Aug 2026· Journal of Human Genetics· 0 citations· 40 references
Medicine
TL;DR
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.
Parkinsonism–dystonia Type 2 (PKDYS2) is a rare autosomal recessive disorder caused by SLC18A2 variants affecting the vesicular monoamine transporter 2 (VMAT2). We report the first genetically confirmed Iranian patient, an 18‐month‐old boy presenting with profound developmental delay, axial hypotonia, limb hypertonia, dystonia, oculogyric crises, ptosis, and autonomic dysfunction. Brain MRI, metabolic studies, and neurophysiological evaluations were normal. Whole‐exome sequencing identified a novel homozygous canonical splice‐site variant in SLC18A2 (NM_003054.6:c.1071‐2A > G), confirmed by Sanger sequencing and absent from population databases. SpliceAI predicted loss of the native splice acceptor site (DS_AL = 0.74), supporting a deleterious effect on RNA splicing. According to ACMG criteria, the variant was classified as likely pathogenic. Levodopa–benserazide failed to provide sustained benefit and caused irritability and insomnia, whereas pramipexole produced modest improvement in bradykinesia, ptosis, and sweating with persistence of dystonia and oculogyric crises. Comparison with reported international cases shows a consistent phenotype and limited therapeutic response. This case expands the mutational spectrum of SLC18A2‐related disease and highlights the importance of early genetic diagnosis.
Ali Nikkhah, R. Badv, S. Habibi et al.· Case Reports in Neurological...· 0 citations
The novel DNAJC6 p.Cys325* variant is associated with severe, early-onset parkinsonism and developmental regression and should be considered in children and adolescents presenting with parkinsonism plus neurodevelopmental decline, particularly when levodopa benefit is modest, and dose-related adverse motor crises occur.
André Luiz Santos Pessoa, T. Guimarães, Diego de Castro Dos Santos et al.· Movement Disorders Clinical...· 0 citations
Introduction and importance: SpADMiSS syndrome (SPOUT1-Associated Developmental delay, Microcephaly, Seizures, and Short stature) is a recently described autosomal recessive neurodevelopmental disorder caused by biallelic variants in SPOUT1/CENP-32. The phenotypic spectrum of this condition is still evolving. Reporting novel clinical features and complex genetic architectures is essential to refine genotype–phenotype correlations, particularly in consanguineous populations. Case presentation: We describe 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. Neuroimaging revealed marked cerebral atrophy and previously unreported bilateral basal ganglia calcification. The patient also developed bilateral cataracts requiring surgical intervention. Whole-exome sequencing identified a recurrent homozygous missense variant in SPOUT1/CENP-32 (c.292 G > A; p.Gly98Ser), confirming the diagnosis of SpADMiSS. In addition, homozygous pathogenic variants were detected in XYLT2 and EYS, indicating multilocus genetic disease. Clinical discussion: This case expands the phenotypic spectrum of SpADMiSS by documenting basal ganglia calcification, a feature not previously reported in affected individuals. The presence of early-onset cataracts and ocular involvement is best explained by concurrent pathogenic variants in XYLT2 and EYS, illustrating a blended phenotype due to multilocus inheritance. These findings highlight the importance of comprehensive genomic analysis in consanguineous families to avoid misattribution of clinical features to a single genetic disorder. Conclusion: We report a novel presentation of SpADMiSS syndrome associated with basal ganglia calcification and multilocus pathogenic variation. This case underscores the expanding neuroimaging phenotype of SPOUT1/CENP-32-related disease and emphasizes 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
The novel NR2F1 variant was classified as likely pathogenic according to ACMG guidelines, confirming the diagnosis of BBSOAS and the ARF3 variant, identified as a secondary finding of uncertain clinical significance, is unlikely to account for the patient's phenotype.
Sina Babaei, Haneieh Honarmand, Mortaza Bonyadi et al.· Molecular Biology Reports· 0 citations
This study expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.
Mohamed Baity, Khalid K Alharbi, Eman Alobeid et al.· International Journal of Mol...· 0 citations
This study may expand the mutation and phenotypic spectrum of SETD1A-related disorders, establishing the relationship between SETD1A variants and isolated early-onset epilepsy without accompanying severe neurodevelopmental deficits, and highlighting the value of genetic testing in infants with unexplained epilepsy.
Rina Su, Lei Zhu, Lin Jiang et al.· Frontiers in Neuroscience· 0 citations