasmalogen levels or composition. Furthermore, human and great ape skin fibroblasts showed only modest differences in peroxisomal plasmalogen biosynthetic activity. Human and chimpanzee microarray data indicated that genes involved in plasmalogen biosynthesis show cross-species differential expression in multiple tissues., Conclusion: We propose that the observed differences in human and great ape RBC plasmalogens are primarily caused by their rates of biosynthesis and/or turnover. Gene expression data raise the possibility that other human and great ape cells and tissues differ in plasmalogen levels. Based on the phenotypes of humans and rodents with plasmalogen disorders, we propose that cross-species differences in tissue plasmalogen levels could influence organ functions and processes ranging from cognition to reproduction to aging.

Background: It has been proposed that anatomical differences in human and great ape guts arose in response to species-specific diets and energy demands. To investigate functional genomic consequences of these differences, we compared their physiological levels of phytanic acid, a branched chain fatty acid that can be derived from the microbial degradation of chlorophyll in ruminant guts. Humans who accumulate large stores of phytanic acid commonly develop cerebellar ataxia, peripheral polyneuropathy, and retinitis pigmentosa in addition to other medical conditions. Furthermore, phytanic acid is an activator of the PPAR-alpha transcription factor that influences the expression of genes relevant to lipid metabolism., Results: Despite their trace dietary phytanic acid intake, all great ape species had elevated red blood cell (RBC) phytanic acid levels relative to humans on diverse diets. Unlike humans, chimpanzees showed sexual dimorphism in RBC phytanic acid levels, which were higher in males relative to females. Cultured skin fibroblasts from all species had a robust capacity to degrade phytanic acid. We provide indirect evidence that great apes, in contrast to humans, derive significant amounts of phytanic acid from the hindgut fermentation of plant materials. This would represent a novel reduction of metabolic activity in humans relative to the great apes., Conclusion: We identified differences in the physiological levels of phytanic acid in humans and great apes and propose this is causally related to their gut anatomies and microbiomes. Phytanic acid levels could contribute to cross-species and sex-specific differences in human and great ape transcriptomes, especially those related to lipid metabolism. Based on the medical conditions caused by phytanic acid accumulation, we suggest that differences in phytanic acid metabolism could influence the functions of human and great ape nervous, cardiovascular, and skeletal systems.

Peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive neurodegenerative disorders that affect multiple organ systems. Approximately 80% of PBD patients are classified in the Zellweger syndrome spectrum (PBD-ZSS). Mutations in the PEX1, PEX6, PEX10, PEX12, or PEX26 genes are found in approximately 90% of PBD-ZSS patients. Here, we sequenced the coding regions and splice junctions of these five genes in 58 PBD-ZSS cases previously subjected to targeted sequencing of a limited number of PEX gene exons. In our cohort, 71 unique sequence variants were identified, including 18 novel mutations predicted to disrupt protein function and 2 novel silent variants. We identified 4 patients who had two deleterious mutations in one PEX gene and a third deleterious mutation in a second PEX gene. For two such patients, we conducted cell fusion complementation analyses to identify the defective gene responsible for aberrant peroxisome assembly. Overall, we provide empirical data to estimate the relative fraction of disease-causing alleles that occur in the coding and splice junction sequences of these five PEX genes and the frequency of cases where mutations occur in multiple PEX genes. This information is beneficial for efforts aimed at establishing rapid and sensitive clinical diagnostics for PBD-ZSS patients and interpreting the results from these genetic tests., (2008 Wiley-Liss, Inc.)

Zellweger spectrum disorders (ZSD) are diagnosed by biochemical assay in blood, urine and cultured fibroblasts and PEX gene mutation identification. In most cases studies in fibroblasts corroborate results obtained in body fluids. In 1996 Clayton and colleagues described a 10-year old girl with evidence of a peroxisome disorder, based on elevated bile acid metabolites and phytanate. At the time it was not possible to distinguish whether she had a ZSD or a single peroxisomal protein defect. Studies in our laboratory showed that she also had elevated plasma pipecolate, supporting the former diagnosis. Despite the abnormal metabolites detected in blood (phytanate, bile acid intermediates and pipecolate), analysis of multiple peroxisomal pathways in fibroblasts yielded normal results. In addition, she had a milder clinical phenotype than usually associated with ZSD. Since complementation analysis to determine the gene defect was not possible, we screened this patient following the PEX Gene Screen algorithm (PGS). The PGS provides a template for sequencing PEX gene exons independent of complementation analysis. Two mutations in PEX10 were identified, a frameshift mutation inherited from her father and a de novo missense mutation in a conserved functional domain on the other allele. This case highlights that molecular analysis may be essential to the diagnosis of patients at the milder end of the ZSD spectrum. Furthermore, it supports the concept that some tissues are less affected by certain PEX gene defects than brain and liver.

Magnetization transfer (MT) imaging has assessed myelin integrity in the brain and spinal cord; however, quantitative MT (qMT) has been confined to the brain or excised tissue. We characterized spinal cord tissue with qMT in vivo, and as a first application, qMT-derived metrics were examined in adults with the genetic disorder Adrenomyeloneuropathy (AMN). AMN is a progressive disease marked by demyelination of the white matter tracts of the cervical spinal cord, and a disease in which conventional MRI has been limited. MT data were acquired at 1.5 Tesla using 10 radiofrequency offsets at one power in the cervical cord at C2 in 6 healthy volunteers and 9 AMN patients. The data were fit to a two-pool MT model and the macromolecular fraction (M(ob)), macromolecular transverse relaxation time (T(2b)) and the rate of MT exchange (R) for lateral and dorsal column white matter and gray matter were calculated. M(ob) for healthy volunteers was: WM = 13.9 +/- 2.3%, GM = 7.9 +/- 1.5%. In AMN, dorsal column M(ob) was significantly decreased (P < 0.03). T(2b) for volunteers was: 9 +/- 2 micros and the rate of MT exchange (R) was: WM = 56 +/- 11 Hz, GM = 67 +/- 12 Hz. Neither T(2b) nor R showed significant differences between healthy and diseased cords. Comparisons are made between qMT, and conventional MT acquisitions.

Auditory brainstem responses (ABR), ipsilateral and contralateral acoustic reflexes and the masking level difference for speech (MLD) were studied in 29 patients with adrenomyeloneuropathy (AMN). Abnormalities were seen for all ABR components with Waves V and III affected to the greatest degree. For male patients with AMN, the I-III, III-V and I-V interpeak latency intervals were abnormal for a majority of patients. For female patients with AMN, the I-V and III-V interpeak latency intervals were abnormal for a majority of patients with the I-III interval less affected. Contralateral acoustic reflexes were elevated or absent for approximately 50% of ears. Ipsilateral acoustic reflexes were abnormal for 25% of ears. MLDs were significantly reduced in 72% of patients. When considered in terms of the earliest ABR wave abnormality, the earlier components of the ABR (i.e., Waves III and I) were the initial components impaired for the majority of ears. Word recognition in quiet was relatively unimpaired for all subjects. Despite the presence of marked ABR abnormalities, patients with AMN denied the presence of significant difficulty hearing.

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder that damages the nervous system and is associated with the accumulation of saturated very long chain fatty acids (SVLCFA). Oral administration of "Lorenzo's oil" (LO), a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, normalizes the SVLCFA levels in plasma, but its clinical efficacy and the clinical indications for its use have been controversial for more than 15 years. We review the biochemical effects of LO administration and the rationale for its use and present a current appraisal of its capacity to reduce the risk for the childhood cerebral phenotype when administered to asymptomatic boys and to slow progression of adrenomyeloneuropathy in patients without cerebral involvement. We also present current efforts to provide definitive evaluation of its clinical efficacy and discuss its possible role in the new therapeutic opportunities that will arise if newborn screening for X-ALD is validated and implemented.

Background: Favourable outcomes have been reported for patients with childhood cerebral adrenoleukodystrophy (CCALD) who had received haematopoietic cell transplantation (HCT) at the early stage of cerebral involvement. However, comparative data for non-transplanted CCALD patients are limited. We analysed survival of CCALD patients who had not received HCT and, in a subgroup with early cerebral disease, compared survival in those who underwent HCT with those who did not., Methods: Retrospective survival analyses were done on 283 CCALD patients identified at the Kennedy Krieger Institute who had not received HCT, focusing on a 30-member early stage cerebral subgroup whose neurological disability and MRI severity scores matched those in a 19-member transplanted subgroup previously reported. A Kaplan-Meier survival curve and log-rank test were used for survival analysis and to estimate the difference between the survival probabilities of the groups with statistical significance set at alpha=0.05., Findings: Mean age at onset of symptoms in the entire 283 non-transplanted group was 7 years (SD 2 years). 131 (46%) patients died during the mean follow-up period of 5.9 years (5.3) at a mean age of 12.3 years (4.9). 5-year survival was 66%. The 5-year survival probability of 54% in the early stage group was significantly poorer (chi(2)=7.47, p=0.006) than the 5-year survival of 95% in the transplanted group with early stage cerebral disease., Interpretation: HCT done in the early and progressive stages of CCALD is beneficial, and our data support the recommendation that transplantation be offered to patients in the early stages of CCALD.

Background: An inherited disorder, X-linked adrenoleukodystrophy (X-ALD) is known to cause progressive inflammatory demyelination., Objective: To analyze the adult pattern of disease progression in X-ALD., Design, Setting, and Patients: We retrospectively assessed magnetic resonance (MR) images obtained in adult patients who had developed cerebral disease between January 1, 1985, and December 31, 2005. We identified 103 adult patients with X-ALD with lesions on their MR images. Of these, 56 had serial MR examinations at least 1 year apart and were included in this study. Main Outcome Measure Progression of X-ALD lesions on MR images., Results: On initial presentation, 17 patients with X-ALD had corticospinal tract lesions without splenium or genu involvement, 24 had symmetric corticospinal tract lesions with additional involvement of the splenium or genu, and 15 did not have corticospinal tract involvement but had other white matter lesions. In 18 of 21 patients with progressive lesions, corticospinal tract involvement preceded or occurred concurrently with progressive inflammatory demyelination., Conclusions: Brain MR imaging abnormalities in adults with X-ALD progress slower than those reported in childhood. The involvement of the corticospinal tracts is prominent and may at times represent a variant course of progressive inflammatory demyelination.

X-linked adrenoleukodystrophy (X-ALD) is caused by a defect in the gene ABCD1, which maps to Xq28 and codes for a peroxisomal membrane protein that is a member of the ATP-binding cassette transporter superfamily. X-ALD is panethnic and affects approximately 1:20,000 males. Phenotypes include the rapidly progressive childhood, adolescent, and adult cerebral forms; adrenomyeloneuropathy, which presents as slowly progressive paraparesis in adults; and Addison disease without neurologic manifestations. These phenotypes are frequently misdiagnosed, respectively, as attention-deficit hyperactivity disorder (ADHD), multiple sclerosis, or idiopathic Addison disease. Approximately 50% of female carriers develop a spastic paraparesis secondary to myelopathic changes similar to adrenomyeloneuropathy. Assays of very long chain fatty acids in plasma, cultured chorion villus cells and amniocytes, and mutation analysis permit presymptomatic and prenatal diagnosis, as well as carrier identification. The timely use of these assays is essential for genetic counseling and therapy. Early diagnosis and treatment can prevent overt Addison disease, and significantly reduce the frequency of the severe childhood cerebral phenotype. A promising new method for mass newborn screening has been developed, the implementation of which will have a profound effect on the diagnosis and therapy of X-ALD.

Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD). PBD are divided into two types--Zellweger syndrome spectrum (ZSS) and rhizomelic chondrodysplasia punctata (RCDP). Biochemical studies performed in blood and urine are used to screen for the PBD. DNA testing is possible for all of the disorders, but is more challenging for the ZSS since 12 PEX genes are known to be associated with this spectrum of PBD. In contrast, PBD-RCDP is associated with defects in the PEX7 gene alone. Studies of the cellular and molecular defects in PBD patients have contributed significantly to our understanding of the role of each PEX gene in peroxisome assembly.

Current therapies for X-linked adrenoleukodystrophy (X-ALD) include replacement therapy with adrenal steroids, which is mandatory for all patients with impaired adrenal function but does not alter neurological progression significantly; dietary therapy with "Lorenzo's Oil," which appears to have a preventive effect in asymptomatic boys whose brain MRI is normal; and hematopoietic stem cell transplantation in patients in the early stage of the cerebral inflammatory phenotype. Application of these interventions requires careful assessment of the patients' phenotype, which often changes over time. Family screening provides important opportunities for disease prevention.

Peroxisome biogenesis disorders (PBDs) are fatal autosomal recessive diseases and are caused by impaired peroxisome biogenesis. PBDs are genetically heterogeneous and classified into 13 complementation groups (CGs). CG8 is one of the most common groups and has three clinical phenotypes, including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and infantile Refsum disease (IRD). We recently isolated PEX26 as the pathogenic gene for PBD of CG8. Pex26p functions in recruiting to peroxisomes the complexes of the AAA ATPase peroxins, Pex1p and Pex6p. In the present work, we identified four distinct mutations in PEX26 from five patients of CG8 PBD including 2 with ZS and 3 with IRD, in addition to 7 mutant alleles in 8 patients in the first report describing the pathogenic PEX26 gene for CG8 PBD. Phenotype-genotype analyses revealed that temperature-sensitive (ts) peroxisome assembly gave rise to a milder IRD in contrast to the non-ts phenotype of the cells from ZS patients. Furthermore, we present several lines of evidence that show that the instability, insufficient binding to Pex1p x Pex6p complexes, or mislocalization of patient-derived Pex26p mutants is most likely responsible for the CG8 PBDs.

Background: Gait abnormalities and sensorimotor disturbances are principal defects in adrenomyeloneuropathy (AMN). However, to our knowledge, their association with overall impairment and neuroanatomical changes has not been defined., Objectives: To understand how sensorimotor impairments create mobility deficits and to analyze how these impairments are related to specific metrics of axonal integrity., Design: Cross-sectional study assessing impairments, including vibration sensation, strength, spasticity, and global measures of walking and balance. Fractional anisotropy was measured to evaluate the integrity of the corresponding brainstem tracts., Participants: Men with AMN and healthy control subjects., Results: Individuals with sensory loss only showed minimal walking deficits. Concomitant strength and sensory loss resulted in slower walking, with abnormal knee control; increased spasticity led to an exaggerated trunk motion and a knee-flexed (crouched) posture. Hip strength was an independent predictor of walking velocity in subjects with AMN. Subjects with sensory loss only had greater sway amplitudes during standing balance testing, which did not worsen with additional impairments. There were significant associations among sway amplitude, great toe vibration sense, and dorsal column fractional anisotropy. Brainstem fractional anisotropy in AMN was significantly negatively correlated with impairment, indicating that overall tract integrity is associated with sensorimotor abnormalities in AMN., Conclusions: Impairment measures capture specific abnormalities in walking and balance that can be used to direct rehabilitation therapy in AMN. Tract-specific magnetic resonance imaging metrics, such as fractional anisotropy (used herein to evaluate structure-function relationships), significantly reflect disease severity in AMN.

Background: Various studies have demonstrated abnormal neuropsychological function in boys with the childhood cerebral phenotype of X-linked adrenoleukodystrophy. Not much is known about the cognitive function of neurologically asymptomatic boys with X-linked adrenoleukodystrophy who have normal brain magnetic resonance imaging results., Objective: To describe the cognitive profile of 52 neurologically asymptomatic boys with X-linked adrenoleukodystrophy (mean +/- SD age, 6.7 +/- 3.6 years)., Methods: Neuropsychological tests included evaluation of IQ (full-scale IQ, verbal IQ, and performance IQ), 5 major cognitive domains (language, visuospatial skills, perception, visuomotor or graphomotor skills, memory, and attention or executive function), adaptive skills, and academic achievement. Standardized z scores relative to age-appropriate published norms were generated. Association between age and cognitive performance was evaluated using nonparametric Spearman rank correlation and robust median regression adjusting for full-scale IQ and socioeconomic status., Results: All but 4 patients had normal cognitive function. There was a negative correlation between age and visual perception as well as age and visuomotor skills after adjustment for full-scale IQ and socioeconomic status., Conclusions: This study provides, to our knowledge, the first evidence of overall normal cognitive function in neurologically and radiologically normal boys with X-linked adrenoleukodystrophy, indicating no evidence of neurodevelopmental abnormalities despite the inherent ABCD1 mutation. Subtle deterioration with age was observed in some functional domains. This suggests that prevention and timely institution of therapy can potentially preserve cognitive function seen in patients with the cerebral X-linked adrenoleukodystrophy phenotype. X-linked adrenoleukodystrophy should be considered a candidate disorder for neonatal screening.

X-linked adrenoleukodystrophy (X-ALD), which was first described in 1923, was viewed until 1976 as a rare and inexorably fatal neurodegenerative disorder that affected boys. The genetic defect and biochemical abnormalities have now been defined. Ongoing research has resulted in new findings: (1) there is a wide range of phenotypic expression. At least half of patients with X-ALD are adults with somewhat milder manifestations, and women who are carriers may become symptomatic. X-ALD is often misdiagnosed as attention-deficit/hyperactivity disorder in boys and as multiple sclerosis in men and women, and is not an uncommon cause of Addison disease; (2) the incidence of X-ALD, estimated to be 1:17,000 in all ethnic groups, approximates that of phenylketonuria; (3) noninvasive and presymptomatic diagnosis and prenatal diagnosis are available; family screening and genetic counseling are key to disease prevention; and (4) new therapies, applied early, show promise. Neonatal screening is likely to become available, and a wider awareness of X-ALD and its various modes of presentation permit new proactive approaches to this distressing disorder.

X-linked adreno-leukodystrophy is a progressive, systemic peroxisomal disorder that affects primarily nervous system myelin and axons as well as the adrenal cortex. Several divergent clinical phenotypes can occur in the same family; thus, there is no correlation between the clinical phenotype and the mutation in the ABCD1 gene in this disease. The most urgent and unresolved clinical issue is the fulminant inflammatory (immune) demyelination of the central nervous system in which a variety of cellular participants, cytokines, and chemokines are noted. A knockout mouse model exhibits mitochondrial deficits and axonal degeneration, but not inflammatory demyelination. To determine whether oxidative stress and damage might play a pathogenic role, we assessed standard biochemical and immunohistochemical markers of such activity both in our knockout mouse model and patients. We find that oxidative stress, as judged by increased immunoreactivity for the mitochondrial manganese-superoxide dismutase, is present in the knockout mouse liver, adrenal cortex, and renal cortex, tissues that normally express high levels of ABCD1 but no evidence of oxidative damage. The brain does not exhibit either oxidative stress or damage. On the other hand, both the human adrenal cortex and brain show evidence of oxidative stress (e.g. hemoxygenase-1 and manganese-superoxide dismutase) and oxidative damage, particularly from lipid peroxidation (4-hydroxynonenal and malondialdehyde). The presence of nitrotyrosylated proteins is strong circumstantial evidence for the participation of the highly toxic peroxynitrite molecule, whereas the demonstration of interferon gamma and interleukin-12 is indicative of a TH1 response in the inflammatory demyelinative lesions of the cerebral phenotype. These differences between the adreno-leukodystrophy mouse and human patients are intriguing and may provide a clue to the phenotypic divergence in this disease.

X-linked adrenoleukodystrophy (X-ALD) in males can present with eight distinct phenotypes, which vary greatly in respect to phenotypic expression, age of onset and rate of progression and therapy. The plasma very long chain fatty acid assay permits precise diagnosis and is already abnormal at birth. The clinical features, molecular biology, pathogenesis, and therapeutic approaches, including the indications for Hematopoietic Stem Cell Transplants (HCT) and dietary therapy are discussed, with emphasis on the asymptomatic, childhood cerebral, and adrenomyeloneuropathy phenotypes. The rationale for neonatal screening and the profound effect that such screening would have on the therapy of X-ALD, including the role of HCT, are discussed.

Objectives: To identify asymptomatic boys with X-linked adrenoleukodystrophy who have a normal magnetic resonance image (MRI), and to assess the effect of 4:1 glyceryl trioleate-glyceryl trierucate (Lorenzo's oil) on disease progression., Method: Eighty-nine boys (mean +/- SD baseline age, 4.7 +/- 4.1 years; range, 0.2-15 years) were identified by a plasma very long-chain fatty acids assay used to screen at-risk boys. All were treated with Lorenzo's oil and moderate fat restriction. Plasma fatty acids and clinical status were followed for 6.9 +/- 2.7 years. Changes in plasma hexacosanoic acid levels were assessed by measuring the length-adjusted area under the curve, and a proportional hazards model was used to evaluate association with the development of abnormal MRI results and neurological abnormalities., Results: Of the 89 boys, 24% developed MRI abnormalities and 11% developed both neurological and MRI abnormalities. Abnormalities occurred only in the 64 patients who were aged 7 years or younger at the time therapy was started. There was significant association between the development of MRI abnormalities and a plasma hexacosanoic acid increase. (For a 0.1-microg/mL increase in the length-adjusted area under the curve for the hexacosanoic acid level, the hazard ratio for incident MRI abnormalities in the whole group was 1.36; P = .01; 95% confidence interval, 1.07-1.72.) Results for patients aged 7 years or younger were similar (P = .04)., Conclusions: In this single-arm study, hexacosanoic acid reduction by Lorenzo's oil was associated with reduced risk of developing MRI abnormalities. We recommend Lorenzo's oil therapy in asymptomatic boys with X-linked adrenoleukodystophy who have normal brain MRI results.

The magnetization transfer ratio (MTR) is a reliable measure of MT effects because it employs an internal standard that allows quantitative comparison between subjects, independent of other contrasts, coil loading, and coil sensitivity profiles. However, at very high spatial resolution in the spinal cord at 1.5 T, the use of MTR quantification has been hampered by low signal-to-noise ratio (SNR) and acute sensitivity to motion. Here, the suitability of cerebrospinal fluid (CSF) as an alternative inter-subject MT signal intensity reference for the spine is evaluated. Contrary to MTR, this so-called MTCSF internal standard does not remove interfering T(1), T(2), and spin density contrast and is not expected to be able to discriminate between myelination and inflammation effects. However, it can detect initial changes in myelination when signal alterations are not yet detectable by conventional MRI. As a first example, this is demonstrated for the noninflammatory spinal cord white matter disease adrenomyeloneuropathy.

Objective: Plasma assay for very long-chain fatty acids has made it possible to perform large-scale screening of at-risk individuals to identify asymptomatic patients with X-linked adrenoleukodystrophy (X-ALD). We evaluated the burden of undiagnosed adrenal insufficiency in 49 such patients (age, 4.5 +/- 3.5 years)., Study Design: Serum adrenocorticotropic hormone (ACTH) and standard-dose ACTH stimulation test were performed at the baseline and followed prospectively until initiation of adrenal replacement therapy (follow-up, 2 +/- 1.7 years)., Results: At baseline, 39 (80%) patients had impaired adrenal function, serum ACTH levels were elevated in 34 (69%) patients, and ACTH stimulation test was abnormal in 21(43%) patients. There was a moderate association between Serum ACTH and age at baseline, ( r = 0.32, P = .05). By the end of follow-up, 86% of patients had borderline or overt adrenal insufficiency (age of onset, 4.8 +/- 3.7 years)., Conclusions: We detected a high prevalence of unrecognized adrenocortical insufficiency in asymptomatic boys with X-ALD. It is known to be a frequent cause of morbidity and can be prevented by careful monitoring, early identification of impaired adrenal reserve, and timely initiation of therapy. It manifests early and before onset of neurologic symptoms, suggesting X-ALD as a candidate disorder for neonatal screening.

Background: Adrenomyeloneuropathy (AMN) is the adult variant of X-linked adrenoleukodystrophy. The disease pathology is usually limited to spinal cord and peripheral nerves, and when this is the case, it is referred to as "pure" AMN. Histopathology shows cerebral involvement even in pure AMN; however, not much is known about the nature, extent, and clinical relevance of these findings., Objective: To investigate brain involvement in AMN patients with normal MRI, employing multislice MR spectroscopic imaging., Methods: Twelve men with pure AMN were compared with 19 age-matched healthy volunteers. Metabolite ratios (N-acetylaspartate [NAA]/choline [Cho], NAA/creatine [Cr], and Cho/Cr) were measured from seven brain regions. Global metabolite ratios were generated as an average of these seven regional ratios. The Expanded Disability Status Scale (EDSS) was used for neurologic evaluation., Results: The patients with AMN showed reduced global NAA/Cho (AMN 1.40 +/- 0.16 vs controls 1.75 +/- 0.34; p = 0.003)) and global NAA/Cr (AMN 2.32 +/- 0.13 vs controls 2.62 +/- 0.43; p = 0.03). Regionally, NAA/Cho was lowered in the internal capsule (AMN 1.30 +/- 0.20 vs controls 1.69 +/- 0.37; p = 0.002) and in parieto-occipital white matter (AMN 1.45 +/- 0.19 vs controls 1.78 +/- 0.55; p = 0.04). NAA/Cr was lowered in parieto-occipital white matter (AMN 2.34 +/- 0.31 vs controls 2.83 +/- 0.71; p = 0.04). EDSS demonstrated an inverse association with global NAA/Cr (r = -0.65, p = 0.02) and NAA/Cr in centrum semiovale (r = -0.73, p = 0.006) and in parieto-occipital white matter (r = -0.64, p = 0.02). Cho/Cr was not significantly elevated., Conclusions: (1)H-MR spectroscopic imaging is able to detect biochemical abnormalities suggestive of axonal damage even in the brains of patients with pure adrenomyeloneuropathy. The axonopathy is most prominent in internal capsule and parieto-occipital white matter and may contribute to clinical disability.

Mental retardation has been categorized into severe mental retardation where genetics plays a very important role and mild mental retardation, in which genetics in some instances plays a role but in which cultural factors also matter a great deal. The pathogenetic, clinical and behavioral characteristics of genetically determined disorders associated with mental retardation differ greatly-as exemplified by two genetic disorders that have been clarified recently, namely Rett syndrome and the Williams syndrome. In the work-up of the developmentally disabled child, previous studies have shown that genetic studies are of have great importance and high yield. Early biochemical diagnosis in newborn screening has tremendous potential and has been strongly supported by NICHD-the PKU story being so much part of what NICHD has done. We must gain a better understanding of structure/function relationships, which becomes more and more possible with neuroimaging. A better understanding of neural plasticity can lead to correction by early intervention.

Many of the peroxisomal diseases exhibit excessive oxidative stress leading to neurological alterations and dysfunction. The role of peroxisomal oxidative stress in cellular function was highlighted by the loss of metabolic functions in peroxisomes of mutant cell lines, where catalase is mistargeted to the cytoplasm, but restored to peroxisomes by genetic manipulation (Sheikh et al. [Proc. Natl. Acad. Sci. USA 95 (1998) 2961)]. We report here that two human skin fibroblast cell lines from Zellweger syndrome-like patients are defective in the import of catalase into peroxisomes, causing impairment of metabolic function of this organelle. However, by lowering the cell culturing temperature (30 degrees C) the targeting of catalase to peroxisomes was restored, and with it the metabolic functions. Furthermore, mislocalization of catalase induces an oxidative imbalance in the cells which on treatment with a natural antioxidant, alpha-tocopherol (vitamin E), resulted in reduction of the oxidative levels and restoration of metabolic function (peroxisomal beta-oxidation and levels of very long chain fatty acids and plasmalogen as well as alpha-oxidation of branched-chain fatty acids). However, restoration of peroxisomal functions was not associated with the targeting of catalase to peroxisomes. Therefore, our finding suggests that correction of mistargeted catalase to peroxisomes is a temperature sensitive event and supports the hypotheses that its location outside peroxisomes induces an oxidative imbalance that results in metabolic dysfunction. The imbalance can be reversed by treatment with vitamin E, leading to normalization of peroxisomal functions. These findings open a novel approach for therapeutic treatment of certain peroxisomal disorders where gene or hypothermic therapies are not an option.

Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P <.01). Baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT. In this first comprehensive report of the international HCT experience for X-ALD, we conclude that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies.

Background and Purpose: Pelizeaus-Merzbacher disease (PMD) is a clinically and molecularly heterogeneous disorder linked to deletion, mutations, or duplication of the proteolipid protein (PLP1) gene locus at Xq22. The current study was conducted to characterize the results of proton MR spectroscopic (MRS) imaging in PMD., Methods: Three boys with PMD (one with the severe connatal form and two with a more mild clinical phenotype [spastic paraplegia type 2]). and three age-matched healthy control subjects (age range, 2-7 years) underwent MR and MRS imaging. All imaging was performed at 1.5 T. For MRS imaging, oblique-axial sections (thickness, 15 mm; intersection gap, 2.5 mm) were recorded parallel to the anterior commissure-posterior commissure line (TR/TE/NEX, 2300/272/1) with lipid and water suppression. Ratios of metabolite peak areas were calculated, and spectra were bilaterally evaluated., Results: Diffuse or focal reductions in N-acetylaspartate were observed in the affected white matter in all three cases. These reductions seemed to be consistent with axonal damage. In addition, mild increases in choline and creatine levels were observed; these may have been due to astrocytic changes., Conclusion: Proton MRS imaging may be helpful in evaluating regional pathophysiologic abnormalities in PMD and in distinguishing PMD from other leukodystrophies, which exhibit different metabolic profiles.

The human disorders of peroxisome biogenesis (PBDs) are subdivided into 12 complementation groups (CGs). CG8 is one of the more common of these and is associated with varying phenotypes, ranging from the most severe, Zellweger syndrome (ZS), to the milder neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD). PEX26, encoding the 305-amino-acid membrane peroxin, has been shown to be deficient in CG8. We studied the PEX26 genotype in fibroblasts of eight CG8 patients--four with the ZS phenotype, two with NALD, and two with IRD. Catalase was mostly cytosolic in all these cell lines, but import of the proteins that contained PTS1, the SKL peroxisome targeting sequence, was normal. Expression of PEX26 reestablished peroxisomes in all eight cell lines, confirming that PEX26 defects are pathogenic in CG8 patients. When cells were cultured at 30 degrees C, catalase import was restored in the cell lines from patients with the NALD and IRD phenotypes, but to a much lesser extent in those with the ZS phenotype, indicating that temperature sensitivity varied inversely with the severity of the clinical phenotype. Several types of mutations were identified, including homozygous G89R mutations in two patients with ZS. Expression of these PEX26 mutations in pex26 Chinese hamster ovary cells resulted in cell phenotypes similar to those in the human cell lines. These findings confirm that the degree of temperature sensitivity in pex26 cell lines is predictive of the clinical phenotype in patients with PEX26 deficiency.