Aug 2026· Journal of Medical Genetics· pp. jmg-2025-111356· 0 citations· 38 references
Medicine
TL;DR
UBTF-related CONDBA presents with early normal or mildly delayed development followed by regression and progressive ataxia, and elevated NFL may serve as a biomarker of neuronal injury in both humans and animal models.
Abstract
Background
The heterozygous variant c.628G>A (p.Glu210Lys) in UBTF (upstream binding transcription factor) causes childhood-onset neurodegeneration with brain atrophy (CONDBA) (OMIM # 600673), characterised by early normal or mildly delayed development followed by regression, with individuals frequently experiencing movement disorders. This study defines the natural history of this rare disorder and explores potential biomarkers in humans and mice.
Methods
Caregivers of individuals with CONDBA completed cross-sectional surveys detailing genetic, developmental and clinical features. Patients evaluated in a neurogenetics clinic underwent Brief Ataxia Rating Scale (BARS) assessments compared with remotely collected wrist and ankle accelerometry data. Neurofilament light chain (NFL) levels were assessed in the clinic cohort and in a Ubtf E210K knock-in mouse model.
Results
All 11 caregiver surveys reported onset of neurodevelopmental regression (median 3.5 years, range 0.5-5 years), at times following anaesthesia or illness and 82% developed ataxia. Motor activity data from five participants (median 11.8 years, range 8.1-12.5 years) had high test-retest reliability, correlated with ataxia severity as measured by the BARS, and showed declines across multiple measures over the study period. NFL was abnormally elevated in both humans and the mouse model.
Conclusion
UBTF-related CONDBA presents with early normal or mildly delayed development followed by regression and progressive ataxia. Wearable accelerometers provide a reliable measure of disease severity, and elevated NFL may serve as a biomarker of neuronal injury in both humans and animal models.
Ataxia-telangiectasia (AT) is a rare, multisystem neurodegenerative disorder with marked clinical heterogeneity. Longitudinal data on neurological progression remain limited, restricting understanding of disease mechanisms and therapeutic trial design. We analysed longitudinal Scale for the Assessment and Rating of Ataxia (SARA) data from the largest published adult AT cohort to date (n = 82, age > 16 years). Linear mixed-effects models were used to estimate severity at the earliest available neurological evaluation (baseline) and annual progression rates (points/year) in classic and variant AT, and to examine clinical and genetic modifiers. Neurological impairment progressed with a mean SARA increase of 0.38 points/year. Adults with classic AT were more severely affected than those with variant AT, with SARA scores approximately 8-9 points higher at baseline. However, neurological progression in adulthood was similar between classic and variant AT (0.33 vs 0.41 points per year), which includes 15 individuals with the antisense oligonucleotide targetable c.5763-1050A>G variant. Although AT subtypes differ substantially in childhood and adolescence, neurological decline converges to a similar pace in adulthood, irrespective of subtype or genotype. SARA remains a useful outcome measure but may underestimate progression in advanced disease and non-cerebellar domains. These findings inform counselling, prognostication, and the design of interventional trials, including mutation-specific therapies.
A. Hensiek, L. Bottolo, M. Tiet et al.· Brain : a journal of neurolo...· 0 citations
CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.
I. Pacheva, Elena Timova, T. Todorov et al.· Frontiers in Psychiatry· 0 citations
Findings support a dose-dependent SLC20A2 disease spectrum and expand the phenotype associated with biallelic loss of function from primary brain calcification toward severe early-onset neurodevelopmental disorder with prominent vascular and leptomeningeal calcification.
Mehmet Burak Mutlu, Abdullah Sezer, Elif Özdemir et al.· Journal of Human Genetics· 0 citations
PPP1R21-related neurodevelopmental disorder (PPP1R21-NDD) is an ultra-rare autosomal-recessive encephalopathy caused by dysfunction of the Five-subunit Endosomal Rab5 and RNA/ribosome intermediarY (FERRY) complex. To delineate the clinical, neuroimaging, and molecular spectrum of PPP1R21-NDD and outline diagnostic and research priorities. Targeted searches of PubMed, EMBASE, Scopus, Web of Science, and Google Scholar through January 2026 were performed. Eligible reports included molecularly confirmed biallelic PPP1R21 cases and related functional studies. Two researchers independently extracted individual-level data following narrative review quality criteria. Twenty-five individuals from 21 families harbored 17 distinct variants (15 loss-of-function, 2 missense), all homozygous, reflecting high consanguinity. Profound global developmental delay/intellectual disability was universal; hypotonia near-universal (22/25, 88%). Ambulation was delayed and ataxic when achieved; expressive language was minimal or absent. A recognizable coarse facial gestalt was observed with thick eyebrows, broad nasal bridge, thick lips, and low-set ears. Systemic features included feeding dysfunction and respiratory morbidity requiring gastrostomy or tracheostomy in severe cases. Mortality was 17% (4/24). Neuroimaging showed callosal thinning, white-matter volume loss, ventricular enlargement, and vermian hypoplasia. Patient fibroblasts showed delayed transferrin clearance and elevated proteasome activity, suggesting endosomal dysfunction and proteasome hyperactivation. PPP1R21-NDD is a severe recessive encephalopathy with a convergent phenotype and evidence of endo-lysosomal dysfunction. Diagnosis should be pursued with exome or genome sequencing in patients with characteristic clinical and neuroimaging features, particularly in consanguineous families. Research priorities include natural history studies, standardized magnetic resonance imaging (MRI) protocols, neural disease models, and therapeutic strategies targeting endosomal trafficking.
F. Comisi, G. Di Pasquale, A. Comisi et al.· Neurogenetics· 0 citations
These prediction models demonstrate the feasibility of early prognostication in KCNQ2-RD and support future prospective external validation and enable more accurate individualised counselling by integrating clinical and genetic information readily available at time of genetic diagnosis.
E. Van Boxstael, C. Millevert, M. Hairabedian et al.· medRxiv· 0 citations
Loss-of-function (LoF) variants in the PRPS1 gene, encoding the phosphoribosyl pyrophosphate (PRPP) synthetase 1 enzyme, cause rare neurometabolic disorders historically viewed as discrete entities: nonsyndromic deafness (DFNX1), Charcot–Marie–Tooth disease type X5 (CMTX5), and Arts syndrome. A major clinical challenge is the temporal dissociation between early auditory failure and subsequent neurodegeneration, causing fragmented diagnostics. We systematically quantified this diagnostic latency and reconceptualized the disease spectrum through a molecular lens. A PRISMA-compliant systematic review identified 19 patients with genetically confirmed PRPS1 LoF variants, including our index case (c.362C>G) presenting a 15-year diagnostic delay. Kaplan–Meier analysis revealed sensorineural hearing loss manifested acutely (median 0 years; 95% CI: 0–1). In contrast, neurological deficits demonstrated a prolonged latency (median 3 years; 95% CI: 1–8), followed by ophthalmological signs (median 11.5 years). The median symptomatic delay was 3 years (range up to 19). We posit that this temporal dissociation reflects differential tissue vulnerability to intracellular ATP/GTP and NAD+ depletion caused by the primary enzymatic defect. Ultimately, DFNX1, CMTX5, and Arts syndrome represent a continuous PRPS1-related neurometabolic spectrum. Because targeted metabolic interventions (such as S-adenosylmethionine or nicotinamide riboside) have limited efficacy on advanced structural nerve damage, recognizing this early diagnostic window to initiate biochemical rescue prior to irreversible axonal degeneration is critical.
Bartosz Rodziewicz, M. Kacperski, Kacper Kisiński et al.· Biomolecules· 0 citations