Jul 2026· Movement Disorders Clinical Practice· 0 citations· 32 references
Medicine
TL;DR
The recurrent GBA2 c.1365G>C;p.(Trp455Cys) variant suggests a potential founder effect and expands the phenotypic spectrum of SPG46 in Brazil.
Abstract
Background
SPG46 is an autosomal recessive hereditary spastic paraplegia (HSP) caused by biallelic GBA2 mutations. As a rare and still poorly understood condition, information about its clinical and genetic spectrum is scarce.
Objective
This study aimed to delineate the clinical, neuroimaging, and genetic characteristics of a Brazilian SPG46 cohort.
Methods
We conducted a retrospective cross-sectional study at two referral centers, identifying nine patients from six unrelated families harboring pathogenic GBA2 variants through whole-exome sequencing. Demographic, clinical, neuroimaging, and genetic data were systematically analyzed.
Results
The cohort (4 males, 5 females) presented disease onset between 6 and 24 years (mean, 10.7). All exhibited progressive spastic paraplegia associated with cerebellar ataxia, dysarthria, and cognitive impairment. Psychiatric manifestations, sleep disturbances, skeletal deformities, and dystonia were frequent. Cerebellar atrophy was observed in four cases, whereas corpus callosum thinning, cataracts, and hearing impairment were absent.
Conclusion
The recurrent GBA2 c.1365G>C;p.(Trp455Cys) variant suggests a potential founder effect and expands the phenotypic spectrum of SPG46 in Brazil.
This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies.
Sheyda Khalilian, Mohadeseh Fathi, Zahra Farbood et al.· Molecular Genetics and Metab...· 0 citations
The results highlight the need for a unified diagnostic framework for ATP1A3-related disorders and demonstrate the feasibility and scientific value of coordinated rare disease research in resource-limited settings.
Victor Rebelo Procaci, Raphael Pinheiro Camurugy da Hora, Anna Maria Gomes et al.· Neurology: Genetics· 0 citations
A 5.5-year-old girl born to consanguineous parents who presented with refractory early-onset seizures, severe global developmental delay, growth failure, and microcephaly is described, highlighting the critical role of whole-exome sequencing in accurately delineating complex phenotypes in consanguineous populations.
Maryam Kachuei, Shayan Eghdami, Sarah Eyvaz-Ziaei et al.· Annals of Medicine and Surge...· 0 citations
Background KBG syndrome (KBGS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in ANKRD11. It is characterized by developmental delay, intellectual disability, behavioral difficulties, macrodontia, craniofacial dysmorphism, short stature, and skeletal anomalies. Objectives To describe the clinical, radiological, and molecular findings of Saudi patients with molecularly confirmed KBGS and compare their presentation with reported features in the literature. Methods We conducted a retrospective case series at King Faisal Specialist Hospital and Research Centre, Riyadh, between January 2002 and December 2024. Clinical, dysmorphological, developmental, behavioral, family history, neuroimaging, and molecular data were reviewed for three pediatric patients with confirmed ANKRD11-related KBGS. Results All patients demonstrated core features of KBGS, including intellectual disability, speech and motor delay, learning difficulties, and behavioral manifestations such as autism spectrum features or aggression. Common dysmorphic findings included long philtrum and prominent ears in all patients, with a triangular face, macrodontia, and synophrys observed in two patients. Short stature and skeletal anomalies were also present. Molecular testing identified heterozygous pathogenic or likely pathogenic ANKRD11 variants: NM_013275.6:c.4087C > T (p.Arg1363Ter), NM_013275.6:c.3382_3383del (p.Asp1128GlufsTer41), and NM_013275.6:c.1977C > G (p.Tyr659Ter). All variants were predicted to result in premature termination. Renal fusion and complex vertebral anomalies were observed, suggesting possible underrecognized systemic involvement, although cautious interpretation is required given the small sample size. Conclusion This Saudi case series adds to the growing evidence of clinical heterogeneity in KBGS. Early recognition, molecular confirmation, multidisciplinary care, and longitudinal follow-up are essential to improve diagnosis, surveillance, and management.
Mai S. Labani, Z. Rahbeeni· Frontiers in Pediatrics· 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
A novel homozygous missense variant in RNF216 gene c.1055T>G (p.(Phe352Cys)) in three siblings with Gordon Holmes syndrome is reported, contributing to the limited knowledge of GHS and highlighting the importance of hypogonadotropic hypogonadism treatment and close observation of neurological symptoms that may develop over time.
