Search

Abstract Adrenomyeloneuropathy (AMN), the slow progressive phenotype of adrenoleukodystrophy (ALD), has no clinical plasma biomarker for disease progression. This feasibility study aimed to determine whether metabolomics and micro‐RNA in blood plasma provide a potential source of biomarkers for AMN disease severity. Metabolomics and RNA‐seq were performed on AMN and healthy human blood plasma. Biomarker discovery and pathway analyses were performed using clustering, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and regression against patient's clinical Expanded Disability Status Score (EDSS). Fourteen AMN and six healthy control samples were analyzed. AMN showed strong disease‐severity‐specific metabolic and miRNA clustering signatures. Strong, significant clinical correlations were shown for 7‐alpha‐hydroxy‐3‐oxo‐4‐cholestenoate (7‐HOCA) (r2 = 0.83, p

Abstract Adrenomyeloneuropathy (AMN) is a rare inherited condition where affected individuals develop slowly progressive spastic paraparesis with a gradual decline in walking ability. There is no cure for AMN and treatment focuses on supportive measures and aids. One treatment option is functional electrical stimulation (FES), a treatment, approved by The National Institute for Health and Care Excellence (NICE), for managing foot drop in upper motor neuron disorders. Limited evidence exists for its use in AMN patients. We describe the effects of FES in an individual case and more broadly within a cohort of 21 patients successfully treated with FES. Patients with AMN referred for FES typically report frequent falls (71%) and foot drop (57%) as the most common barriers to walking. When using FES, walking speed at baseline (0.70 m/s [SD = 0.2]) was maintained at the 2‐year review (0.68 m/s [SD = 0.2]) with a persistent orthotic effect (improvement in walking speed when device on vs. off) seen from wearing FES over the same 2‐year period (11%–19%). Patient walking satisfaction (visual analogue scale: 0 – very dissatisfied; 10 – very satisfied) was also greater when comparing no‐FES versus FES over the same period (Year 1: 2.5 vs. 7.7; Year 2: 2.1 vs. 6.1). FES is not effective in all patients. Twelve patients referred found no benefit from the device; although there was no clear evidence, this was related to the degree of AMN associated peripheral neuropathy. However, FES is a safe, cost‐effective treatment option and should be considered, along with assessment in a multidisciplinary clinic, for all AMN patients with walking difficulties.

Background: The most common manifestation of X-linked adrenoleukodystrophy (ALD) is a slowly progressive myeloneuropathy, which leads to imbalance and gait disturbances. The variable progression of the disease complicates evaluation of its progression rate. Wearable sensors allow for easy and frequent balance and gait collection. This study reports baseline data from a longitudinal study on the quantitative assessment of balance and gait with wearable sensors and their clinical relevance., Methods: Data were collected from adult patients in two institutions. Postural body sway and gait parameters were measured using accelerometers. Disease severity was measured by the Expanded Disability Severity Scale (EDSS). Falling frequency and quality of life (QOL) were collected in men. The relationship between sway and gait variables and EDSS score, participants' use of a walking aid, and falling frequency was evaluated., Results: One hundred twenty individuals with ALD were included. Sway variables significantly differentiate participants' assistive device use. Sway and gait variables were correlated to the EDSS in both sexes. Both gait speed and sway were correlated with falling frequency in men from one institution. Select QOL subscores were correlated with the EDSS in males from one institution. Accelerometry generated comparable results across sites., Discussion: This study confirms the clinical correlation between spinal cord disease and imbalance and gait in ALD. For the first time, this study shows clinically meaningful relationships for sway and gait with use of an assistive device, falling frequency and QOL. Wearable accelerometers are a valid means to measure sway and gait in ALD. These measures are promising outcomes for clinical trial designs to assess myeloneuropathy in ALD and to monitor disease progression in individuals., (© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Abstract A 65‐year‐old woman with mutation of the ABCD1 gene for adrenoleukodystrophy (ALD) was admitted to our hospital with a urinary tract infection. Abdominal computed tomography showed dilation of the urinary tract. Although she had noticed pollakisuria since her forties, she had not been followed up by any medical institutions until we diagnosed her as a female carrier with ALD. ALD is an X‐linked pattern of inheritance that typically affects males, but many female carriers actually present slowly progressive myelopathy and neuropathy. Therefore, it is important to identify female carriers with ALD and treat them at the earliest stage possible.

Abstract Background Adrenomyeloneuropathy (AMN) is a rare genetic disease. In this study, a case of AMN was uncovered in a Chinese family. Methods Clinical manifestations were collected and observed through medical records, physical examination, laboratory tests, and magnetic resonance imaging (MRI). Generation sequencing of the ABCD1 gene was performed, and the pedigree of the family was analyzed. Results The proband suffered from adrenocortical insufficiency at 8 years old and presented with a slowly progressive gait disorder at 21 years old. Physical examination, laboratory tests, and MRI showed that he had adult‐onset AMN manifestations, including spasticity and hyperactive tendon reflexes with Hoffman and Babinski signs in the limbs, difficulty in performing the heel‐to‐shin test, hyperpigmentation, increased levels of adrenocorticotropic hormone and very long‐chain fatty acids, decreased levels of corticosteroid and serum gesterol, and salient atrophy of the cervical and thoracic spinal cord. DNA analysis revealed a missense variant, c.290A>C (p.His97Pro) in exon 1 of the ABCD1 gene, in the proband. Sanger sequencing confirmed that the proband's mother was heterozygous for the same variant. The ABCD1 gene mutation transmitted in an X‐linked inheritance manner. Conclusion A novel missense mutation in the ABCD1 gene was identified in a Chinese family, which caused an unusual manifestation of adult‐onset AMN. This discovery is beneficial for the genetic counseling of patients with X‐linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a rare inherited neurological disorder that poses considerable challenges for clinical management throughout the lifespan. Although males are generally more severely affected than females, the time course and presentation of clinical symptoms are otherwise difficult to predict. Opportunities to improve outcomes for individuals with ALD are rapidly expanding due to the introduction of newborn screening programs for this condition and an evolving treatment landscape. The aim of this comprehensive review is to synthesize current knowledge regarding the neurocognitive and mental health effects of ALD. This review provides investigators and clinicians with context to improve case conceptualization, inform prognostic counseling, and optimize neuropsychological and mental health care for patients and their families. Results highlight key predictive factors and brain-behavior relationships associated with the diverse manifestations of ALD. The review also discusses considerations for endpoints within clinical trials and identifies gaps to address in future research., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Adrenomyeloneuropathy (AMN), the slow progressive phenotype of adrenoleukodystrophy (ALD), has no clinical plasma biomarker for disease progression. This feasibility study aimed to determine whether metabolomics and micro-RNA in blood plasma provide a potential source of biomarkers for AMN disease severity. Metabolomics and RNA-seq were performed on AMN and healthy human blood plasma. Biomarker discovery and pathway analyses were performed using clustering, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and regression against patient's clinical Expanded Disability Status Score (EDSS). Fourteen AMN and six healthy control samples were analyzed. AMN showed strong disease-severity-specific metabolic and miRNA clustering signatures. Strong, significant clinical correlations were shown for 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) ( r 2  = 0.83, p  < 0.00001), dehydroepiandrosterone sulfate (DHEA-S; r 2  = 0.82, p  < 0.00001), hypoxanthine ( r 2  = 0.82, p  < 0.00001), as well as miRNA-432-5p ( r 2  = 0.68, p  < 0.00001). KEGG pathway comparison of mild versus severe disease identified affected downstream systems: GAREM, IGF-1, CALCRL, SMAD2&3, glutathione peroxidase, LDH, and NOS. This feasibility study demonstrates that miRNA and metabolomics are a source of potential plasma biomarkers for disease severity in AMN, providing both a disease signature and individual markers with strong clinical correlations. Network analyses of affected systems implicate differentially altered vascular, inflammatory, and oxidative stress pathways, suggesting disease-severity-specific mechanisms as a function of disease severity., Competing Interests: Potential competing interest for Ali Fatemi: Paid member of drug safety monitoring board – Bluebird Bio, Co‐inventor of Compositions and methods for treatment of peroxisomal disorders and leukodystrophies, Patent #US20170119899A1. Potential competing interest for Bela Rui Turk: Co‐inventor of Compositions and methods for treatment of peroxisomal disorders and leukodystrophies, Patent #US20170119899A1. Laila Marie Poisson, Christina Linnea Nemeth, Jordan Goodman, Richard Owen Jones, and Jordan Goodman have no relevant potential competing interests to report., (© 2022 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)