Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS), Online Mendelian Inheritance in Man (OMIM) 618,170, is an autosomal-recessive disorder caused by biallelic ADPRS (ADPRHL2) variants, encoding ADP-ribosylserine hydrolase (ARH3). Its stress-precipitated, stepwise course may resemble pediatric mitochondrial disease, delaying diagnosis. Four unrelated pediatric probands from three Italian tertiary centers were characterized retrospectively and integrated with a structured literature review to June 2026. Data were collected into a 20-item dataset, variants were standardized to Matched Annotation from NCBI and EMBL-EBI (MANE) Select NM_017825.3 and classified by American College of Medical Genetics and Genomics / Association for Molecular Pathology (ACMG/AMP) criteria. The two novel missense variants were assessed by conservation profiling and FoldX. Onset occurred between 13 months and 2.5 years in three males and one female; three were alive at 7 to 14 years and one died at 10 years 6 months. Three were compound heterozygous and one homozygous. Four novel variants were identified, c.74G > T, p.(Gly25Val) and c.827 C > T, p.(Ser276Leu) in Patient 1, c.827dup, p.(Val277GlyfsTer17) in Patient 2, and c.1060 C > T, p.(Gln354Ter) in Patient 4, bringing the cohort to 62 patients and 31 unique alleles. In our cohort, ataxia, paroxysmal neck dystonia, peripheral neuropathy and progressive respiratory failure were identified as core features. In silico modeling supported a destabilizing, likely loss-of-function effect for both novel missense variants. Progressive cerebellar ataxia with paroxysmal neck dystonia may help to orient the diagnosis. ADPRS should be early considered in stress-precipitated childhood-onset ataxia.
Skilled motor behaviour relies on complex predictive control and error processing. Despite its indispensable position in our everyday lives, neurobiological mechanisms of motor skill acquisition remain poorly understood. The presented study evaluates the functional dynamics and microstructural substrate of expertise-related reorganisation in predictive timing circuits using multimodal functional and quantitative magnetic resonance imaging (MRI) data. Forty-one baseball/softball players, representing a natural model of optimised motor timing programs, were compared against forty-six non-athletic controls using a structural connectome-informed hierarchical Bayesian framework jointly modelling task-based functional MRI dynamics of feedforward predictive control and error-driven modulation. Expertise-related microstructural differences were then characterised using neurite orientation dispersion and density imaging and adiabatic T₁ρ mapping. In non-athletic controls, predictive control was found to engage a distributed cortico-subcortical sensorimotor, visuospatial, attentional and frontoparietal loops, while higher-order associative systems were relatively down-regulated. However, quantitative deviation from the task optimum was associated with lower response across this predictive network. Expertise was characterised by higher behavioural performance but also by attenuated prediction-related functional engagement alongside enhanced error-related modulation. Furthermore, neurite density and orientation dispersion indices were higher in experts across distributed cortical networks, while the cerebellum exhibited a divergent profile characterised by higher neurite density, lower orientation dispersion and faster T₁ρ relaxation. These findings indicate that expertise involves lower task engagement within an established architecture despite higher behavioural performance, together with enhanced error sensitivity and distributed microstructural differences. This pattern is consistent with more efficient neural dynamics complemented with underlying tissue alterations.
Gait disturbance in hereditary cerebellar ataxia may obscure coexisting, potentially treatable disorders. We describe a patient with genetically confirmed spinocerebellar ataxia type 6 (SCA6) and coexisting idiopathic normal-pressure hydrocephalus (iNPH) whose gait disturbance partially improved after cerebrospinal fluid drainage and shunting. A 73-year-old Japanese man with progressive gait disturbance over 2 years exhibited gaze-evoked nystagmus, dysarthria, bilateral limb ataxia, and a broad-based shuffling gait. The patient also reported urinary urgency. Brain magnetic resonance imaging revealed disproportionately enlarged subarachnoid-space hydrocephalus and cerebellar atrophy. Genetic testing identified a heterozygous CAG repeat expansion in CACNA1A (22/13 repeats), consistent with SCA6. After a cerebrospinal fluid tap test, the mean 3-m Timed Up-and-Go time decreased from 52 to 37 s by day 7. Following lumboperitoneal shunting, the International Cooperative Ataxia Rating Scale posture and gait subscore improved from 21 to 15, whereas the limb coordination subscore worsened from 15 to 20. Postural sway area decreased from 9.37 to 5.77 cm2. Gait improvement was maintained at 6 months, while cerebellar signs persisted. The differential response to shunting suggests a hydrocephalic contribution to gait and postural impairment alongside persistent SCA6-related cerebellar dysfunction. Coexisting iNPH should be considered in patients with hereditary ataxia when suggestive clinical and imaging features are present, as identifying a shunt-responsive component may provide meaningful symptomatic benefit.
Ataxia-telangiectasia (A-T) causes progressive neurological disability. Following two phase III trials published in 2026, this study is an updated randomized evidence for pharmacological interventions targeting neurological manifestations of A-T. PubMed/MEDLINE, Scopus, Web of Science Core Collection, and Cochrane Library were searched. Eligible studies were RCTs in children or adults with A-T. Risk of bias was assessed using Cochrane RoB 2. N-acetyl-L-leucine/levacetylleucine SARA treatment effects were pooled using a random-effects generic inverse-variance model with restricted maximum likelihood (REML), with common-effect and Hartung-Knapp-Sidik-Jonkman sensitivity analyses. Secondary analyses pooled full-ICARS efficacy and safety outcomes from the two eDSP trials. Six RCTs evaluated oral betamethasone, N-acetyl-L-leucine/levacetylleucine, erythrocyte-encapsulated dexamethasone sodium phosphate (eDSP), and triheptanoin. Two crossover trials contributed to the SARA meta-analysis. The pooled REML effect was not significant (MD -0.90, 95
COQ8A-ataxia is the most common form of primary coenzyme Q10 (CoQ10) deficiency, a group of autosomal recessive mitochondrial disorders resulting from biallelic loss of function variants in COQ8A gene, which encodes an atypical kinase/ATPase essential for the integrity of the CoQ10 biosynthetic complex. The condition typically presents as early onset, progressive cerebellar ataxia that may be accompanied by epilepsy, intellectual disability, dystonia, and exercise intolerance. A 67-year-old woman, daughter of consanguineous parents (first cousins), presented with gait instability and exercise intolerance beginning at 10 years of age, with very slow progression over five decades. Neurological examination revealed bilateral palpebral ptosis, bilateral hypometric saccades, dysmetria, dysdiadochokinesia, and ataxic gait, without cognitive impairment. Brain MRI showed severe cerebellar atrophy. Following a negative panel for spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, and SCA17), a next-generation sequencing (NGS)-based ataxia panel identified a homozygous pathogenic variant in COQ8A: NM_020247.4:c.1358del p.(Leu453Argfs*24). Baseline SARA score was 24/40 and decreased to 8/40 after 30 months of CoQ10 supplementation, representing a sustained 16-point reduction temporally associated with treatment. We report the first molecularly confirmed case of COQ8A-ataxia in Colombia, notable for a 57-year diagnostic delay, bilateral palpebral ptosis as a noteworthy ocular manifestation, and a clinically significant clinical improvement temporally associated with CoQ10 supplementation.
