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Although the pathology of X-linked adrenoleukodystrophy (ALD) is well described, it represents the end-stage of neurodegeneration. It is still unclear what cell types are initially involved and what their role is in the disease process. Revisiting the seminal post-mortem studies from the 1970s can generate new hypotheses on pathophysiology. This review describes (histo)pathological changes of the brain and spinal cord in ALD. It aims at integrating older works with current insights and at providing an overarching theory on the pathophysiology of ALD. The data point to an important role for axons and glia in the pathology of both the myelopathy and leukodystrophy of ALD. In-depth pathological analyses with new techniques could help further unravel the sequence of events behind the pathology of ALD. [ABSTRACT FROM AUTHOR]

Background: Adrenoleukodystrophy (ALD) is a multifaceted, X-linked, neurodegenerative disorder that comprises several clinical phenotypes. ALD affects patients through a variety of physical, emotional, social, and other disease-specific factors that collectively contribute to disease burden. To facilitate clinical care and research, it is important to identify which symptoms are most common and relevant to individuals with any subtype of ALD. Methods: We conducted semi-structured qualitative interviews and an international cross-sectional study to determine the most prevalent and important symptoms of ALD. Our study included adult participants with a diagnosis of ALD who were recruited from national and international patient registries. Responses were categorized by age, sex, disease phenotype, functional status, and other demographic and clinical features. Results: Seventeen individuals with ALD participated in qualitative interviews, providing 1709 direct quotes regarding their symptomatic burden. One hundred and nine individuals participated in the cross-sectional survey study, which inquired about 182 unique symptoms representing 24 distinct symptomatic themes. The symptomatic themes with the highest prevalence in the overall ALD sample cohort were problems with balance (90.9%), limitations with mobility or walking (87.3%), fatigue (86.4%), and leg weakness (86.4%). The symptomatic themes with the highest impact scores (on a 0–4 scale with 4 being the most severe) were trouble getting around (2.35), leg weakness (2.25), and problems with balance (2.21). A higher prevalence of symptomatic themes was associated with functional disability, employment disruption, and speech impairment. Conclusions: There are many patient-relevant symptoms and themes that contribute to disease burden in individuals with ALD. These symptoms, identified by those having ALD, present key targets for further research and therapeutic development. [ABSTRACT FROM AUTHOR]

Background: This article presents a case study of two white male siblings of 24 and 31 years of age of self-reported Ukrainian ethnicity diagnosed with adrenomyeloneuropathy (AMN) associated with a novel splice site mutation in the ABCD1 gene. AMN represents a form of X-linked adrenoleukodystrophy (X-ALD) characterized by demyelination of the spinal cord and peripheral nerves. The case also presents the first adult haematopoietic stem cell transplant (HSCT) for adrenomyeloneuropathy in Ukraine. The rarity of this mutation and its cerebral involvement and the treatment make this case noteworthy and underscore the significance of reporting it to contribute to the existing medical knowledge. Case presentation: The patients of 24 and 31 years initially exhibited progressive gait disturbance, lower extremity pain, and urinary incontinence, with the older sibling experiencing more advanced symptoms of speech, hearing, and vision disturbances. A comprehensive genetic analysis identified an unreported splice site mutation in exon 3 of the ABCD1 gene, leading to the manifestation of AMN. The inheritance pattern was consistent with X-linked recessive transmission. The article also outlines the clinical features, magnetic resonance imaging (MRI), and nerve conduction study (NCS) findings. Moreover, it discusses the genetic profile of the affected individuals and female carriers within the family. The younger sibling underwent HSCT, which was complicated by mediastinal lymph node and lung tuberculosis, adding to the complexity of managing adult ALD patients. Conclusions: This report emphasizes the importance of genetic testing in diagnosing and comprehending the underlying mechanisms of rare genetic disorders, such as AMN with cerebral involvement. The identification of a novel splice site mutation expands our understanding of the genetic landscape of this condition. Additionally, the challenges and complications encountered during the hematopoietic stem cell transplant procedure underscore the need for cautious consideration and personalized approaches in adult ALD patients. [ABSTRACT FROM AUTHOR]

X-linked adrenoleukodystrophy (X-ALD) is a rare inborn error of the peroxisomal metabolism caused by pathologic variants in the ATP-binding cassette transporter type D, member 1 (ABCD1) gene located on the X-chromosome. ABCD1 protein, also known as adrenoleukodystrophy protein, is responsible for transport of the very long chain fatty acids (VLCFA) from cytoplasm into the peroxisomes. Therefore, altered function or lack of the ABCD1 protein leads to accumulation of VLCFA in various tissues and blood plasma leading to either rapidly progressive leukodystrophy (cerebral ALD), progressive adrenomyeloneuropathy (AMN), or isolated primary adrenal insufficiency (Addison's disease). We report two distinct single nucleotide deletions in the ABCD1 gene, c.253delC [p.Arg85Glyfs*18] in exon 1, leading to both cerebral ALD and to AMN phenotype in one family, and c.1275delA [p.Phe426Leufs*15] in exon 4, leading to AMN and primary adrenal insufficiency in a second family. For the latter variant, we demonstrate reduced mRNA expression and a complete absence of the ABCD1 protein in PBMC. Distinct mRNA and protein expression in the index patient and heterozygous carriers does not associate with VLCFA concentration in plasma, which is in line with the absence of genotype–phenotype correlation in X-ALD. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate plantar pressure dynamics in the occurrence of active diabetic neuropathic ulceration (DNU) and any changes in loadings occurring in individuals with a history of diabetic neuropathic ulceration (DHNU). Since current gold standard offloading strategies are not producing desirable healing outcomes and optimum ulcer prevention, this study aimed to better understand the effect of diabetic peripheral neuropathy (DPN) and ulceration on mean peak plantar pressure (MPPP) and pressure-time integral (PTI) changes. Is there a redistribution of plantar pressure during gait in the presence of active and history of diabetic neuropathic ulceration? A prospective, cross-sectional study was conducted, in which, eighty adult participants were divided into four groups, namely, the DM, DPN, DNU and DHNU groups. Participants were instructed to walk barefoot over a Tekscan HR Mat™ at self-selected speed. MPPP and PTI data were analysed under five forefoot anatomical landmarks and compared between individuals with and without active neuropathic ulceration. Minimal MPPP significant changes were observed between ulcerated and non-ulcerated groups, however, PTI values were significantly increased in the ulcerated groups under all plantar ulceration regions. No significant plantar pressure differences were observed between the DNU and DHNU groups. Logistic regression tests demonstrated that as PTIs under the hallux increase, the likelihood of an individual living with DPN developing ulceration increases. A significant increase in PTI values in the presence of ulceration highlights the importance of evaluating the duration of loads under forefoot regions during gait rather than just focusing on the magnitude of pressures during ulcer management and prevention. Moreover, results show that PTI values remain high in the presence of a history of neuropathic ulceration, possibly demonstrating the value of PTI as a clinical tool over MPPP in the assessment of the high-risk diabetic foot. • MPPP and PTI changes were analysed in the presence of active and history of neuropathic ulceration. • Minimal MPPP significant changes were observed. • Significant increase in PTI values detected under all plantar ulceration regions. • Evaluating duration of loads might be a better clinical tool for ulcer management and prevention. [ABSTRACT FROM AUTHOR]

Adrenomyeloneuropathy (AMN) is a late-onset axonopathy of spinal cord tracts caused by mutations of the ABCD1 gene that encodes adrenoleukodystrophy protein (ALDP), a peroxisomal transporter of very long-chain fatty acids (VLCFA). Disturbed metabolic interaction between oligodendrocytes (OL) and axons is suspected to play a major role in AMN axonopathy. To develop a vector targeting OL, the human ABCD1 gene driven by a short 0.3 kb part of the human myelin-associated glycoprotein (MAG) promoter was packaged into an adeno-associated viral serotype 9 (rAAV9). An intravenous injection of this vector on postnatal day 10 in Abcd1−/− mice, a model of AMN, allowed a near normal motor performance to persist for 24 months, while age-matched untreated mice developed major defects of balance and motricity. Three weeks postvector, 50–54% of spinal cord white matter OL was expressing human ALDP (hALDP) at the cervical level, and only 6–7% after 24 months. In addition, 29–32% of cervical spinal cord astrocytes at 3 weeks and 16–19% at 24 months also expressed ALDP. C26:0-lysoPC, a sensitive VLCFA marker of AMN, was lower by 41% and 50%, respectively, in the spinal cord and brain of vector-treated compared with untreated mice. In a nonhuman primate, the intrathecal injection of the rAAV9-MAG vector induced abundant ALDP expression at 3 weeks in spinal cord OL (43%, 29%, and 26% at cervical, thoracic, and lumbar levels) and cerebellum OL (35%). In addition, 33–41% of spinal cord astrocytes expressed hALDP, and 27% of cerebellar astrocytes. To our knowledge, OL targeting had not been obtained before in primates with other vectors or promoters. The current results thus provide a robust proof-of-concept not only for the gene therapy of AMN but also for other central nervous system diseases, where the targeting of OL with the rAAV9-MAG vector may be of interest. [ABSTRACT FROM AUTHOR]

Objective: Adult spinal deformity (ASD) have lower health-related quality of life (HRQoL) compared to the general population. Applying Rasch measurement theory (RMT), this study tested the revised Scoliosis Research Society-22 (SRS-22r) HRQoL instrument among symptomatic adult patients with degenerative spinal disorders and varying degrees of ASD. Methods: SRS-22r data from 637 outpatient spine clinic patients with degenerative spine conditions were investigated for unidimensionality, item/scale fit, differential item functioning (DIF), scale coverage/targeting, and person separation index (PSI) using RMT. Results: Unidimensionality of the SRS-22r was not supported for either the total score or for 3 of its 5 domains. Item fit was acceptable for 11/22 items. The individual domains showed good coverage despite the degree of structural disorders. Ordered thresholds were achieved by merging response categories in some of the items. DIF towards age or sex was found in 11/22 items and in some domain items. The PSI exceeded 0.7 for the SRS-22r total score. Conclusion: The individual domain scores of the SRS-22r perform better than the total score providing good coverage and targeting among patients with ASD. Refinements of items and domains may improve the structural validity of the instrument to meet the criteria for measuring ASD patients, even when multidimensionality persists. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to describe the typical and atypical clinical and neuroimaging features of ALD in Chinese patients, which will help early diagnosis and intervention to improve prognosis of ALD.Methods: Forty-one patients in the Leukoencephalopathy Clinic of Neurology Department, Peking Union Medical College Hospital were enrolled. Detailed clinical manifestations and MRI features were analyzed. The relationship between phenotype and genotype as well as biochemical analysis was observed.Results: The patients were classified according to phenotype and onset age, including 14 childhood cerebral ALD (CCALD), 8 adolescent cerebral ALD (adoCALD), 3 adult cerebral ALD (ACALD), 14 adrenomyeloneuropathy (AMN), and 2 ALD in women. AMN was the main presentation in adults. Visual impairment was usual onset symptom in CCALD and cognitive decline and psychiatric symptoms were found in adoCALD and ACALD. Typical MRI feature of CALD was symmetrical peri-ventricular "butterfly wings" like lesions in frontal and/or occipital lobe with peripheral DWI hyperintensities and Gd enhancement. Corpus callosum and internal capsule were always involved. Unilateral lesions were also possible. Cerebral AMN presented with centrum semiovale diffuse involvement. Spinocerebellar variant was a special subtype of AMN with obvious cerebellar and brainstem lesions. No relationships between phenotype and genotype as well as biochemical VLCFAs analysis were found.Conclusions: We emphasize that corpus callosum and internal capsule are always involved in ALD. A unilateral lesion is also possible. Neuroimaging of cerebral AMN is different from typical CALD with more centrum semiovale involvement. We support spinocerebellar variant was a rare subtype of AMN. [ABSTRACT FROM AUTHOR]

Objective/background: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. We sought to investigate the prevalence and severity of Restless Legs Syndrome (RLS) in patients with ALD.Patients/methods: We administered questionnaires and conducted diagnostic telephone interviews to assess RLS severity. We retrospectively extracted data from neurological examinations, functional gait measures, and laboratory assessments.Results and Conclusions: Thirty-two adults with ALD (21 female, 11 male) were recruited to participate. Thirteen patients (40.6%) had RLS (10/21 females and 3/11 males). The median age of RLS onset was 35 years [IQR = 22-54]. Patients with RLS had more signs and symptoms related to myelopathy, but not the brain demyelination seen in ALD. This pilot study suggests a high prevalence of RLS in adults with ALD, which may contribute to sleep problems and impair quality of life. [ABSTRACT FROM AUTHOR]

Background: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by mutations in the ABCD1 gene. The clinical manifestations of ALD vary widely with some patients presenting with adrenomyeloneuropathy (AMN) that resembles the phenotype of hereditary spastic paraplegia (HSP). The aim of this study is to investigate the frequency, spectrum, and clinical features of ABCD1 mutations in Taiwanese patients with HSP phenotype.Methods: Mutational analysis of the ABCD1 gene was performed in 230 unrelated Taiwanese patients with clinically suspected HSP by targeted resequencing. Clinical, electrophysiological, and neuroimaging features of the patients carrying an ABCD1 pathogenic mutation were characterized.Results: Ten different ABCD1 mutations were identified in eleven patients, including two novel mutations (p.Q177Pfs*17 and p.Y357*) and eight ever reported in ALD cases of other ethnicities. All patients were male and exhibited slowly progressive spastic paraparesis with onset ages ranging from 21 to 50 years. Most of them had additional non-motor symptoms, including autonomic dysfunction in nine patients, sensory deficits in seven, premature baldness in seven, skin hyperpigmentation in five, psychiatric symptoms in one and cerebellar ataxia in one. Seven of the ten patients who ever received nerve conduction studies showed axonal polyneuropathy. Magnetic resonance imaging (MRI) revealed diffuse spinal cord atrophy in seven patients, cerebral white matter hyperintensity in one patient, and cerebellar involvement in one patient.Conclusions: ABCD1 mutations account for 4.8% (11/230) of the cases with HSP phenotype in Taiwan. This study highlights the importance to consider ABCD1 mutations in patients with clinically suspected HSP of unknown genetic causes. [ABSTRACT FROM AUTHOR]

• X-linked adrenoleukodystrophy is caused by mutations in the gene, ABCD1. • p.Arg163Cys substitution caused by c.487C>T in exon 1 is a novel missense mutation. • There is no correlation between the genotype and phenotype of adrenoleukodystrophy. • Axonal neuropathy with multifocal demyelination is common in adrenoleukodystrophy. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder that primarily affects the white matter of central nervous system and the adrenal cortex. It is caused by mutations in the adenosine triphosphate-binding cassette, subfamily D, member 1 (ABCD1) gene that results in elevated plasma levels of very long chain fatty acids (VLCFAs). The disease is characterized by an unpredictable variation in phenotypic expressions, including childhood cerebral form (CCALD) and adrenomyeloneuropathy (AMN). Genetic analysis is a reliable method for the diagnosis of X-ALD. We reported a 46-year-old male admitted to Department of Neurology, Chang Gung Memorial Hospital with progressive paraparesis and Addison's disease, which was diagnosed when he was around 20-year-old. Plasma levels of VLCFA showed that his C26:0, C24:0/C22:0 and C26:0/C22:0 ratios were significantly elevated. A novel missense mutation (p.Arg163Cys) caused by the nucleotide change c.487C > T in exon 1 was identified in the ABCD1 gene of the proband and his subclinical family members. In this article, we reviewed the mutations that had been reported at the same position with different phenotypes. Given that the nerve conduction study (NCS) of the proband demonstrated a rare finding of demyelinating polyneuropathy with conduction blocks, we also reviewed the findings of NCS in patients with AMN in literature. [ABSTRACT FROM AUTHOR]

Objective: To characterize the prevalence, onset, and burden of urinary and bowel dysfunction in adult patients with adrenoleukodystrophy (ALD) and to evaluate any sex differences in symptom presentation.Methods: In this retrospective and prospective study, we performed medical record review (n = 103), analyzed the results of clinically indicated urodynamic testing (n = 11), and developed and distributed a symptom and quality of life (QOL) survey (n = 59).Results: Urinary and bowel symptoms are highly prevalent in both males (75.0%) and females (78.8%) in this population, most commonly urinary urgency, often leading to incontinence. Time to onset of first urinary or bowel symptom occurs approximately a decade earlier in males. Seventy-two percent of symptomatic patients report a limitation to QOL. Urodynamic evaluation provides evidence of three distinct mechanisms underlying lower urinary tract dysfunction: involuntary detrusor contractions (indicating uncontrolled neuronal stimulation with or without leakage), motor underactivity of the bladder, and asynergy between detrusor contraction and sphincter relaxation.Conclusions: Beyond gait and balance difficulties, urinary and bowel symptoms are common in adults with ALD and impair QOL. Males are affected at a younger age but both sexes experience a higher symptom burden with age. As this population also experiences gait and balance impairment, patients with ALD are more vulnerable to urinary urgency leading to incontinence. Urodynamic evaluation may help better elucidate the pathophysiologic mechanisms underlying neurogenic lower urinary tract dysfunction, which can allow more targeted treatment. [ABSTRACT FROM AUTHOR]

Background: Adrenoleukodystrophy (ALD) encompasses different neurological phenotypes, ranging from the most severe cerebral forms (C-ALD) to the less severe adrenomyeloneuropathy (AMN). As visual system can be varyingly involved, we aimed at exploring whether optical coherence tomography (OCT) may detect retinal abnormalities and their longitudinal changes in adult ALD patients. Methods: In this cross-sectional and longitudinal study, we measured the thicknesses of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell complex (mGCC), and segmented inner and outer macula at baseline and their changes over time in 11 symptomatic adult ALD males and 10 age- and sex-matched healthy controls. Statistical analyses were performed for the patients as complete group, and splitting them into two subgroups, one (C-ALD) with and the other (AMN) without cerebral parieto-occipital white matter (WM) lesions. Results: In the complete ALD group and in the C-ALD subgroup, the average pRNFL, mGCC, and inner macula were significantly thinner than in controls (p ≤ 0.01), whereas in the AMN subgroup, they were constantly, though non-significantly, thinner. Significant outer macula thinning was also observed (p < 0.01). In the complete ALD group, follow-up assessment (mean 26.8 months, range 8–48) showed mildly progressive thinning of inferior pRNFL, average mGCC, and inner macula. Conclusions: In adult ALD patients, OCT can reveal retinal abnormalities which are prominent in the more compromised patients, namely those with parieto-occipital WM lesions. The inferior pRNFL, average mGCC and inner macula thicknesses might be sensitive-to-change OCT parameters, but their utility and consistency for short-term longitudinal studies deserve further investigations. [ABSTRACT FROM AUTHOR]

Background: X‐linked adrenoleukodystrophy is a progressive demyelinating disease that primarily affects males with an incidence of 1:20 000‐30 000. The disease has a wide spectrum of phenotypic expression and may include adrenal insufficiency, cerebral X‐linked adrenoleukodystrophy and adrenomyeloneuropathy. The condition has implications for the administration of anesthesia and reports of anesthetic management in those patients are limited at this point. Aim: To review the perioperative care, complications and outcomes of patients diagnosed with X‐linked adrenoleukodystrophy at the University of Minnesota Masonic Children's Hospital. Method: After obtaining IRB approval, we performed a retrospective chart review of pediatric patients diagnosed with X‐linked adrenoleukodystrophy who underwent either surgery or diagnostic/therapeutic procedures that included anesthesia services between January 2014 and December 2016. Data included demographics, American Society of Anesthesiologists classification, preoperative diagnosis, history of hematopoietic stem cell transplant, anesthetic approaches, airway management, medications used, intra‐ and postoperative complications, and patient disposition. Results: We identified 38 patients who had a total of 166 anesthetic encounters. The majority of patients underwent procedures in the sedation unit (75.9%) and received a total intravenous anesthetic with spontaneous ventilation via a natural airway (86.1%). Preoperative adrenal insufficiency was documented in 87.3% of the encounters. Stress‐dose steroids were administered in 70.5% of the performed anesthetics. A variety of anesthetic agents were successfully used including sevoflurane, isoflurane, propofol, midazolam, ketamine, and dexmedetomidine. There were few perioperative complications noted (6.6%) and the majority were of low severity. No anesthesia‐related mortality was observed. Conclusions: With the availability of skilled pediatric anesthesia care, children with X‐linked adrenoleukodystrophy can undergo procedures under anesthesia in sedation units and regular operating rooms with low overall anesthesia risk. [ABSTRACT FROM AUTHOR]

Mutations in the gene encoding the peroxisomal ATP-binding cassette transporter (ABCD1) cause elevations in very long-chain fatty acids (VLCFAs) and the neurodegenerative disease adrenoleukodystrophy (ALD). In most adults, this manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN). A challenge in virus-based gene therapy in AMN is how to achieve functional gene correction to the entire spinal cord while minimizing leakage into the systemic circulation, which could contribute to toxicity. In the present study, we used an osmotic pump to deliver adeno-associated viral (AAV) vector into the lumbar cerebrospinal fluid space in mice. We report that slow intrathecal delivery of recombinant AAV serotype 9 (rAAV9) achieves efficient gene transfer across the spinal cord and dorsal root ganglia as demonstrated with two different transgenes, GFP and ABCD1. In the Abcd1–/– mouse, gene correction after continuous rAAV9-CBA-hABCD1 delivery led to a 20% decrease in VLCFA levels in spinal cord compared with controls. The major cell types transduced were astrocytes, vascular endothelial cells, and neurons. Importantly, rAAV9 delivered intrathecally by osmotic pump, in contrast to bolus injection, reduced systemic leakage into peripheral organs, particularly liver and heart tissue. [ABSTRACT FROM AUTHOR]

Highlights • Adrenomyeloneuropathy may present with only mild myelopathic features. • Targeted gene approach aids diagnosis in atypical presentations. • Functional assay confirmation is needed to confirm causality of genetic variants. Abstract X-linked adrenoleukodystrophy is a peroxisomal disorder caused by a mutation in ABCD1 gene. The three main phenotypes of X-linked adrenoleukodystrophy include cerebral adrenoleukodystrophy, adrenomyeloneuropathy, and isolated primary adrenal insufficiency. More than 750 non-recurrent mutations exist throughout the coding region of the ABCD1 gene. We report a 62-year-old man with a 17-year history of progressive gait imbalance and numb feet. He had noted difficulty rising from a chair for 3 years. Examination revealed proximal lower limb weakness and length-dependent sensory loss with preservation of reflexes and unilateral Babinski sign. Electrodiagnostic evaluation confirmed a length-dependent sensorimotor peripheral neuropathy and proximal myopathy. Family history was remarkable for similar symptoms in 6 siblings. A targeted gene approach for 102 known peripheral neuropathy genes led to discovery of ABCD1 mutation confirmed by kindred evaluation and biochemical assay. This case highlights the importance of combining targeted gene approaches with functional assay confirmation especially for atypical clinical presentations. [ABSTRACT FROM AUTHOR]

Abstract Precise pathophysiology with respect to the phenotypic variations and severity of X-ALD, specifically between adrenomyeloneuropathy (AMN) and childhood cerebral adrenoleukodystrophy (CCALD), has not been fully discovered. Herein, a systematic analysis using multi-layered lipidomics and transcriptomics was conducted to elucidate distinctive metabolic biosignatures among healthy control, AMN, and CCALD. Significant alterations regarding the accumulation of very long chain fatty acids were found in various lipid species such as phospholipids, glycerolipids, and sphingolipids. Remarkably, TG and CER that are physiologically essential were markedly down-regulated in CCALD than AMN. Transcriptomic analysis further supported the robustness of our findings by providing valuable information on the gene expressions of the regulatory factors. For instance, regulators of sphingolipid catabolism (SMPD1, CERK, and SPHK1) and TG anabolism (GPAM, GPAT2, and MBOAT2) were more up-regulated in AMN than in CCALD. These observations, among others, were in line with the recognized alterations of the associated lipidomes. In conclusion, the homeostatic imbalance of the complex lipid networks may be pathogenically important in X-ALD and the particular dysregulations of TG and CER may further influence the severity of CCALD among X-ALD patients. Highlights • Lipid profiling reveals distinctive biosignatures of X-linked adrenoleukodystrophy. • Adrenomyeloneuropathy, mild type, activates the anabolism of sphingolipid pathway. • Childhood cerebral adrenoleukodystrophy lacks the synthesis of triacylglycerol. • The collapse of the lipid homeostasis is related to the severity of disease. [ABSTRACT FROM AUTHOR]

Objective This meta-analysis evaluated the clinical outcomes of skip laminectomy relative to laminoplasty for the treatment of cervical compressive myelopathy. Methods The Cochrane library, PubMed MEDLINE, EMBASE, and Web of Science databases were comprehensively searched to identify relevant articles published up to March 18, 2018. All values of weighted mean difference (WMD) or odds ratio are expressed as skip laminectomy relative to laminoplasty. Results Four studies comprising 241 patients were included. Skip laminectomy and laminoplasty were comparable in terms of cervical lordotic curvature (weighted mean difference [WMD] −2.37°; 95% confidence interval [CI] −6.18 to 1.43; P = 0.22) and range of motion (WMD –2.65°; 95% CI −6.02 to 0.72; P = 0.12). The pooled data revealed that the mean visual analogue scale score for pain of the skip laminectomy group was significantly lower than that of the laminoplasty group (WMD –0.97; 95% CI −1.90 to −0.05; P = 0.04), and the rate of axial pain was also significantly lower (WMD 0.26; 95% CI 0.07–0.93; P = 0.04). The atrophy rates of the deep extensor muscles in the skip laminectomy group (14%) were significantly lower than that of the laminoplasty group (60%). Conclusions This meta-analysis determined that skip laminectomy was superior to laminoplasty in terms of visual analogue scale score and rates of axial pain and muscle atrophy. These results warrant further confirmation in future research. Highlights • This meta-analysis is the first quantitative comparison of laminoplasty and skip laminectomy. • Skip laminectomy resulted in lower VAS scores and rate of axial pain and muscle atrophy. • The 2 procedures were comparable between cervical lordotic curvature and ROM. [ABSTRACT FROM AUTHOR]

Background: Adult adrenomyeloneuropathy (AMN) is caused by mutations in the ABCD1 gene. Some pure AMN patients develop cerebral demyelination late in life. However, hypoplasia and agenesis of the corpus callosum (CC) has never been reported in AMN patients. Objective: To describe a new clinical variant of AMN that is possibly caused by a novel ABCD1 gene mutation. Methods: A total of 10 members in an X-linked inherited family were examined. The age at onset, progression of disability, and clinical manifestations were collected. Blood tests of the index case were conducted in an academic hospital. Cerebral and spinal MRI was performed in 4 affected members using a Siemens 3.0-T or Hitachi 1.0-T MR scanner. Whole-exome sequencing was conducted in the index case, which was subsequently validated by Sanger sequencing in the family. Results: The patients displayed typical degenerative spastic paraparesis and peripheral sensorimotor neuropathy with some intrafamilial variations. In addition to neurological deficits, all male patients displayed alopecia since adolescence. Furthermore, an increase in plasma long-chain fatty acids was observed. Based on these presentations, adult AMN was diagnosed for the patients. Intriguingly, cerebral MRI showed multiple types of hypoplasia and agenesis of the CC including anterior remnant CC agenesis, truncated corpus and splenium, anterior remnant CC agenesis along with thin corpus and splenium. Whole-exome sequencing revealed a nonsense mutation (c.231G>A) which results in a truncated protein product (p.W77X) that might be nonfunctional. No other mutations associated with alopecia or hypoplasia and agenesis of the CC were identified in the exome-sequencing database. Conclusion: In addition to the typical symptoms such as spastic myelopathy, cognitive impairment, mixed neuropathy, and alopecia, AMN patients can also display hypoplasia and agenesis of the CC, which was not described in the other AMN patients reported before. [ABSTRACT FROM AUTHOR]

Human T-cell lymphotropic virus (HTLV)-1-associated myelopathy (HAM) is well described. Clinical features are predominantly consistent with cord pathology, though imaging and autopsy studies also demonstrate brain inflammation. In general, this is subclinical; however, six cases have previously been reported of encephalopathy in HTLV-1-infected patients, without alternative identified aetiology. We describe three further cases of encephalitis in the UK HAM cohort (n = 142), whereas the annual incidence of acute encephalitis in the general population is 0.07-12.6 per 100,000. Clinical features included reduced consciousness, fever/hypothermia, headaches, seizures, and focal neurology. Investigation showed: raised CSF protein; pleocytosis; raised CSF:peripheral blood mononuclear cell HTLV-1 proviral load ratio; and MRI either normal or showing white matter changes in brain and cord. Four of the six previous case reports of encephalopathy in HTLV-infected patients also had HAM. Histopathology, reported in three, showed perivascular predominantly CD8+ lymphocytic infiltrates in the brain. One had cerebral demyelination, and all had cord demyelination. We have reviewed the existing six cases in the literature, together with our three new cases. In all seven with HAM, the spastic paraparesis deteriorated sub-acutely preceding encephalitis. Eight of the nine were female, and four of the seven treated with steroids improved. We propose that HTLV-associated encephalopathy may be part of the spectrum of HTLV-1-induced central nervous system disease. [ABSTRACT FROM AUTHOR]

Introduction: Adrenoleukodystrophy (ALD) is a hereditary genetic disease linked to the X chromosome. It is caused by mutations in ABCD1, a gene that codes for ALD protein, a peroxisomal membrane protein of unclear function. A very large spectrum of symptoms, as well as different degrees of intensity among the members of the same family may be a serious diagnostic challenge. Aim: To examine current views with respect to ALD pathogenesis and treatment methods and to present the case of its specific variant: adrenomyeloneuropathy. Additionally, we wish to direct attention to the possibility of such a diagnosis in each patient (including women) with progressive paraparesis. Case study: We present the case of a 29-year-old male patient with progressive paraparesis. The implemented diagnostics procedures (neuroimaging studies and levels of very long chain fatty acids) led to a correct diagnosis: adrenomyeloneuropathy. Results and discussion: Symptomatology as well as diagnostic and therapeutic methods implemented for patients with ALD are discussed in detail. Conclusions: Only a very thorough patient interview and family history as well as a detailed physical examination can provide proper direction for diagnostic procedures. This is important due to the necessity of periodic screening for male children in order to earlier detect the cerebral form of ALD. Early diagnosis is associated with better benefits concerning allogeneic hematopoietic stem cell transplants. [ABSTRACT FROM AUTHOR]

Objective Patients with adrenomyeloneuropathy may have dysfunctions of visual, auditory, motor and somatosensory pathways. We thought on examining the nociceptive pathways by means of laser evoked potentials (LEPs), to obtain additional information on the pathophysiology of this condition. Methods In 13 adrenomyeloneuropathic patients we examined LEPs to leg, arm and face stimulation. Normative data were obtained from 10 healthy subjects examined in the same experimental conditions. We also examined brainstem auditory evoked potentials (BAEPs), pattern reversal full-field visual evoked potentials (VEPs), motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs). Results Upper and lower limb MEPs and SEPs, as well as BAEPs, were abnormal in all patients, while VEPs were abnormal in 3 of them (23.1%). LEPs revealed abnormalities to stimulation of the face in 4 patients (30.7%), the forearm in 4 patients (30.7%) and the leg in 10 patients (76.9%). Conclusions The pathologic process of adrenomyeloneuropathy is characterized by a preferential involvement of auditory, motor and somatosensory tracts and less severely of the visual and nociceptive pathways. This non-inflammatory distal axonopathy preferably damages large myelinated spinal tracts but there is also partial involvement of small myelinated fibres. Significance LEPs studies can provide relevant information about afferent pain pathways involvement in adrenomyeloneuropathic patients. [ABSTRACT FROM AUTHOR]

Objective: Mutations in ABCD1 cause the neurodegenerative disease, adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease, but its role in the spinal cord is unclear.Methods: We assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. Because mutations in ABCD1 lead to incorporation of very-long-chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia.Results: Within the spinal cord of humans and mice with AMN, upregulation of several phagocytosis-related markers, such as MFGE8 and TREM2, precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1-deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis, and leads to neuronal injury. Furthermore, exposure to a MFGE8-blocking antibody reduces phagocytic activity.Interpretation: Spinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. Ann Neurol 2017;82:813-827. [ABSTRACT FROM AUTHOR]

Due to the heterogeneous nature of the disease, it is a challenge to capture disease activity of multiple sclerosis (MS) in a reliable and valid way. Therefore, it can be difficult to assess the true efficacy of interventions in clinical trials. In phase III trials in MS, the traditionally used primary clinical outcome measures are the Expanded Disability Status Scale and the relapse rate. Secondary outcome measures in these trials are the number or volume of T2 hyperintense lesions and gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) of the brain. These secondary outcome measures are often primary outcome measures in phase II trials in MS. Despite several limitations, the traditional clinical measures are still the mainstay for assessing treatment efficacy. Newer and potentially valuable outcome measures increasingly used or explored in MS trials are, clinically, the MS Functional Composite and patient-reported outcome measures, and on MRI, brain atrophy and the formation of persisting black holes. Several limitations of these measures have been addressed and further improvements will probably be proposed. Major improvements are the coverage of additional functional domains such as cognitive functioning and assessment of the ability to carry out activities of daily living. The development of multidimensional measures is promising because these measures have the potential to cover the full extent of MS activity and progression. In this review, we provide an overview of the historical background and recent developments of outcome measures in MS trials. We discuss the advantages and limitations of various measures, including newer assessments such as optical coherence tomography, biomarkers in body fluids and the concept of 'no evidence of disease activity'. [ABSTRACT FROM AUTHOR]

In a certain group of patients with syringomyelia, even with the advent of sophisticated magnetic resonance imaging (MRI), no associated abnormality or cerebrospinal fluid (CSF) block is easily identified. This type of syringomyelia is often termed idiopathic. Current literature has less than 10 reports of arachnoid webs to be the causative factor. We present our experience in the management of two cases of syringomyelia secondary to arachnoid webs. Both our patients presented with progressive neurological deterioration with MRI scans demonstrating cervical/thoracic syrinx without Chiari malformation or low-lying cord. There was no history of previous meningitis or trauma. Both patients underwent myelography that demonstrated dorsal flow block implying CSF obstruction. Cord displacement/change in caliber was also noted and this was not evident on MRI scans. Both patients underwent thoracic laminectomy. After opening the dura, thickened/abnormal arachnoid tissue was found that was resected thus widely communicating the dorsal subarachnoid space. Postoperatively at 6 months, both patients had significant symptomatic improvement with follow-up MRI scans demonstrating significant resolution of the syrinx. In patients with presumed idiopathic syringomyelia, imaging studies should be closely inspected for the presence of a transverse arachnoid web. We believe that all patients with idiopathic symptomatic syringomyelia should have MRI CSF flow studies and/or computed tomography (CT) myelography to identify such arachnoid abnormalities that are often underdiagnosed. Subsequent surgery should be directed at the establishment of normal CSF flow by laminectomy and excision of the offending arachnoid tissue. [ABSTRACT FROM AUTHOR]

Context: Preoperative severity of myelopathy, age, and duration of symptoms have been shown to be highly predictive of the outcome in compressive cervical myelopathy (CCM). The role of radiological parameters is still controversial. Aims: Define the prognostic factors in CCM and formulate a prognostic score to predict the outcome following surgery in CCM. Settings and Design: Retrospective. Materials and Methods: This study included 78 consecutive patients with CCM treated surgically. The modified Japanese Orthopaedic Association (mJOA) scale was used to quantify severity of myelopathy at admission and at 12-month follow-up. The outcome was defined as "good" if the patient had mJOA score ≥16 and "poor" if the score was <16. Age, sex, duration of symptoms, comorbidities, intrinsic hand muscle wasting (IHMW), diagnosis, surgical technique, Torg ratio, instability on dynamic radiographs, and magnetic resonance imaging (MRI) signal intensity changes were assessed. Statistics: Statistical Package for the Social Sciences (SPSS) (version 20.0) was used for statistical analysis. The association was assessed amongst variables using logistic regression analysis. Parameters having a statistically significant correlation with the outcome were included in formulating a prognostic score. Results: Severity of myelopathy, IHMW, age, duration, diabetes, and instability on radiographs were predictive of the outcome with a P value <0.01. Genders, diagnosis, surgical procedure, Torg ratio, and intensity changes on MRI were not significantly related to the outcome. A 8-point scoring system was devised incorporating the significant clinicoradiological parameters, and it was found that nearly all patients (97.82%) with a score below 5 had good outcome and all patients (100%) with a score above 5 had poor outcome. The outcome is difficult to predict with a score of 5. Conclusions: Clinical parameters are better predictors of the outcome as compared to radiological findings, following surgery in CCM. A simple scoring system based on clinicoradiological parameters is suggested in this paper to predict the outcome following surgery in cases of CCM. [ABSTRACT FROM AUTHOR]

Key Clinical Message X-linked adrenoleukodystrophy may present with a deceptively mild phenotype, even in adult males. Tight collaboration between clinicians, geneticists, biochemists, and other specialists is increasingly required for clarification of diagnosis in cases with atypical presentation. [ABSTRACT FROM AUTHOR]

Introduction Microendoscopic techniques through a unilateral paramedian approach or muscle-preserving techniques using a microscope have been reported as minimally invasive spinal decompression procedures for the cervical spine. In this study, we developed a novel technique, cervical microendoscopic interlaminar decompression (CMID) through a midline approach, for treating cervical compression myelopathy. Methods A total of 29 consecutive patients with single- or two-level cervical compression myelopathy were reviewed. For the single-level cases (e.g., C5-C6), a midline skin incision, ∼ 2 cm in length, was made at the spinal level to be decompressed (C5-C6) under fluoroscopic guidance. The nuchal ligament was longitudinally cut, and tips of the spinous processes (C5 and C6) were exposed. A 16-mm tubular retractor was inserted between the tips of the C5 and C6 spinous processes. A dome-like laminectomy of C5, partial laminectomy of the upper part of C6, and flavectomy were performed. For the two-level cases (e.g., C4-C5 and C5-C6), the decompression procedure was completed by splitting the spinous process (C5). Pre- and postoperative neurologic status was evaluated using the Japanese Orthopedic Association (JOA) score. Neck and arm pain was also evaluated using a numerical rating scale (NRS). Results Overall, 10 patients underwent single-level decompression, and 19 patients underwent two-level decompression. The average age was 67 years (range: 40-83 years), and the mean follow-up period was 11 months (range: 4-14 months). The average pre- and postoperative JOA scores were 10.2 and 13.5, with a mean recovery rate of 49%. The mean preoperative and postoperative NRS scores were 3.5 and 1.5 for neck pain and 4.6 and 2.9 for arm pain, respectively. One patient showed transient mild weakness of the leg that recovered neurologically within a few weeks. No other postoperative complications were observed. Conclusion This procedure revealed good short-term surgical results. This technique has advantages including (1) a symmetrical orientation of the surgical field, (2) an intermuscular incision that minimizes blood loss and muscle trauma, and (3) the ability to safely complete the decompression procedure without retracting the cervical spinal cord compared with the unilateral approach. Although long-term surgical results are required, this technique is not only safe but also minimally invasive as a treatment for cervical compression myelopathy. [ABSTRACT FROM AUTHOR]

Highlights: [•] The axonal myelination occurred earlier on VG cells than on CG cells. [•] The myelination occurred earlier on AMN than on UN and SN in the VG. [•] The perikaryal myelination occurred at the same time on both types of ganglion cells. [•] These regional differences in myelination reflect the onset of functional activity. [Copyright &y& Elsevier]

Abstract: Although peroxisome biogenesis and β-oxidation disorders are well known for their neurodevelopmental defects, patients with these disorders are increasingly diagnosed with neurodegenerative pathologies. In order to investigate the cellular mechanisms of neurodegeneration in these patients, we developed a mouse model lacking multifunctional protein 2 (MFP2, also called D-bifunctional protein), a central enzyme of peroxisomal β-oxidation, in all neural cells (Nestin-Mfp2−/− ) or in oligodendrocytes (Cnp-Mfp2−/− ) and compared these models with an already established general Mfp2 knockout. Nestin-Mfp2 but not Cnp-Mfp2 knockout mice develop motor disabilities and ataxia, similar to the general mutant. Deterioration of motor performance correlates with the demise of Purkinje cell axons in the cerebellum, which precedes loss of Purkinje cells and cerebellar atrophy. This closely mimics spinocerebellar ataxias of patients affected with mild peroxisome β-oxidation disorders. However, general knockouts have a much shorter life span than Nestin-Mfp2 knockouts which is paralleled by a disparity in activation of the innate immune system. Whereas in general mutants a strong and chronic proinflammatory reaction proceeds throughout the brain, elimination of MFP2 from neural cells results in minor neuroinflammation. Neither the extent of the inflammatory reaction nor the cerebellar degeneration could be correlated with levels of very long chain fatty acids, substrates of peroxisomal β-oxidation. In conclusion, MFP2 has multiple tasks in the adult brain, including the maintenance of Purkinje cells and the prevention of neuroinflammation but this is not mediated by its activity in oligodendrocytes nor by its role in very long chain fatty acid degradation. [Copyright &y& Elsevier]

The article describes the case report of a 45-year-old male patient with a history of mild bilateral legs stiffness, ejaculation difficulty leading to infertility and mild cord atrophy, and who was diagnosed with adrenomyeloneuropathy (AMN) and severe cerebral inflammation. The patient was precribed with rosuvastatin, cortisone and atorvastatin for spastic weakness of upper extremeties and respiratory muscles. Stain was given to treat metabolic defects in very long chain fatty acid (VLCFA).

Abstract: Seizures in cerebral X-linked adrenoleucodystrophy (X-ALD) more frequently occur in the early-onset compared to the late-onset form. Here we describe an adult in whom X-ALD deteriorated after head trauma and who developed epilepsy with progression of X-ALD. In a 50year-old Caucasian male, cerebral X-ALD was diagnosed upon progressive gait disturbance, intellectual decline, elevated very-long chain fatty acids in the serum or leucocytes, cerebral MRI, showing extensive, symmetric, homogenous demyelination in the parieto-occipital areas, the splenium corporis callosum, the thalamus, the crura cerebri, the brain stem, and the pedunculi cerebelli, and the deletion c.1415-1416delAG in the ABCD1-gene. After a head trauma the phenotype deteriorated to mutism, dysphagia, and severe spastic quadruparesis. At an age of 50years the patient experienced his first, self-limiting, tonic–clonic seizure during an infection, which is why valproic acid was started. Recurrence of seizures after discharge required repeated adaptation of the valproic acid-dosage. Adult X-ALD may be associated with late-onset seizures, which respond favourably to valproic acid. Since any type of seizure episode in adult-onset cerebral X-ALD is usually followed by neurological decline, prophylactic treatment with antiepileptic drugs should be considered not only in early-onset but also in adult-onset epilepsy in X-ALD. [Copyright &y& Elsevier]

Background: Optic neuritis is associated with neurodegeneration leading to chronic impairment of visual functions. Objective: This study investigated whether early treatment with interferon beta (IFN-β) slows retinal nerve fibre layer (RNFL) thinning in clinically isolated optic neuritis. Methods: Twenty patients with optic neuritis and visual acuity decreased to ⩽0.5 (decimal system) were included into this prospective, open-label, parallel group 4-month observation. After methylprednisolone pulse therapy, 10 patients received IFN-β from week 2 onwards. This group was compared to 10 patients free of any disease modifying treatment (DMT). The parameter of interest was change in RNFL thickness assessed at baseline and at weeks 4, 8, and 16. Changes in visual acuity, visual field, and visual evoked potentials (VEPs) served as additional outcome parameters. Results: RNFL thinning did not differ between the groups with a mean reduction of 9.80±2.80 mm in IFN-β-treated patients (±SD) vs. 12.44±5.79 μm in patients who did not receive DMT (baseline non-affected eye minus affected eye at week 16; p = 0.67, t-test, 95% confidence interval: -15.77 to 10.48). Parameters of visual function did not show any differences between the groups either. Conclusions: In isolated optic neuritis, early IFN-β treatment did not influence RNFL thinning nor had it any effect on recovery of visual functions. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging sequences such as diffusion and spectroscopy have been well studied in X-linked adrenoleukodystrophy, but no data exist on magnetic resonance perfusion imaging. Since inflammation is known to modulate the microcirculation, we investigated the hypothesis that changes in the local perfusion might be one of the earliest signs of lesion development. Twenty patients with different phenotypes of adrenoleukodystrophy and seven age-matched controls were evaluated between 2006 and 2011. Fluid attenuated inversion recovery, post-contrast T1-weighted and normalized dynamic susceptibility contrast magnetic resonance perfusion cerebral blood volume maps were co-registered, segmented when cerebral lesion was present, and normalized cerebral blood volume values were analysed using a Food and Drug Association approved magnetic resonance perfusion software (NordicICE). Clinical and imaging data were reviewed to determine phenotype and status of progression. All eight patients with cerebral adrenoleukodystrophy had an average 80% decrease in normalized cerebral blood volume at the core of the lesion (P < 0.0001). Beyond the leading edge of contrast enhancement cerebral perfusion varied, patients with progressive lesions showed an average 60% decrease in normalized cerebral blood volume (adults P < 0.05; children P < 0.001), while one child with arrested progression normalized cerebral blood volume in this region. In six of seven patients with cerebral adrenoleukodystrophy lesions and follow-up imaging (2–24 month interval period), we found progression of contrast enhancement into the formerly hypoperfused perilesional zone. Asymptomatic, adrenomyeloneuropathy and female heterozygote patients had no significant changes in cerebral perfusion. Our data indicate that decreased brain magnetic resonance perfusion precedes leakage of the blood–brain barrier as demonstrated by contrast enhancement in cerebral adrenoleukodystrophy and is an early sign of lesion progression. [ABSTRACT FROM AUTHOR]

Abstract: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease resulting from mutations in the gene ABCD1 and alterations in peroxisomal beta-oxidation of long chain fatty acids. As it has been frequently discussed, it manifests a wide range of phenotypes in male, with progressive myelopathy being the most common. Even though the gene is localized to the X-chromosome and a region subject to X-inactivation, female carriers still are affected significantly by this condition. It has been stated that between 20 and 50% of women who are carriers may manifest some symptoms and recent evidence has suggested the differences in disease manifestations and relative rates of progression between men and women. However there have been only limited studies specifically addressing this and to date there has been no comprehensive review discussing the different phenotypes in female carriers, as well as the differences in disease onset, progression, disability, nervous system pathology and neuroimaging patterns compared to affected males. This is of key importance as similarities and differences between genders will assist in determining how best to target therapies in all affected individuals as opportunities for treatment present themselves. As will be further addressed in this review, we need to improve our understanding of the associations of emergent neuroimaging techniques to physical disability in this population. We reviewed the clinical presentations in the carrier population, the distinct disability profile and neuroimaging findings in order to put together pieces of this neglected segment in X-ALD and give direction to further studies. [Copyright &y& Elsevier]

Background: X-linked adrenoleukodystrophy (X-ALD) is the most frequent, severely neurodegenerative, clinically heterogeneous peroxisomal disorder, the signs of which are a consequence of myelin, adrenal cortex, and testes impairment. Objective: We studied testosterone, LH, and FSH levels in X-ALD/adrenomyeloneuropathy (AMN) patients. We evaluate the ability to procreate of these patients by analysis of pedigree and family screening by detection of very long-chain fatty acid (VLCFA) levels. Subject and methods: Seventeen patients with X-ALD/AMN (16 with AMN and one asymptomatic) aged 24-48 (mean±S.D., 34.7±5.9) years, were identified based on the clinical picture, magnetic resonance imaging, and the presence of increased serum VLCFA levels. Nine X-ALD/AMN patients' daughters, mean ages ±S.D.Z7.7±3.8 years, were identified as heterozygote by elevated VLCFA levels. Serum VLCFA levels were determined as ester derivatives by a gas chromatography method. Serum testosterone, LH, and FSH levels in X-ALD/AMN patients were detected by IRMAs. Results: Serum testosterone levels were at the lowest levels of normal range but serum LH and FSH concentrations were increased in 57.1 and in 42.9% of X-ALD/AMN patients respectively. Among the 11 investigated of X-ALD/AMN married adult men, nine had produced offspring, a total of 13 children. All patients' daughters showed elevated serum VLCFA at heterozygote levels. Conclusion: In this study, we report that in a group of X-ALD/AMN married adult men, we did not find a significant decrease in fertility compared with the Polish population (18.2 vs 15%). [ABSTRACT FROM AUTHOR]

Background: Adrenomyeloneuropathy (AMN) is one of several phenotypes of the adrenoleukodystrophy spectrum caused by mutations in the ABCD1 gene on the X chromosome. An inflammatory component is part of the disease complex ranging from severe childhood CNS demyelination to spinal cord and peripheral nerve degeneration. Case presentation: We present a patient with clinical progressive AMN and severe lower limb pain. Longitudinal brain magnetic resonance spectroscopy showed a constant slightly elevated myoinositol/total creatine ratio during the five year treatment period, probably reflecting demyelination, microglial activation and gliosis, indicating an inflammatory response. The pain was refractory to conventional therapy but intravenous immunoglobulin (IVIG)treatment was highly efficient. Conclusion: IVIG may be considered as a last resort for treatment of refractory pain in AMN patients with indications of an inflammatory component [ABSTRACT FROM AUTHOR]

X-linked adrenoleukodystrophy (X-ALD) is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN) to childhood cerebral ALD (CCALD). X-ALD is caused by mutations in the ABCD1 gene, but no genotypephenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved in the neuroinflammatory process of CCALD. CD1 proteins are lipid- antigen presenting molecules encoded by five CD1 genes in human (CD1A-E). Association studies with 23 tag SNPs covering the CD1 locus was performed in 52 patients with AMN and 87 patients with CCALD. The minor allele of rs973742 located 4-kb downstream from CD1D was significantly more frequent in AMN patients (x2 = 7.6; P = 0.006). However, this association was no longer significant after Bonferroni correction for multiple testing. The other polymorphisms of the CD1 locus did not reveal significant association. Further analysis of other CD1D polymorphisms did not detect stronger association with X-ALD phenotypes. Although the association with rs973742 warrants further investigations, these results indicate that the genetic variants of CD1 genes do not contribute markedly to the phenotypic variance of X-ALD. [ABSTRACT FROM AUTHOR]

Abstract: X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in plasma. In contrast, only 80% of female carriers have elevated plasma VLCFA; therefore targeted mutation analysis is the most effective means for carrier detection. Amongst 489 X-ALD families tested at Kennedy Krieger Institute, we identified 20 cases in which the ABCD1 mutation was de novo in the index case, indicating that the mutation arose in the maternal germ line and supporting a new mutation rate of at least 4.1% for this group. In addition, we identified 10 cases in which a de novo mutation arose in the mother or the grandmother of the index case. In two of these cases studies indicated that the mothers were low level gonosomal mosaics. In a third case biochemical, molecular and pedigree analysis indicated the mother was a gonadal mosaic. To the best of our knowledge mosaicism has not been previously reported in X-ALD. In addition, we identified one pedigree in which the maternal grandfather was mosaic for the familial ABCD1 mutation. Less than 1% of our patient population had evidence of gonadal or gonosomal mosaicism, suggesting it is a rare occurrence for this gene and its associated disorders. However, the residual maternal risk for having additional ovum carrying the mutant allele identified in an index case that appears to have a de novo mutation is at least 13%. [Copyright &y& Elsevier]

The article presents the case history of 34-year-old patient with adrenomyeloneuropathy (AMN), the adult variant of adrenoleukodystryphy (ALD). The patient's diagnoses was confirmed via increased serum very long chain fatty acid concentration (VLCFA). His treatment started with atorvastatin, followed by add-on therapy with Lorenzo's oil and finally supplementation with docosahexaenoic acid (DHA).

X-adrenoleukodystrophy (X-ALD) is a metabolic, peroxisomal disease affecting the nervous system, adrenal cortex and testis resulting from inactivating mutations in ABCD1 gene which encodes a peroxisomal membrane half-adenosine triphosphate (ATP)-binding cassette transporter, ABCD1 (or ALDP), whose defect is associated with impaired peroxisomal β-oxidation and accumulation of saturated very long-chain fatty acids (VLCFA) in tissues and body fluids. Several phenotypes are recognized in male patients including cerebral ALD in childhood, adolescence or adulthood, adrenomyeloneuropathy (AMN), Addison's disease and, eventually, gonadal insufficiency. Female carriers might present with mild to severe myeloneuropathy that resembles AMN. There is a lack of phenotype–genotype correlations, as the same ABCD1 gene mutation may be associated with different phenotypes in the same family, suggesting that genetic, epigenetic, environmental and stochastic factors are probably contributory to the development and course of the disease. Degenerative changes, like those seen in pure AMN without cerebral demyelination, are characterized by loss of axons and secondary myelin in the long tracts of the spinal cord, possibly related to the impaired lipid metabolism of VLCFAs and the associated alterations (ie, oxidative damage). Similar lesions are encountered following inactivation of ABCD1 in mice ( ABCD1-). A different and more aggressive phenotype is secondary to cerebral demyelination, very often accompanied by inflammatory changes in the white matter of the brain and associated with activation of T lymphocytes, CD1 presentation and increased levels of cytokines, γ-interferon, interleukin (IL)-1α, IL-2 and IL-6, Granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α, chemokines and chemokine receptors. [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic, proximal and distal, asymmetrical or symmetrical, motor and sensory demyelinating polyneuropathy with a progressive course for at least 2 months. The accurate diagnosis is crucial as CIDP is amenable to treatment. Recent advances have provided new strategies and options for management of this syndrome. In this article, we review the clinical and diagnostic features as well as discuss recent insights and treatment strategies along with our experience in the management of patients with CIDP. [ABSTRACT FROM AUTHOR]

Abstract: X-linked adreno-leukodystrophy and its adult variant, adrenomyeloneuropathy, are caused by mutations in ABCD1 that encodes a peroxisomal membrane protein of unknown physiological significance. In spite of identical mutations, they can have markedly divergent neurological and neuropathologic characteristics. Adreno-leukodystrophy classically presents in normal boys with mild neuropsychiatric features, which progress to frank neurological signs, the vegetative state and death in approximately three years. Adrenomyeloneuropathy typically affects young men with spastic paraparesis and sensory ataxia that can progress over decades. The neuropathologic correlate for adreno-leukodystrophy is severe inflammatory demyelination of posterior cerebral white matter, while a chronic distal axonopathy of spinal cord and peripheral nerve occurs in adrenomyeloneuropathy. Consequently, both modifier genes and environmental factors have been implicated in their pathogeneses. We report five cases of adreno-leukodystrophy whose onsets were initiated by moderate to severe head trauma, two of whom were conversions from adrenomyeloneuropathy. Their clinical courses were rapidly incapacitating, short (i.e., weeks to a few years) and fatal due to marked cerebral inflammatory demyelination. These cases, in concert with several previous reports, indicate that head trauma is one environmental factor that can have a profoundly deleterious effect on those genetically at risk for, or with milder clinical phenotypes of, this disease. Avoidance of potential head trauma and a rapid response to episodes of moderate to severe head trauma in this patient population seem prudent. [Copyright &y& Elsevier]

Abstract: Objective: This paper investigates efferent and afferent conductions of the central nervous system by various evoked potentials in patients with adrenomyeloneuropathy (AMN). Patients and methods: Ten pure AMN patients without cerebral involvement were studied. Motor evoked potentials (MEPs), somatosensory evoked potentials (SEPs), auditory brainstem response (ABR), and pattern reversal full-field visual evoked potentials (VEPs) were recorded. For MEP recording, single-pulse or double-pulse magnetic brainstem stimulation (BST) was also performed. Results: Abnormal MEP was observed in all ten patients, abnormal SEP in all ten, abnormal ABR in nine, and abnormal VEP in only one. Brainstem latency was measured in three of the seven patients with central motor conduction time (CMCT) prolongation. The cortical–brainstem conduction time was severely prolonged along the normal or mildly delayed brainstem–cervical conduction time in those three patients. Conclusions: The pattern of normal VEP and abnormal MEP, SEP, ABR is a clinically useful electrophysiological feature for the diagnosis. BST techniques are helpful to detect, functionally, intracranial corticospinal tract involvement, probably demyelination, in pure AMN patients. [Copyright &y& Elsevier]

Abnormalities in the transport of saturated very long chain fatty acids (VLCFA; >C18:0) contribute to their toxic levels in peroxisomal disorders of fatty acid metabolism, such as adrenoleukodystrophy and adrenomyeloneuropathy. We previously showed that VLCFA desorb much slower than normal dietary fatty acids from both albumin and protein-free lipid bilayers. The important step of transbilayer movement (flip-flop) was not measured directly as a consequence of this very slow desorption from donors, and the extremely low aqueous solubility of VLCFA precludes addition of unbound VLCFA to lipid membranes. We have overcome these limitations using methyl-β-cyclodextrin to solubilize VLCFA for rapid delivery to "acceptor" phosphatidylcholine vesicles (small and large unilamellar) and to cells. VLCFA binding was monitored in real time with the fluorescent probe fluorescein-labeled phosphatidylethanolamine in the outer membrane leaflet, and entrapped pyranine was used to detect flip-flop across the membrane. The upper limit of the rate of flip-flop across the membrane was independent of temperature and media viscosity and was similar for model raft and non-raft membranes as well as living cells. We further showed that cyclodextrins can extract VLCFA rapidly (within seconds) from vesicles and cells, which have implications for the mechanism and potential alternative approaches to treat adrenoleukodystrophy. Because VLCFA diffuse through the lipid bilayer, proteins may not be required for their transport across the peroxisomal membrane. [ABSTRACT FROM AUTHOR]

Chronic fatigue syndrome/myalgic encephalomyelitis (CFE/ME) is an invisible disability that forces researchers to delineate new boundaries between illness and impairment, and between medical knowledge and patients' experience. As a neurological impairment, this condition attacks memory and cognition, which paradoxically become the focus of patients' own accounts of their experience and understanding. This paper addresses the pedagogical implications of this invisible disability. Drawing on emergent research on the social ties and social memory of elephants, this paper compares the forgetting in and about invisible disabilities with the cultures of remembering and caring exemplified by the elephant who 'never forgets'. Just as the elephant exemplifies the interdependency of social relations and memory, so teachers and administrators can acknowledge different kinds of memory and expectations of memory and social process in pedagogical environments. [ABSTRACT FROM AUTHOR]

The article focuses on a study related to erucic acid and adrenomyeloneuropathy. Topics discussed include a peroxisomal disorder of beta-oxidation resulting in tissue accumulation of long-chain of fatty acids, mutations in the ATP-binding cassette transporters, a delayed progression of neurological signs in early adrenoleucodystrophy due to dietary treatment.

Objective. Fabry disease (FD) is an X-linked lipid storage disorder showing a high prevalence and early occurrence of painful neuropathy. Early detection of this likely underdiagnosed disease is an important approach because a causal therapy is available. Design. We used a quantitative sensory testing to determine the detailed somatosensory profile of male Fabry patients and compare this profile with somatosensory profiles of other painful sensory neuropathies (SN). Results. Within this pilot-study, the profile revealed a small-fiber sensory neuropathy selectively affecting C- and A-delta fibers. The comparison with different somatosensory profiles of painful SN, including painful small-fiber sensory neuropathies of other etiologies, showed that the FD profile differs significantly and is characterized by a severe impairment of thermal and preserved vibratory and mechanical discrimination. Conclusion. Thus, somatosensory profiling in male patients with painful extremities may be useful in the detection of FD. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]