Search

Background and ObjectivesWe sought to characterize the natural history and standard-of-care practices between the radiologic appearance of brain lesions, the appearance of lesional enhancement, and treatment with hematopoietic stem-cell transplant or gene therapy among boys diagnosed with presymptomatic childhood-onset cerebral adrenoleukodystrophy (CCALD).MethodsWe analyzed a multicenter, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score = 0, Loes Score [LS] = 0.5–9.0, and age ResultsSeventy-one boys were diagnosed with presymptomatic cerebral lesions at a median age of 6.4 years [2.4–12.1] with a LS of 1.5 [0.5–9.0]. Fifty percent of patients had lesional enhancement at diagnosis. In the remaining 50%, the median Kaplan-Meier (KM)-estimate of time from diagnosis-to-lesional enhancement was 6.0 months (95% CI 3.6–17.8). The median KM-estimate of time from enhancement-to-treatment is 3.8 months (95% CI 2.8–5.9); 2 patients (4.2%) developed symptoms before treatment. Patients with a diagnostic LS ≤ 1 were younger (5.8 years [2.4–11.5]), had a time-to-enhancement of 4.7 months (95% CI 2.7–9.30), and were treated in 3.8 months (95% CI 3.1–7.1); no patients developed symptoms before treatment. Time from CCALD diagnosis-to-treatment decreased over the course of the study (ρ = −0.401, p = 0.003).DiscussionOur findings offer a more refined understanding of the timing of lesion formation, enhancement, and treatment among boys with presymptomatic CCALD. These data offer benchmarks for standardizing clinical care and designing future clinical trials.

Context Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. Objective To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. Design We conducted a retrospective medical chart review of pediatric patients with ALD. Setting All patients were seen in a leukodystrophy clinic in an academic medical center. Patients We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). Main Outcome Measures We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. Results Thirty-one (27%) patients were diagnosed with ALD by NBS and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9,12.12] months vs 6.05 [3.74,8.35] years) (p Conclusions Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.

Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 10

Magnetic resonance spectroscopy (MRS) and functional MRI (fMRI), related through common biophysical bases, provide complementary information about brain function. The link between MRS and fMRI measures is of interest, especially in the ultra-rare, metabolic disease late-onset GM2 gangliosidosis (LOGG). Imaging studies on LOGG have been few and far between, with cerebellar atrophy and neurochemical impairments being the most prominent findings. However, it remains unknown as to how these neurochemical aberrations relate to neurofunctional characteristics. The goal of this study (7 LOGG, 7 age/sex matched controls) was to assess the relationship between MRS concentrations and fMRI measures derived from the same MRS ROI (cerebellum, thalamus, precuneus) in LOGG. To quantify the communication between MRS regions and rest of the brain, we employed graph measures estimated from resting-state fMRI functional connectivity. We found that one such measure, local efficiency, which quantifies the aggregate relationship between a MRS region and rest of the brain, was significantly associated with N-acetylaspartate (NAA) in the cerebellum and thalamus (pp=0.002). These findings hint at a model of impaired neurochemical concentrations in these regions, leading to aberrant communication between them and rest of the brain, which may exacerbate disease progression. Future research must replicate these findings in larger cohorts, and further investigate such abnormalities in the cerebellum, thalamus and precuneus in this ultra-rare neurological disease.

Late-onset GM2 gangliosidosis (LOGG) is an ultra-rare neurological disease with motor, cognitive and psychiatric manifestations. It is caused by mutations in the HEXA or HEXB genes. Although cerebellar structural and metabolic impairments have been established, global brain functional impairments in this disease remain unknown. In this first functional MRI (fMRI) report on LOGG (N=14), we took an exploratory, multi-pronged approach by assessing impairments in several resting-state fMRI signal characteristics: fMRI signal strength, neurovascular coupling, static and time-varying functional connectivity, and network topology. Contrary to the predominance of cerebellar aberrations in prior non-functional studies, we found more widespread cortical aberrations (pHEXA and HEXB gene expression. These aberrations might contribute to psychiatric symptoms (psychosis, mood disturbances), cognitive impairments (memory, attention, executive function), and oculomotor disturbances commonly seen in LOGG. Future LOGG imaging studies should probe brain function in addition to structure/metabolism while looking for mechanistic insights beyond the cerebellum.

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by three core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals, and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age of onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary.We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of ALD patients. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoeitic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses as well as presymptomatic individuals is increasing due to newborn screening and greater availability of next generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerges. This knowledge gap should direct future research and illustrates once again that international collaboration amongst physicians, researchers and patients is essential to improving care.

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.

Lesions of the cerebral white matter (WM) result in focal neurobehavioral syndromes, neuropsychiatric phenomena, and dementia. The cerebral WM contains fiber pathways that convey axons linking cerebral cortical areas with each other and with subcortical structures, facilitating the distributed neural circuits that subserve sensorimotor function, intellect, and emotion. Recent neuroanatomical investigations reveal that these neural circuits are topographically linked by five groupings of fiber tracts emanating from every neocortical area: (1) cortico-cortical association fibers; (2) corticostriatal fibers; (3) commissural fibers; and cortico-subcortical pathways to (4) thalamus and (5) pontocerebellar system, brain stem, and/or spinal cord. Lesions of association fibers prevent communication between cortical areas engaged in different domains of behavior. Lesions of subcortical structures or projection/striatal fibers disrupt the contribution of subcortical nodes to behavior. Disconnection syndromes thus result from lesions of the cerebral cortex, subcortical structures, and WM tracts that link the nodes that make up the distributed circuits. The nature and the severity of the clinical manifestations of WM lesions are determined, in large part, by the location of the pathology: discrete neurological and neuropsychiatric symptoms result from focal WM lesions, whereas cognitive impairment across multiple domains--WM dementia--occurs in the setting of diffuse WM disease. We present a detailed review of the conditions affecting WM that produce these neurobehavioral syndromes, and consider the pathophysiology, clinical effects, and broad significance of the effects of aging and vascular compromise on cerebral WM, in an attempt to help further the understanding, diagnosis, and treatment of these disorders.