A 62-year-old woman presenting with apathy, hyperorality, and language impairment, harbouring a novel heterozygous c.440 A > G CHMP2B variant of uncertain significance, causing D147G substitution is reported, raising the possibility that this variant may be relevant in the context of an FTD-like phenotype.
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
Neurodevelopmental disorder with spasticity, epilepsy and brain atrophy (NEDESBA) is a rare autosomal recessive condition, first described in 2020. It has been associated with biallelic pathogenic variants in the Trafficking Protein Particle Complex Subunit 4 (TRAPPC4) gene. This disorder belongs to the expanding group of TRAPPopathies, caused by mutations in genes encoding components of the transport protein particle (TRAPP) complex, which are essential for intracellular trafficking, autophagy and dendritic spine morphogenesis. Variants in these genes typically result in overlapping clinical features, including microcephaly, early‐onset epilepsy, intellectual disability, neurodevelopmental regression, spasticity and abnormal brain MRI findings. Here, we report a 13‐month‐old affected male born to consanguineous parents, presenting with epileptic spasms and progressive neurodevelopmental delay. Importantly, proband also exhibits hair loss and skin rashes in early infancy. Initial metabolic screening suggested biotinidase deficiency, based on low biotin levels (0.6 nmol/min/mL; normal > 5) and overlapping clinical symptoms. However, confirmatory biochemical and enzymatic studies ruled out classic biotinidase deficiency. Whole exome sequencing revealed a homozygous splice‐site variant (c.454+3A>G) in the TRAPPC4 gene, confirming the diagnosis of NEDESBA. This variant has been reported in multiple previous reports, mainly born out of consanguineous marriages. The phenotypic overlap between metabolic and genetic neurodevelopmental disorders in these cases emphasizes the critical role of early molecular testing in achieving a precise diagnosis.
Anil Kumar, Ajay Kumar, Arvinder Wander et al.· International Journal of Dev...· 0 citations
SLC13A3 pathogenic variants are associated with acute reversible leukoencephalopathy and α‐ketoglutarate accumulation (ARLIAK), a rare neurological disorder characterized by recurrent episodes of encephalopathy and transient white matter abnormalities. Pathogenic variants reported so far include missense, nonsense and small deletion variants, highlighting substantial allelic heterogeneity. We describe a patient presenting with multiple episodes of acute encephalopathy, elevated urinary α‐ketoglutarate and reversible white matter lesions on MRI, consistent with SLC13A3‐related ARLIAK. Genetic analysis identified novel compound heterozygous variants: a missense variant (p.Leu46Pro) in a highly conserved region and a larger deletion encompassing exons 2–3. Our findings indicate that conventional sequencing alone may miss larger deletions, suggesting the need for copy number analysis as part of the diagnostic protocol for suspected ARLIAK cases. The elevated urinary α‐ketoglutarate in our patient supports its potential as a noninvasive biomarker. MRI findings demonstrated typical transient and reversible white matter abnormalities, aligning with previously reported cases. This study expands the molecular and phenotypic spectrum of SLC13A3‐related ARLIAK and underscores the importance of combining sequencing with copy number analysis for accurate diagnosis. The identification of novel variants contributes to a better understanding of the disease mechanism and suggests a broader allelic heterogeneity than previously recognized.
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
CLDN11 has recently been associated with hypomyelinating leukodystrophy caused by de novo stop-loss variants. Here, we present a new case involving a homozygous variant in order to expand the genetic and clinical spectrum of the disease. We performed a comprehensive clinical, neuroradiological, and genetic evaluation in a child presenting with global developmental delay. Brain MRI and MR spectroscopy were obtained, and next-generation sequencing with parental segregation analysis was conducted. The patient presented with developmental delay, hypotonia, limb hypertonia, esotropia, and an absence of early developmental milestones in infancy, followed by partial motor improvement and persistent language and cognitive impairment. Brain MRI revealed diffuse supratentorial hypomyelination with stability over time. Genetic analysis identified a novel homozygous CLDN11 start-loss variant (c.1A>G; p.Met1Val), which is predicted to result in biallelic loss of function. Both parents were found to be heterozygous carriers. This case supports an autosomal recessive mechanism of CLDN11-related disease, which differs from the dominant stop-loss variants reported previously. The phenotype partially overlaps with that of earlier cases, but is characterized by milder motor involvement and more pronounced cognitive impairment. These findings broaden the mutational spectrum and suggest distinct pathogenic mechanisms, with important implications for diagnosis and genetic counselling.
F. Acquaviva, S. Troisi, G. Errichiello et al.· Clinical Genetics· 0 citations
Background: Gordon Holmes syndrome (GHS) is a rare genetic disorder, usually manifesting as a broad spectrum of neurological symptoms and hypogonadotropic hypogonadism. Only a limited number of cases presenting this congenital disorder have been reported in the literature. Since the genetic and phenotypic heterogeneity of GHS, it is crucial to report novel cases.
Case presentation: Here we report a novel homozygous missense variant in RNF216 gene c.1055T>G (p.(Phe352Cys)) in three siblings. Primary concerns were absence of secondary sexual characteristics, and amenorrhea occurred among female patients. Based on laboratory test results and clinical features, hypogonadotropic hypogonadism was diagnosed. Neurological examination revealed no signs of ataxia in siblings. However, brain magnetic resonance imaging revealed pronounced changes in the cerebral white matter for female patients. Due to primary amenorrhea and the absence of secondary sexual characteristics, treatment was initiated. Treatment might be adjusted in the presence of fertility considerations.
Conclusions: This case contributes to the limited knowledge of GHS and highlights the importance of hypogonadotropic hypogonadism treatment and close observation of neurological symptoms that may develop over time.