A multicenter retrospective analysis of 15 pediatric patients from 12 unrelated families with genetically confirmed tubulinopathies across five tertiary centers in Turkey identified a rare case of TUBGCP2-related tubulinopathy presenting with cystic leukomalacia, expanding the known radiological spectrum.
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
It is indicated that reduced protein stability and functional impairment of β-tubulin represent key pathogenic mechanisms underlying this condition, and the experimental evidence further supports the implication of TUBB dysfunctions in haematological abnormalities.
Ilaria Svezia, Riccardo Zocchi, Michela Piccione et al.· Orphanet Journal of Rare Dis...· 0 citations
The findings support a possible domain‐related genotype–phenotype association for the role of ALG13 in neurodevelopmental disorders and provide additional developmental context for the role of ALG13 in neurodevelopmental disorders.
Song Su, Wandong Hu, Ying Ren et al.· Human Mutation· 0 citations
Background and Objectives ATP1A3-related disorders comprise an expanding group of ultra-rare neurologic conditions, classically including rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. However, accumulating reports suggest a broader and overlapping phenotypic spectrum. In this context, we established the ATP1A3 Study Group to comprehensively characterize the phenotypic and genotypic spectrum of ATP1A3-related disorders in a Brazilian cohort. Methods We conducted a multicenter, cross-sectional study of individuals with ATP1A3 variants. Cases were recruited across reference centers in 9 Brazilian states, with standardized extraction of demographic, genetic, neuroimaging, EEG, ECG, and clinical data. Variants were annotated using transcript NM_152296.5 (hg19). AlphaFold was used for structural visualization. Multiple correspondence analysis (MCA) was performed to explore symptom clustering. This study was approved by the Ethics Committee of Federal University of São Paulo (Approval No.: 82533124.0.0000.5505). Results A total of 41 patients with ATP1A3 variants were included. Seven phenotypic categories were represented: AHC (17/41), RDP (10/41), CAPOS (7/41), relapsing encephalopathy with cerebellar ataxia (RECA; 4/41), fever-induced paroxysmal weakness and encephalopathy (FIPWE; 1/41), developmental and epileptic encephalopathy 99 (DEE99; 1/41), and malformation of cortical development (MCD; 1/41). Two neonatal-onset cases (DEE99 and MCD) were fatal. We identified 22 distinct ATP1A3 variants, including 4 novel variants (p.Gln920His, p.Arg827Gly, p.Glu670Ala, and c.606+5G>T). Clinical overlap was substantial: Cognitive impairment and seizures occurred across all phenotypes; hypotonia was present in 6 of 7 main phenotypes; abnormal eye movements and fever-induced symptoms occurred in all except MCD; and paroxysmal symptoms were reported in all, except DEE99. MCA demonstrated no discrete clustering by classical phenotype, reinforcing the continuous nature of the ATP1A3 spectrum. ECG abnormalities were rare in our cohort (1/20). Discussion Our findings expand the clinical and genetic landscape of ATP1A3-related disorders and underscore major phenotypic overlap among classical syndromes. The results highlight the need for a unified diagnostic framework. This study also demonstrates 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
BACKGROUND
Pathogenic missense variants in the MORC2 gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy) phenotype, which encompasses a broad range of clinical manifestations that vary significantly between individuals.
METHODS
Clinical and imaging data from 16 patients were collected. Western blot analysis was performed on 10 identified variants in affected patients as well as on two novel variants without clinical data. Those missense variants were introduced into the wild-type vector transfected into HEK293T cells, and western blot analysis was performed to assess protein expression level.
RESULTS
A total of 11 different missense variants in the MORC2 gene were identified in our cohort, including four novel variants. We demonstrate that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form. The p.Ser87Leu variant, which defines the neuromuscular cluster, was uniquely characterised by a significant reduction in MORC2 protein levels, distinguishing it mechanistically from other variants. Overall, western blot analysis revealed no statistically significant difference in protein expression levels between variants related to CMT2Z and DIGFAN cases.
CONCLUSION
A comparison of our patients with previously reported cases revealed an intriguing trend suggesting a probable dependence of the leading clinical features on specific variants in the MORC2 gene. Further accumulation of patient data is required to determine whether this observation correlates with other specific variants.
A. Murtazina, Eugenii Tatarsky, I. Viakhireva et al.· Journal of Medical Genetics· 0 citations
To summarize the clinical and genetic characteristics of
DNM1L
-related disorders and explore genotype-phenotype correlations and prognosis.
We retrospectively analyzed clinical data from 18 children with
DNM1L
variants diagnosed between 2015 and October 2025. Combined with systematic literature review (2007-October 2025) to analyze reported
DNM1L
variant types and clinical phenotypes.
The cohort included 18 children (10 male, 8 female) with a median onset age of 3.5 years. Epilepsy occurred in 88.9% of patients, with 72.2% developing super-refractory status epilepticus; 66.7% had dystonia. Most patients exhibited brain MRI and EEG abnormalities. Eight novel pathogenic variants were identified (four missense, three frameshift, one compound heterozygous). Notably, eight patients with middle domain variants (primarily p.Arg403Cys) presented a novel “hemiconvulsion-hemiplegia-epilepsy syndrome” phenotype. At last follow-up, 83.3% had a modified Rankin Scale score ≥4, indicating severe disability and poor prognosis. Literatures review confirmed
DNM1L
variants are predominantly missense, with the middle domain as a hotspot. The p.Arg403Cys variant is recurrent and highly prevalent in the Chinese. Middle domain variants are more common in Asians, while GTPase domain variants are more frequent in Europeans. Missense variants in the middle domain correlated with higher rates of neurological dysfunction and mortality.
This study represents an extension of our earlier work by incorporating an additional 18 cases, which expands the genetic and phenotypic spectrum of
DNM1L
-related disorders. It identifies “hemiconvulsion-hemiplegia-epilepsy syndrome” as a distinct feature and potential prognostic indicator for middle domain variants. The established genotype-phenotype patterns, based on protein domains and ethnic differences, provide critical insights for precise diagnosis and management.
Han Xu, Chaolong Xu, Ying Zou et al.· Frontiers in Neurology· 0 citations