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Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal disorder. The condition progresses relentlessly, with severe disability typically established within 6-14 years of symptom onset. There is no cure, and limited treatment options are available to slow disease progression. We describe the case of a 23-year-old woman with forgetfulness, unsteady gait, and falls. Neurologic examination revealed intermittent dystonic posturing of the right upper and lower limb when walking. The Addenbrooke's Cognitive Examination (ACE) score was 70/100. MRI sequences demonstrated frontal-predominant atrophy and extensive white matter hyperintensity. Differential diagnoses such as autoimmune, inflammatory, and neoplastic diseases were excluded, and a genetic diagnosis was considered. Lysosomal enzyme testing showed low arylsulfatase with elevated urinary sulfatides, and genetic testing revealed a homozygous pathogenic mutation in the ARSA gene securing a diagnosis of adult-onset MLD. A male sibling also had early cognitive impairment and was found to have the same mutation. Hematopoietic stem cell transplantation (HSCT) was offered after discussion with experts. The male sibling died of multiple complications after HSCT. The index patient is now 24 months after HSCT, and disease progression has halted. This case highlights the challenges in the accurate diagnosis of adult-onset leukoencephalopathies and explores potential treatment strategies. A stepwise approach to the differential diagnosis of white matter diseases is demonstrated. HSCT may be an effective treatment, but the significant complication rate needs to be carefully considered., (© 2022 American Academy of Neurology.)

Background and Objectives: Silent cerebrovascular disease (SCD), comprising silent brain infarction (SBI) and white matter disease (WMD), is commonly found incidentally on neuroimaging scans obtained in routine clinical care. Their prognostic significance is not known. We aimed to estimate the incidence of and risk increase in future stroke in patients with incidentally discovered SCD., Methods: Patients in the Kaiser Permanente Southern California (KPSC) health system aged ≥50 years, without prior ischemic stroke, transient ischemic attack (TIA), or dementia/Alzheimer disease receiving a head CT or MRI between 2009 and 2019 were included. SBI and WMD were identified by natural language processing (NLP) from the neuroimage report., Results: Among 262,875 individuals receiving neuroimaging, NLP identified 13,154 (5.0%) with SBI and 78,330 (29.8%) with WMD. The incidence of future stroke was 32.5 (95% confidence interval [CI] 31.1, 33.9) per 1,000 patient-years for patients with SBI: 19.3 (95% CI 18.9, 19.8) for patients with WMD and 6.8 (95% CI 6.7, 7.0) for patients without SCD. The crude hazard ratio (HR) associated with SBI was 3.40 (95% CI 3.25 to 3.56) and for WMD 2.63 (95% CI 2.54 to 2.71). With MRI-discovered SBI, the adjusted HR was 2.95 (95% CI 2.53 to 3.44) for those <65 years of age and 2.15 (95% CI 1.91 to 2.41) for those ≥65. With CT scan, the adjusted HR was 2.48 (95% CI 2.19 to 2.81) for those <65 and 1.81 (95% CI 1.71 to 1.91) for those ≥65. The adjusted HR associated with a finding of WMD was 1.76 (95% CI 1.69 to 1.82) and was not modified by age or imaging modality., Discussion: Incidentally discovered SBI and WMD are common and associated with increased risk of subsequent symptomatic stroke, representing an important opportunity for stroke prevention., (© 2021 American Academy of Neurology.)

Objective: To test the hypotheses that hypertension and nocturnal blood pressure are related to white matter hyperintensity (WMH) volume, an MRI marker of small vessel cerebrovascular disease, and that WMH burden statistically mediates the association of hypertension and dipping status with memory functioning, we examined the relationship of hypertension and dipping status on WMH volume and neuropsychological test scores in middle-aged and older adults., Methods: Participants from the community-based Maracaibo Aging Study received ambulatory 24-hour blood pressure monitoring, structural MRI, and neuropsychological assessment. Four hundred thirty-five participants (mean ± SD age 59 ± 13 years, 71% women) with available ambulatory blood pressure, MRI, and neuropsychological data were included in the analyses. Ambulatory blood pressure was used to define hypertension and dipping status (i.e., dipper, nondipper, and reverse dipper based on night/day blood pressure ratio <0.9, 0.9-1, and >1, respectively). Outcome measures included regional WMH and memory functioning derived from a neuropsychological test battery., Results: The majority of the participants (59%) were hypertensive. Ten percent were reverse dippers, and 40% were nondippers. Reverse dipping in the presence of hypertension was associated with particularly elevated periventricular WMH volume ( F 2,423 = 3.78, p = 0.024) and with lowered memory scores ( F 2,423 = 3.911, p = 0.021). Periventricular WMH volume mediated the effect of dipping status and hypertension on memory (β = -4.1, 95% confidence interval -8.7 to -0.2, p < 0.05)., Conclusion: Reverse dipping in the presence of hypertension is associated with small vessel cerebrovascular disease, which, in turn, mediates memory functioning. These results point toward reverse dipping as a marker of poor nocturnal blood pressure control, particularly among hypertensive individuals, with potentially pernicious effects on cerebrovascular health and associated cognitive function., (© 2020 American Academy of Neurology.)

Objectives: To investigate spatial heterogeneity of white matter lesions or hyperintensities (WMH)., Methods: MRI scans of 1,836 participants (median age 52.2 ± 13.16 years) encompassing a wide age range (22-84 years) from the cross-sectional Study of Health in Pomerania (Germany) were included as discovery set identifying spatially distinct components of WMH using a structural covariance approach. Scans of 307 participants (median age 73.8 ± 10.2 years, with 747 observations) from the Baltimore Longitudinal Study of Aging (United States) were included to examine differences in longitudinal progression of these components. The associations of these components with vascular risk factors, cortical atrophy, Alzheimer disease (AD) genetics, and cognition were then investigated using linear regression., Results: WMH were found to occur nonuniformly, with higher frequency within spatially heterogeneous patterns encoded by 4 components, which were consistent with common categorizations of deep and periventricular WMH, while further dividing the latter into posterior, frontal, and dorsal components. Temporal trends of the components differed both cross-sectionally and longitudinally. Frontal periventricular WMH were most distinctive as they appeared in the fifth decade of life, whereas the other components appeared later in life during the sixth decade. Furthermore, frontal WMH were associated with systolic blood pressure and with pronounced atrophy including AD-related regions. AD polygenic risk score was associated with the dorsal periventricular component in the elderly. Cognitive decline was associated with the dorsal component., Conclusions: These results support the hypothesis that the appearance of WMH follows age and disease-dependent regional distribution patterns, potentially influenced by differential underlying pathophysiologic mechanisms, and possibly with a differential link to vascular and neurodegenerative changes., (© 2018 American Academy of Neurology.)

Objective: We aimed to evaluate the role of endothelial-dependent and endothelial-independent vascular reactivity in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), both cerebral small vessel diseases are considered models for stroke, vascular dementia, and migraine., Methods: RVCL-S (n = 18) and CADASIL (n = 23) participants with TREX1 and NOTCH3 mutations, respectively, were compared with controls matched for age, body mass index, and sex (n = 26). Endothelial function was evaluated by flow-mediated vasodilatation, and endothelial-independent vascular reactivity (i.e., vascular smooth muscle cell function) was assessed by dermal blood flow response to capsaicin application., Results: Flow-mediated vasodilatation was decreased in participants with RVCL-S compared with controls (2.32% ± 3.83% vs 5.76% ± 3.07% change in diameter, p = 0.023) but normal in participants with CADASIL. Vascular smooth muscle cell function was reduced in participants with CADASIL compared with controls (maximal dermal blood flow increase at 40 minutes after capsaicin: 1.38 ± 0.88 vs 2.22 ± 1.20 arbitrary units, p = 0.010) but normal in participants with RVCL-S., Conclusions: We identified endothelial dysfunction in RVCL-S and confirmed impaired vascular smooth muscle cell relaxation in CADASIL. Our findings may prove to be biomarkers for disease progression in both monogenic cerebral small vessel diseases and improve mechanistic insight in their pathophysiology. This may help in understanding common neurovascular disorders, including stroke, dementia, and migraine., (© 2018 American Academy of Neurology.)

Objective: To characterize the clinical and MRI features of 2 families with adult-onset dominant leukoencephalopathy and strokes and identify the underlying genetic cause., Methods: We applied MRI pattern recognition, whole-exome sequencing, and neuropathology., Results: Based on brain imaging, 13 family members of 40 years or older from 2 families were diagnosed with the disease; in 11 family members of the same age, MRI was normal. In the affected family members, MRI showed a leukoencephalopathy that was disproportionately severe compared to the clinical disease. The clinical picture was dominated by ischemic and hemorrhagic strokes, slow and late cognitive deterioration, and therapy-resistant hypertension. With whole-exome sequencing, we identified one variant shared by both families and segregating with the disease: c.973C>T in CTSA. Haplotype analysis revealed a shared 1,145-kb interval encompassing the CTSA variant on chromosome 20q13.12, suggesting a common ancestor. Brain autopsy of 3 patients showed a leukoencephalopathy that was disproportionately extensive compared to the vascular abnormalities. CTSA encodes cathepsin A. Recessive CTSA mutations cause galactosialidosis. One of the numerous cathepsin A functions is to degrade endothelin-1. In the patients, striking endothelin-1 immunoreactivity was found in white matter astrocytes, correlating with increased numbers of premyelinating oligodendrocyte progenitors. This finding supports a role for endothelin-1 in the leukoencephalopathy through inhibition of oligodendrocyte progenitor maturation., Conclusions: CARASAL (cathepsin A-related arteriopathy with strokes and leukoencephalopathy) is a novel hereditary adult-onset cerebral small vessel disease. It is of interest that, next to the cerebral vascular abnormalities, endothelin-1 may have a role in the pathogenesis of the extensive leukoencephalopathy., (© 2016 American Academy of Neurology.)

Objective: To identify the genetic etiology of a distinct leukoencephalopathy with autosomal recessive inheritance in a single family., Methods: We analyzed available MRIs and retrospectively reviewed clinical information and laboratory investigations. We performed whole-exome sequencing to find the causal gene variants., Results: We identified 3 family members with a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons. Cerebellar atrophy was noted in advanced disease stages. Clinical features were childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. Whole-exome sequencing revealed compound heterozygous missense variants in the HMBS gene, both associated with the autosomal dominant disorder acute intermittent porphyria. Sanger sequencing of 6 healthy siblings confirmed the bi-allelic location of the variants and segregation with the disease. Patients had a slight and moderate increase in urinary and plasma porphobilinogen and 5'-aminolevulinic acid, respectively, and a 50% to 66% decrease in hydroxymethylbilane synthase enzyme activity compared to normal., Conclusions: Bi-allelic HMBS variants have been reported before as cause of severe encephalopathy with early childhood fatality in acute intermittent porphyria. Our cases demonstrate childhood onset, but milder and slower disease progression in middle-aged patients. With this, a novel phenotype can be added to the disease spectrum associated with bi-allelic HMBS variants: a leukoencephalopathy with early onset, slowly progressive neurologic symptomatology, and long life expectancy., (© 2016 American Academy of Neurology.)

Objective: To describe the expanding clinical spectrum of a recently described hereditary leukoencephalopathy, hypomyelination with brainstem and spinal cord involvement and leg spasticity, which is caused by mutations in the aspartyl tRNA-synthetase encoding gene DARS, including patients with an adolescent onset., Methods: Three patients with mutations in DARS were identified by combining MRI pattern recognition and genetic analysis., Results: One patient had the typical infantile presentation, but 2 patients with onset in late adolescence had a disease mimicking an acquired inflammatory CNS disorder. Adolescent-onset patients presented with subacute spastic paraplegia and had positive response to steroids. They had only minor focal supratentorial white matter abnormalities, but identical spinal cord changes involving dorsal columns and corticospinal tracts. Clinical presentation included subacute spastic paraplegia with partial improvement on steroids., Conclusions: Focal T2 hyperintense white matter changes on brain MRI in combination with spinal cord signal abnormalities usually suggest acquired inflammatory conditions such as multiple sclerosis, especially in the context of relapsing course and a positive response to steroid treatment. Adolescents with mutations in DARS can present with a comparable clinical picture, broadening the clinical spectrum of hypomyelination with brainstem and spinal cord involvement and leg spasticity., (© 2014 American Academy of Neurology.)

Objective: To report a consecutive series of neonates with seizures or apnea and displaying white matter injuries with distinctive magnetic resonance diffusion-weighted imaging (DWI) pattern, and to discuss the high positive rate of rotavirus infection seen in these patients., Methods: In a retrospective review of neonates who were admitted to a tertiary referral center with seizures or apnea, we found a distinctive pattern of white matter injury (symmetrical restricted diffusion in the periventricular white matter and white matter tracts including the corpus callosum) in 18 patients. We describe the clinical and laboratory features of these 18 neonates. Additional PCR analyses for rotaviruses and parechoviruses were performed on banked frozen samples of CSF of 4 patients and blood of 15 patients., Results: All 18 patients were born at term and healthy until symptoms occurred 4-7 days after birth. No history of asphyxia was observed. Only 1 patient presented with fever, and no patient showed a rash. All patients except 1 (94.4%) were rotavirus-positive in stool samples. However, neither rotaviruses nor enteroviruses/parechoviruses were detected in the CSF and blood. Tissue loss was observed in 5 of 8 subjects on repeat MRI scans., Conclusions: Neonates with this distinctive DWI pattern had a high positive rate of rotavirus infection, without evidence of other pathogens, and were characterized as term newborns with neurologic symptoms arising approximately the fifth day after birth. Although the specificity of this pattern is unclear, rotavirus testing should be considered for neonates presenting with this DWI pattern., (© 2014 American Academy of Neurology.)

Objective: We performed whole-exome sequencing analysis of patients with genetically unsolved hypomyelinating leukoencephalopathies, identifying 8 patients with TUBB4A mutations and allowing the phenotypic spectrum of TUBB4A mutations to be investigated., Methods: Fourteen patients with hypomyelinating leukoencephalopathies, 7 clinically diagnosed with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and 7 with unclassified hypomyelinating leukoencephalopathy, were analyzed by whole-exome sequencing. The effect of the mutations on microtubule assembly was examined by mapping altered amino acids onto 3-dimensional models of the αβ-tubulin heterodimer., Results: Six heterozygous missense mutations in TUBB4A, 5 of which are novel, were identified in 8 patients (6/7 patients with H-ABC [the remaining patient is an atypical case] and 2/7 patients with unclassified hypomyelinating leukoencephalopathy). In 4 cases with parental samples available, the mutations occurred de novo. Analysis of 3-dimensional models revealed that the p.Glu410Lys mutation, identified in patients with unclassified hypomyelinating leukoencephalopathy, directly impairs motor protein and/or microtubule-associated protein interactions with microtubules, whereas the other mutations affect longitudinal interactions for maintaining αβ-tubulin structure, suggesting different mechanisms in tubulin function impairment. In patients with the p.Glu410Lys mutation, basal ganglia atrophy was unobserved or minimal although extrapyramidal features were detected, suggesting its functional impairment., Conclusions: TUBB4A mutations cause typical H-ABC. Furthermore, TUBB4A mutations associate cases of unclassified hypomyelinating leukoencephalopathies with morphologically retained but functionally impaired basal ganglia, suggesting that TUBB4A-related hypomyelinating leukoencephalopathies encompass a broader clinical spectrum than previously expected. Extrapyramidal findings may be a key for consideration of TUBB4A mutations in hypomyelinating leukoencephalopathies., (© 2014 American Academy of Neurology.)

Objective: We aimed to quantify the effects of white matter hyperintensities (WMHs) on specific cognitive functions with particular attention to WMH progression and localization., Methods: PubMed (January 1990-July 2013) and bibliographies from included articles were used. Studies that were included (1) used MRI; (2) had a population-based or case-control design with a healthy control group that could be used for analysis; (3) matched/adjusted for age, sex, and education; and (4) addressed ≥1 predefined cognitive domains with ≥1 validated neuropsychological tests. Data were independently extracted by 2 investigators. Pearson r was extracted/calculated and used as the common metric for the effect size across studies., Results: Twenty-three cross-sectional and 14 longitudinal studies were included with a total of 8,685 and 7,731 participants. Presence of WMHs was significantly associated with concurrent cognitive deficits in all examined domains: general intelligence (Fisher z -0.10, 95% confidence interval [CI] -0.19 to -0.04), memory (-0.08, -0.13 to -0.06), processing speed (-0.11, -0.17 to -0.07), attention and executive functions (-0.11, -0.16 to -0.07), and perception/construction (-0.15, -0.21 to -0.07). Similar effect sizes were observed for cognitive decline over time. WMH progression was associated with greater cognitive decline, particularly for general intelligence (Fisher z -0.31, 95% CI -0.5 to -0.02) and attention and executive functions (-0.32, -0.34 to -0.28)., Conclusions: The small but robust and consistent effects of WMHs on all cognitive domains suggest a more global effect on cognition than previously thought. Progression of WMHs was associated with even worse cognitive functioning, most pronounced in attention and executive functioning., (© 2014 American Academy of Neurology.)

A 38-year-old woman was diagnosed with cutaneous anaplastic T-cell lymphoma that proved refractory to methotrexate, bexarotene, denileukin diftitox, interferon γ-1b, interferon α-2b, vorinostat, and pralatrexate. She was therefore started on the newly approved monoclonal anti-CD30 antibody brentuximab vedotin. Treatment with brentuximab 1.8 mg/kg IV every 3 weeks quickly led to disappearance of her cutaneous tumors. The day after her second brentuximab infusion she developed word-finding difficulties and unsteady gait. Due to further neurologic deterioration, she was admitted to an outside hospital. Brain MRI revealed multifocal enhancing white matter lesions throughout bilateral cerebral hemispheres and posterior fossa (figure, A-C). Brain biopsy was performed 15 days after her last brentuximab dose to rule out metastases and she was diagnosed with progressive multifocal leukoencephalopathy (PML) (figure, J). The patient was discharged home with hospice care. Upon discharge, she was started on prednisone 50 mg daily to help treat her eczema. Her family brought her to our clinic for a second opinion.

Objective: Vanishing white matter (VWM) is an autosomal recessive leukoencephalopathy characterized by slowly progressive ataxia and spasticity with additional stress-provoked episodes of rapid and major deterioration. The disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B, which is pivotal in translation of mRNAs into proteins. The disease onset, clinical severity, and disease course of VWM vary greatly. The influence of genotype and gender on the phenotype is unclear., Methods: From our database of 184 patients with VWM, we selected those with the following mutations in the gene EIF2B5: p.Arg113His in the homozygous state (n = 23), p.Arg113His in the compound-heterozygous state (n = 49), p.Thr91Ala in the homozygous state (n = 8), p.Arg113His/p.Arg339any (n = 9), and p.Thr91Ala/p.Arg339any (n = 7). We performed a cross-sectional observational study. Evaluated clinical characteristics were gender, age at onset, age at loss of walking without support, and age at death. Means, male/female ratios, and Kaplan-Meier curves were compared., Results: Patients homozygous for p.Arg113His had a milder disease than patients compound heterozygous for p.Arg113His and patients homozygous for p.Thr91Ala. Patients with p.Arg113His/p.Arg339any had a milder phenotype than patients with p.Thr91Ala/p.Arg339any. Overall, females tended to have a milder disease than males., Conclusions: The clinical phenotype in VWM is influenced by the combination of both mutations. Females tend to do better than males.