Human and great ape red blood cells differ in plasmalogen levels and composition.

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.

SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency.

Multiple Sulfatase Deficiency (MSD) is caused by mutations in the sulfatase-modifying factor 1 gene encoding the formylglycine-generating enzyme (FGE). FGE post translationally activates all newly synthesized sulfatases by generating the catalytic residue formylglycine. Impaired FGE function leads to reduced sulfatase activities.

Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions.

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.

Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders.

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.

Quantitative magnetization transfer characteristics of the human cervical spinal cord in vivo: application to adrenomyeloneuropathy.

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.

Auditory function in adrenomyeloneuropathy.

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.

Attitudes of families affected by adrenoleukodystrophy toward prenatal diagnosis, presymptomatic and carrier testing, and newborn screening.

Families affected by adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) were surveyed to elicit attitudes toward prenatal, presymptomatic and carrier testing, and newborn screening in order to determine the level of support that these families have for current and future genetic testing protocols. Identifying attitudes toward genetic testing, including newborn screening, is especially important because of new data regarding therapeutic options and the possible addition of ALD to newborn screening regimens. The Kennedy Krieger Institute (KKI) database identified 327 prospective participants.

"Lorenzo's oil" therapy for X-linked adrenoleukodystrophy: rationale and current assessment of efficacy.

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.

Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study.

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.

Magnetic resonance imaging detection of lesion progression in adult patients with X-linked adrenoleukodystrophy.

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.

X-linked adrenoleukodystrophy.

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.

Peroxisome biogenesis disorders.

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.

Combined liquid chromatography-tandem mass spectrometry as an analytical method for high throughput screening for X-linked adrenoleukodystrophy and other peroxisomal disorders: preliminary findings.

Utilizing combined liquid chromatography-tandem mass spectrometry (LC-MS/MS) as the analytical method, we have demonstrated a ten to sixtyfold excess of lysophosphatidyl choline containing hexacosanoic acid (26:0) in dried blood spots on a filter paper matrix from 25 male patients with X-linked adrenoleukodystrophy and nine patients with peroxisome biogenesis disorders compared to 19 controls. There was no overlap between normal subjects versus affected subjects.

Therapy of X-linked adrenoleukodystrophy.

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.

Sensorimotor function and axonal integrity in adrenomyeloneuropathy.

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.

Cognitive evaluation of neurologically asymptomatic boys with X-linked adrenoleukodystrophy.

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.

Adrenoleukodystrophy: new approaches to a neurodegenerative disease.

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.

Adreno-leukodystrophy: oxidative stress of mice and men.

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.

Progressive cavitating leukoencephalopathy: a novel childhood disease.

We report 19 patients with a previously undelineated neurodegenerative syndrome characterized by episodic acute onset of irritability or neurological deficits between 2 months and 3.5 years of age, followed by steady or intermittent clinical deterioration. Seven children died between 11 months and 14 years of age.

X-linked adrenoleukodystrophy: therapeutic approaches to distinct phenotypes.

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.

Mutations in the peroxin Pex26p responsible for peroxisome biogenesis disorders of complementation group 8 impair its stability, peroxisomal localization, and interaction with the Pex1p x Pex6p complex.

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).

Diffusion tensor-based imaging reveals occult abnormalities in adrenomyeloneuropathy.

"Pure" adrenomyeloneuropathy (AMN) is the noninflammatory myeloneuropathic variant of X-linked adrenoleukodystrophy, where the disease process appears to be restricted to spinal cord tracts and peripheral nerves. The absence of obvious brain involvement makes it distinct from the inflammatory cerebral phenotypes of X-linked adrenoleukodystrophy. However, some pure AMN patients later experience development of cerebral demyelination, but little is known about the extent of brain involvement in pure AMN patients who have normal brain magnetic resonance imaging.

Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's oil.

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.