Neurology-Genetics最新文献

Background and objectives: Becker muscular dystrophy (BMD) is due to Duchenne muscular dystrophy gene variants allowing partial expression of dystrophin. A detailed description of disease trajectories in different genetic subgroups, and the identification of factors predicting progressive vs stable disease, are indispensable for designing and interpreting current and future clinical trials.

Methods: We recruited male participants with a molecularly confirmed diagnosis of BMD at our Institution, and followed them up with an observational longitudinal design with functional evaluations, including North Star Ambulatory Assessment (NSAA), 6-minute walk test, and timed function tests.

Results: We recruited 107 participants. Time-to-event analyses of age at loss of ambulation estimated that only 25% of individuals with BMD lose ambulation by age 60 years. Functional measures, over a follow-up of a mean ± SD of 6.4 ± 3.5 evaluations per participant, and a time of 6.1 ± 3.6 years, showed a poor performance in the common deletions del 45-47 and del 45-48, and preserved muscle function with del 48 and deletions ending on exon 51. In the overall cohort, all measures declined significantly over time, but this decrease was more evident in genetic groups with more marked weakness, and in participants with baseline values of NSAA of 32/34 or lower.

Discussion: These data refine genotype-phenotype correlations in BMD; quantify the decline in several practical and reliable motor outcome measures, which can be directly applied to power calculations for clinical trials; and point to useful inclusion/exclusion criteria for trials. Long-term outcomes will serve as a comparator for "real-world" efficacy data of upcoming therapeutics.

Background and objectives: Executive dysfunction is a core feature of frontotemporal dementia (FTD). While there has been extensive research into such impairments in sporadic FTD, there has been little research in the familial forms.

Methods: Seven hundred fifty-two individuals were recruited in total: 214 C9orf72; 205 progranulin (GRN) and 86 microtubule associated protein tau (MAPT) mutation carriers, stratified into asymptomatic, prodromal, and fully symptomatic; and 247 mutation-negative controls. Attention and executive function were measured using the Weschler Memory Scale-Revised (WMS-R) Digit Span Backwards (DSB), Wechsler Adult Intelligence Scale-Revised Digit Symbol task, Trail Making Test Parts A and B, and the Delis-Kaplan Executive Function System Color Word Interference Test. Linear regression models with bootstrapping were used to assess differences between groups. Correlation of task score with disease severity was also performed, as well as an analysis of the neuroanatomical correlates of each task.

Results: Fully symptomatic C9orf72, GRN, and MAPT mutation carriers were significantly impaired on all tasks compared with controls (all p < 0.001), except on the WMS-R DSB in the MAPT mutation carriers (p = 0.147). While asymptomatic and prodromal C9orf72 individuals also demonstrated differences compared with controls, neither the GRN or MAPT asymptomatic or prodromal mutation carriers showed significant deficits. All tasks were significantly correlated with disease severity in each of the genetic groups (all p < 0.001).

Discussion: Some individuals with C9orf72 mutations show difficulties with executive function from very early on in the disease and this continues to deteriorate with disease severity. By contrast, similar difficulties occur only in the later stages of the disease in GRN and MAPT mutation carriers. This differential performance across the genetic groups will be important in neuropsychological task selection in upcoming clinical trials.

Background and objectives: The APOE (apolipoprotein E) ε4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology. However, APOE ε4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis. Existing studies have been limited by potential confounding due to inclusion of individuals carrying APOE ε4 or ε2 (which has a modest protective association). We hypothesized that genome-wide association study (GWAS) and genetic risk score (GRS) analyses in APOE ε3/ε3 individuals would uniquely identify novel predictors of β-amyloid pathology in older adults.

Methods: We analyzed data from the Mayo Clinic Study of Aging (MCSA), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Rush Religious Orders Study and Memory and Aging Project. Frequency of APOE ε3/ε3 in those samples ranged from 48% to 61%. A GWAS was performed across 1,496 individuals with amyloid PET to identify candidate variants for GRS generation. Postmortem neuropathologic data (N = 710) were used to refine the variant list to capture high-likelihood true associations. An independent sample (N = 641) with plasma p-tau₁₈₁ data was used for validation.

Results: The GWAS identified previously implicated (e.g., PICALM and RBFOX1) and novel potential associations with amyloid PET burden. A non-APOE GRS of top variants was strongly associated with amyloid PET levels in the MCSA (p = 4.34 × 10^-9, β = 5.88) and ADNI (p = 1.87 × 10^-8, β = 12.1) cohorts. In both cohorts, this non-APOE amyloid GRS outperformed a comparator GRS (based on variants associated with clinically diagnosed AD dementia risk) in explaining phenotypic variation. The non-APOE amyloid GRS was also associated with postmortem neuropathologic β-amyloid and neurofibrillary tangle burden and in an independent sample was associated with plasma p-tau₁₈₁ concentrations (a robust indicator of cerebral amyloidosis).

Discussion: Our non-APOE amyloid GRS, which appropriately includes variants associated with amyloid deposition in APOE ɛ4/ɛ2 noncarriers, may advance personalized prediction of genetic susceptibility to β-amyloid accumulation within the large segment of the population that is APOE ε3/ε3. This may have future implications for risk modification, trial enrollment, and treatment selection.

Background and objectives: Valosin Containing Protein-associated multisystem proteinopathy (VCP-MSP) is a progressive, autosomal dominant disorder caused by pathogenic variants in the VCP gene, resulting in a heterogeneous clinical presentation. Muscle biopsy findings are characteristic but not pathognomonic. This study aimed to comprehensively analyse VCP-related myopathology and explore correlations with clinical phenotypes, genetic variants, and disease progression.

Methods: Muscle biopsy images and data were collected retrospectively from adults (≥18 years) with pathogenic or likely pathogenic VCP variants enrolled in the VCP Multicentre International Study. Biopsy data were standardized using the "Common Data Elements for Muscle Biopsy Reporting." Variations in biopsy findings were analysed by biopsy site, time from disease onset, the four most common VCP variants, and clinical phenotypes.

Result: A total of 112 muscle biopsies were included. Most individuals were male (66.0%). The mean age at biopsy was 53.3 years (SD 10.0), with a mean disease duration of 6.5 years (SD 4.5). The most frequent VCP variant was c.464G>A (p.Arg155His) (18.8%). The top clinical phenotypes were isolated myopathy (37.5%), myopathy with Paget disease of bone (17.9%), and myopathy with motor neuron involvement (13.4%). The vastus lateralis was the most common biopsy site (34.8%), and 91% were open biopsies. Histopathologic findings included atrophic fibres (87.5%), rimmed vacuoles (72.3%), endomysial fibrosis (58.0%), and protein aggregates (51.8%), primarily p62 (60.3%) and VCP (36.2%). Degeneration niches with fibrofatty replacement and atrophic fibres were seen in 33.3% of biopsies without frequency differences by clinical phenotypes. There were no differences in biopsy findings among the 4 most common VCP gene variants, except for the absence of degeneration niches in muscle biopsies of 12 patients with c.277C>T (p.Arg93Cys). MRI data from 30 patients showed fat pockets corresponding to these niches and STIR hyperintensity correlated with inflammatory infiltrates in 42.9%. Concordance between clinical phenotype, biopsy, and neurophysiology was observed in only 49.4% of cases, indicating significant heterogeneity.

Discussion: VCP-MSP muscle biopsies consistently show myopathic or mixed patterns with rimmed vacuoles and p62/VCP-positive inclusions, regardless of clinical phenotype, age, or progression. Some lack vacuoles, challenging diagnosis. Discrepancies between clinical, neurophysiology, and biopsy findings should prompt consideration of VCP-MSP to improve detection and management.

Background and objectives: Alexander disease is a rare monogenic disorder caused by dominant variants in GFAP (glial fibrillary acidic protein). Over 180 variants have been associated with the disease, with a wide spectrum of severity and clinical manifestations. Previous attempts at genotype-phenotype correlations have been hampered by the small numbers of cases that have been published for many of the variants. We sought to determine whether genotype-phenotype correlations could be discerned from available information.

Methods: We compiled a list of variants in GFAP for which 7 or more unrelated cases had been either published or identified through an ongoing natural history study and other sources (with a closing date of July 27, 2024). For each of these cases, we tabulated age at onset, age at death (or last contact), and sex. We used a Kruskal-Wallis test to evaluate statistical differences in age at onset in relation to variant. Differences in survival across variants were studied using Kaplan-Meier curves.

Results: Fourteen variants met our criteria for detailed analysis (10 with 7 or more unrelated cases and 4 additional variants involving 2 of the most commonly affected amino acids, R79 and R239) derived from a total of 231 cases. The variants seem to fall into 3 distinct groups-some with consistent early onsets (N77S, R79C and R79L, and most of the R239s), some with consistent late onsets (R70W and N386S), and some with more variable onsets (R416W). Pairwise comparison results found that R239H was associated with significantly earlier onsets than R239C. We found similar groupings for survival. Finally, we evaluated sex as a potential modifying factor for either age at onset or survival but found no significant association.

Discussion: Genotype-phenotype correlations do exist in Alexander disease, at least for a limited number of GFAP variants for which sufficient numbers of individual cases can be identified to allow valid statistical analysis.

[This corrects the article DOI: 10.1212/NXG.0000000000200246.].

Background and objectives: Guanidinoacetate methyltransferase deficiency (GAMT-D), a rare inborn error of creatine metabolism, is a disabling neurodevelopmental disorder due to the combined effect of cerebral creatine depletion and guanidinoacetate accumulation. Existing therapies efficiently improve both of the biochemical abnormalities. The goal of this study was to provide evidence for the crucial role of age at treatment initiation in clinical outcomes in affected individuals.

Methods: In a mixed-method interview-based and questionnaire-based cohort study, 4 sibling pairs with GAMT-D (case group) and 8 healthy, age-matched sibling pairs (control group) were enrolled. In the case group, each younger sibling was diagnosed and treated earlier than their older sibling. Interviews with parents in the case group were performed to ascertain major perceived differences between the siblings and to construct a questionnaire that was completed by the parents for each child in both groups.

Results: In the case group, all younger, earlier treated siblings had distinctly better outcomes in all ascertained domains compared with their older siblings, including development, cognition, school level, motor skills, coordination, adaptive functioning, behavior, needs or supportive measures, and seizures. Remarkably, in the case group, the outcomes in 2 children treated as neonates were not different from the healthy controls; the outcomes in 2 other children treated since infancy were better compared with those treated after the age of 2 years.

Discussion: The favorable outcome observed in patients with GAMT-D when treatment is initiated in the presymptomatic period or early infancy should serve as a compelling argument for those programs that have not already implemented newborn screening of GAMT-D.