Brain malformations and seizures by impaired chaperonin function of TRiC.

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individuals with brain malformations, intellectual disability, and seizures.

Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome.

Purpose: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed.

Methods: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome.

Results: Computational facial and Human Phenotype Ontology-based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity.

Clinical and molecular description of 19 patients with GATAD2B-Associated Neurodevelopmental Disorder (GAND).

De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions.

Unilateral Hearing Loss Due to Cochlear Nerve Involvement as Isolated Symptom of a Primary Medulloblastoma.

Unilateral sensorineural hearing loss is a common symptom of vestibular schwannomas in adolescent patients with neurofibromatosis type 2 or sporadic vestibular schwannomas and is often the initial clinical feature. While rare cases of sensorineural impairment presenting as vision or hearing loss due to metastatic medulloblastoma are known, hearing loss as an isolated presenting symptom of primary malignant neuroepithelial tumors of the central nervous system has not been reported in the pediatric population so far. We present two adolescents with unilateral hearing loss due to cochlear nerve dysfunction as the only symptom of a primary nonmetastatic medulloblastoma of the WNT signaling pathway family members subgroup.

Intranasal Administration of Mesenchymal Stem Cells Ameliorates the Abnormal Dopamine Transmission System and Inflammatory Reaction in the R6/2 Mouse Model of Huntington Disease.

Intrastriatal administration of mesenchymal stem cells (MSCs) has shown beneficial effects in rodent models of Huntington disease (HD). However, the invasive nature of surgical procedure and its potential to trigger the host immune response may limit its clinical use. Hence, we sought to evaluate the non-invasive intranasal administration (INA) of MSC delivery as an effective alternative route in HD.

Mitochondrial Morphology, Function and Homeostasis Are Impaired by Expression of an N-terminal Calpain Cleavage Fragment of Ataxin-3.

Alterations in mitochondrial morphology and function have been linked to neurodegenerative diseases, including Parkinson disease, Alzheimer disease and Huntington disease. Metabolic defects, resulting from dysfunctional mitochondria, have been reported in patients and respective animal models of all those diseases. Spinocerebellar Ataxia Type 3 (SCA3), another neurodegenerative disorder, also presents with metabolic defects and loss of body weight in early disease stages although the possible role of mitochondrial dysfunction in SCA3 pathology is still to be determined.

Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat.

Huntington's disease is a fatal human neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, which translates into a mutant huntingtin protein. A key event in the molecular pathogenesis of Huntington's disease is the proteolytic cleavage of mutant huntingtin, leading to the accumulation of toxic protein fragments. Mutant huntingtin cleavage has been linked to the overactivation of proteases due to mitochondrial dysfunction and calcium derangements.

Gene expression changes in a transgenic mouse model overexpressing human wildtype and mutant torsinA.

Primary torsion dystonia is an autosomal-dominantly inherited, neurodevelopmental movement disorder caused by a GAG deletion (ΔGAG) in the DYT1 gene, encoding torsinA. This mutation is responsible for approximately 70% of cases of early-onset primary torsion dystonia. The function of wildtype torsinA is still unknown, and it is unsolved how the deletion in the DYT1 gene contributes to the development of the disease.