Heterozygous variants in FBXW7 have recently been recognized as a cause of a rare neurodevelopmental disorder with variable developmental delay, neurological manifestations, and multisystem involvement. The breadth of clinical variability and penetrance remains incompletely defined. We report a retrospective multicenter case series of seven previously unreported individuals (five males, two females) with heterozygous FBXW7 variants identified through clinical genetic testing, aged 5–9 years at last evaluation (median 6 years). Six variants occurred de novo and one was inherited. Neurodevelopmental involvement was present in six individuals and was characterized by global developmental delay and language impairment; hypotonia was observed in all seven. Formal intellectual disability was documented in four cases, while one individual showed preserved cognitive functioning with predominant behavioral difficulties. Epileptic seizures occurred in four individuals, whereas three had no history of epilepsy. Brain MRI was available for six individuals and was normal in four, whereas two showed structural anomalies involving the corpus callosum. Extracerebral features were variably reported, most commonly constipation and recurrent respiratory/otolaryngological infections. Comparison with previously reported individuals confirmed the core neurodevelopmental phenotype and further refined the spectrum. This case series expands the phenotypic spectrum associated with FBXW7-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance, including clinically relevant variants presenting with mild or atypical phenotypes. These findings support considering FBXW7 across a broad range of neurodevelopmental presentations and inform genetic counseling.
Salvatore Savasta, F. Comisi, G. Dell’Isola et al.· Journal of Neurodevelopmenta...· 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