Jan 2026· Case Reports in Neurological Medicine· Vol 2026· 0 citations· 9 references
Medicine
TL;DR
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 is reported, expanding the mutational spectrum of SLC18A2‐related disease and highlighting the importance of early genetic diagnosis.
Abstract
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.
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
The molecular and phenotypic spectrum of SLC13A3‐related ARLIAK is expanded and the importance of combining sequencing with copy number analysis for accurate diagnosis is underscored, suggesting the need for copy number analysis as part of the diagnostic protocol for suspected ARLIAK cases.
E. Uctepe, Melike Ersoy, F. N. Esen et al.· International Journal of Dev...· 0 citations
The findings support the pathogenicity of this variant and further expand the pathogenic variant spectrum of the PPP2CA gene, and the observed genotype–phenotype correlation provides valuable information for prognosis and genetic counseling.
Lei Xu, Yanfeng Shen, Guixiang Zhang· Frontiers in Psychiatry· 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
The molecular and functional spectrum of SLC25A4-associated disease is expanded and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.
Mazhor Aldosary, Hanan Alqudairy, Nourah Alshalan et al.· International Journal of Mol...· 0 citations
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both upper and lower motor neurons, disturbing communication between the brain and muscles. So far, few reports have been published for the SPG11-associated ALS, and this is the first documented case from Pakistan. We report a rare subtype of ALS with an autosomal recessive mode of inheritance with juvenile onset before 25 years of age in the five affected individuals from two unrelated families. Whole-exome sequencing was performed to identify disease-causing variants, and selected variants were further prioritized based on predicted pathogenicity and similarity to clinical phenotypes. Two homozygous variants within the SPG11 gene were identified as pathogenic according to the ACMG and ClinGen Sequence Variant Interpretation (SVI) Working Group recommendations: a novel truncation (NM_025137.4:c.6738dup, p.Glu2247Ter) variant as validated by Sanger sequencing and a recurrent nonsense (NM_025137.4: c.782C>A, p.Ser261Ter) variant (rs765477482) previously reported in a family affected with autosomal recessive hereditary spastic paraplegia (ARHSP). In silico prediction tools further confirmed their pathogenicity. Five patients with juvenile-onset ALS born to consanguineous parents were found to have homozygous SPG11 gene variants. Our findings describe the overlapping phenotypes ofSPG11-related autosomal recessive juvenile ALS and ARHSP, suggesting that these disorders show a clear overlapping phenotype with common genetic defects. In clinical practice, it is challenging to distinguish between these two disorders. Additional Mendelian cases should be included to clarify further and investigate whether these represent two diverse diseases caused by variants in a single gene.
Riaz Ahmad, Muhammad Naeem, H. Houlden· Molecular Biology Reports· 0 citations
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