The expansion of genomics provides opportunity to screen individuals beyond clinical indication yet the classification of genomic variants and implications for health outcomes in this context is still emerging. We investigated this further by analysing clinically relevant variants and expected clinical implications in a population with no reported medical conditions. Whole genomes from 9637 healthy unrelated research-consented participants in Singapore were analysed focusing on 1619 genes associated with severe paediatric disease. Association between causative variants and expected phenotype was assessed in correlation with participant characteristics and medical history where available. After considering protein impact, mode of inheritance and participant demographics for 110 variants, further analysis was performed for 44 variants occurring in 150 participants to understand clinical implications. Most carried variants associated with a mild phenotype (cystinuria), late onset (Fabry disease) or a potentially missed phenotype (Hajdu-Cheney syndrome). However, nine participants had variants associated with severe paediatric disease predicted to be symptomatic, such as limb-girdle muscular dystrophy and spastic paraplegia. Despite a cohort selected for absence of pre-existing health conditions, individuals were identified carrying variants associated with severe paediatric conditions. Further work is required to examine for subtle clinical symptoms or alternate genetic suppression mechanisms. This study revealed the challenge of predicting clinical outcomes from genotype-derived screening and emphasises the importance of expanding phenotype characterisation which is highly relevant in population and reproductive screening settings. Trial registration: NCT02791152.

Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1-year prospective follow-up study on PLS and efforts to distinguish it from ALS. Seventy-six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1-year follow-up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Seventy participants completed 1-year follow-up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow-up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1-year follow-up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.

Neuropsychological deficits have been observed in patients with cerebellar damage, but never thoroughly investigated in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The goal is the characterization of presence, severity, and profile of neuropsychological deficits in ARSACS using the cerebellar cognitive-affective syndrome (CCAS) scale. Prospective study including a discovery cohort from Saguenay/Canada (n = 31, median [inter-quartile range] age: 57 [54-62] years), and a validation cohort from Tübingen, Germany (n = 17, 35 [21-43] years) with matched controls (n = 19). All ARSACS patients failed in multiple CCAS-related subtests and exceeded cutoffs for "definite CCAS." Even the younger validation cohort failed more subtests than controls (5 [3-7] vs. 1 [1-2], P < 0.001) and had lower CCAS total scores (81 [67-86] vs. 101 [91-106], P < 0.001). Total scores worsened in the older discovery cohort (40 [25-52], P < 0.001) and correlated with age/disease duration (ρ = -0.575, P < 0.001) and ataxia severity (Scale for the Assessment and Rating of Ataxia: ρ = -0.527, P = 0.003). Neuropsychological deficits consistent with CCAS are consistent in ARSACS, present early, and progress in the disease course. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The gait analysis is a relatively commonly used tool for evaluating the functional deficits of various groups of patients, regardless of the origin of these deficits, but is especially common in patients with neurological deficits. One of the problems they encounter is disrupted coordination. One of the methods to asses it is cyclogram, or angle-angle plot. Could cyclogram index, based on cyclograms for lower limbs contribute to understanding of the disrupted coordination in neurological patients? This paper presents the coordination index, which is based on the perimeters of four cyclograms: hip/pelvis, knee/hip and ankle/knee in the sagittal plane and hip/pelvis in the frontal plane. Data extracted from retrospective gait analyses of patients with spastic diplegia cerebral palsy, dystrophy and Guillain-Barre syndrome were used to calculate cyclograms, coordination index and gait indices: Gillette Gait Index (GGI), Gait Deviation Index (GDI) and Gait Profile Score (GPS). The main finding of this paper is the independence of the new coordination index from commonly used indices: GGI, GDI and GPS. A discriminant analysis, in which the grouping variable was the name of the disease, revealed that cyclogram perimeters and coordination index were statistically significant predictors. Coordination index could be used as additional measure assessing the disrupted coordination in patients. This paper shows the potential usefulness of the proposed method in clinical application, especially in the long-term changes induced by the various treatment methods.

Atypical neuroaxonal dystrophy (ANAD) is a rare form of neurodegeneration linked to the PLA2G6 gene. Unlike classical infantile neuroaxonal dystrophy (INAD), it occurs later in childhood and seems less progressive. It appears phenotypically different from juvenile form of Parkinson disease linked to PLA2G6 (PARK14). A genotype-phenotype correlation has been suggested. We describe a large genetically confirmed cohort of pediatric patients with ANAD, describe their clinical symptomatology, brain imaging, other complementary explorations, symptomatic medication and compare to patients reported in the literature. Fourteen patients were identified with early childhood onset and slowly progressive cerebello-spastic syndrome with variable dystonia and parkinsonism. Complementary investigations were inconsistently abnormal compared to INAD, with variable iron deposits on brain imaging, infrequent rapid rhythms on EEG and absence of neuronal spheroids on skin biopsy leading to diagnosis difficulties in absence of large molecular analysis. Nine of the seventeen reported variants were novel variants and a relative genotype-phenotype correlation was confirmed. This study reports a large cohort of ANAD, providing new insights into this paediatric phenotype; which is less frequently described in the literature compared to INAD or PARK14.