The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK.

The C9orf72 hexanucleotide repeat expansion (HRE) is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The inheritance is autosomal dominant, but a high proportion of subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18-20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18-20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based ancestral haplotype. Our results demonstrate that the haplotypes with longer IAs belong to the same pool of haplotypes as the HRE and suggest that longer IAs represent potential premutation alleles.

Childhood motor difficulties and cognitive impairment in midlife: A 40-year cohort study.

OBJECTIVE: We aimed to examine the association of childhood motor difficulties (MD) with cognitive impairment in midlife. METHOD: We studied 357 participants from a cohort born in 1971-1975. At age 9, they had completed the Test of Motor Impairment, which classified them into three groups: childhood MD (cMD), borderline cMD (bcMD), or no cMD. Participants with attention-deficit/hyperactivity disorder were excluded. At age 40, participants comprised 18 (5.0%) with cMD, 43 (12.0%) with bcMD, and 296 (82.9%) with no cMD. They underwent neuropsychological assessment covering six domains: executive functions, processing speed, attention and working memory, learning and memory, verbal symbolic abilities, and visuoperceptual and visuospatial abilities. A participant was considered to have an impairment if their performance was in the 15th percentile of a normative group. RESULTS: Participants with cMD were more likely than those with no cMD to have an impairment in executive functions (OR = 6.73, p < .01), processing speed (OR = 3.85, p < .05), attention and working memory (OR = 4.79, p < .01), and a cross-domain impairment (OR = 3.62, p < .01). These differences remained significant after adjusting for parents' occupation, sex, and low birth weight and after multiple imputation. No consistent difference emerged between participants with bcMD and no cMD. CONCLUSIONS: Childhood MD are associated with midlife cognitive impairment, which underscores their long-term implications. In the neuropsychological assessment of an adult patient, information on childhood motor development is of value. The assessment may help adapt the patient's physical or occupational therapy to the patient's cognitive profile. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Motor difficulties from childhood to midlife: A 40-year cohort study.

BACKGROUND: There are few studies of the persistence of childhood motor difficulties (MD) into adulthood. AIMS: To investigate the association of childhood MD with motor skills and body mass index (BMI) in midlife. METHODS AND PROCEDURES: We studied 324 adults aged 40 from a cohort born in 1971-1974. At age 9, they had undergone the Test of Motor Impairment, used to classify them into groups: childhood MD (cMD), borderline cMD (bcMD), or no cMD. At age 40, participants comprised 23 with cMD, 47 with bcMD, and 254 with no cMD. Participants completed motor tests of balance, manual dexterity, and visuomotor speed, followed by recording of their BMI. OUTCOMES AND RESULTS: At age 40, the cMD group performed worse than the no-cMD group on all motor tests (p < .001-.008). The bcMD group had slower visuomotor speed than the no-cMD group (p = .025). The groups differed in BMI (p = .002). Having cMD was associated with obesity in midlife (p < .001). After adjusting for sex, childhood socioeconomic status, and BMI at age 9, both cMD and bcMD were associated with obesity in midlife (p = .015). CONCLUSIONS AND IMPLICATIONS: Childhood MD are associated with poor motor skills, overweight, and obesity in midlife. This emphasises the importance of early intervention and follow-up when a child exhibits MD. WHAT THIS PAPER ADDS: This prospective longitudinal study presents novel evidence that individuals with a history of comprehensively and objectively assessed childhood motor difficulties (MD) have worse motor skills and a higher risk of obesity in midlife than do those with no childhood MD. There is a growing literature on adults with developmental coordination disorder or a history of MD. There is, however, a scarcity of longitudinal studies of childhood MD that continue beyond early adulthood, into midlife. In a systematic search, we could identify only one longitudinal study of objectively measured childhood MD with a reassessment of motor skills in those same participants in adulthood, and no study with a reassessment after age 20. Furthermore, longitudinal studies of the association of comprehensively and objectively assessed childhood MD with BMI in midlife have been lacking.