The effect of intrathecal recombinant arylsulfatase A therapy on structural brain magnetic resonance imaging in children with metachromatic leukodystrophy.

This study aimed to evaluate the effect of intrathecal (IT) recombinant human arylsulfatase A (rhASA) on magnetic resonance imaging (MRI)-assessed brain tissue changes in children with metachromatic leukodystrophy (MLD). In total, 510 MRI scans were collected from 12 intravenous (IV) rhASA-treated children with MLD, 24 IT rhASA-treated children with MLD, 32 children with untreated MLD, and 156 normally developing children. Linear mixed models were fitted to analyze the time courses of gray matter (GM) volume and fractional anisotropy (FA) in the posterior limb of the internal capsule.

Pridopidine subtly ameliorates motor skills in a mouse model for vanishing white matter.

The leukodystrophy vanishing white matter (VWM) is characterized by chronic and episodic acute neurological deterioration. Curative treatment is presently unavailable. Pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B) cause VWM and deregulate the integrated stress response (ISR).

Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models.

Autosomal dominant leukodystrophy (ADLD) is an ultra-rare, slowly progressive, and fatal neurodegenerative disorder associated with the loss of white matter in the central nervous system (CNS). Several years after its first clinical description, ADLD was found to be caused by coding and non-coding variants in the LMNB1 gene that cause its overexpression in at least the brain of patients. LMNB1 encodes for Lamin B1, a protein of the nuclear lamina.

Focal lesions following intracerebral gene therapy for mucopolysaccharidosis IIIA.

Objective: Mucopolysaccharidosis type IIIA (MPSIIIA) caused by recessive SGSH variants results in sulfamidase deficiency, leading to neurocognitive decline and death. No disease-modifying therapy is available. The AAVance gene therapy trial investigates AAVrh.

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1.

Objective: Vanishing white matter (VWM) is a leukodystrophy, characterized by stress-sensitive neurological deterioration and premature death. It is currently without curative treatment. It is caused by bi-allelic pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B).

Gene Therapy Developments for Pompe Disease.

Pompe disease is an inherited neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The most severe form is infantile-onset Pompe disease, presenting shortly after birth with symptoms of cardiomyopathy, respiratory failure and skeletal muscle weakness. Late-onset Pompe disease is characterized by a slower disease progression, primarily affecting skeletal muscles.

Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants.

Objective: Heterozygous variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the gene.

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency.

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects.

Translation initiation factor eIF2Bε promotes Wnt-mediated clonogenicity and global translation in intestinal epithelial cells.

Modulation of global mRNA translation, which is essential for intestinal stem cell function, is controlled by Wnt signaling. Loss of tumor supressor APC in stem cells drives adenoma formation through hyperactivion of Wnt signaling and dysregulated translational control. It is unclear whether factors that coordinate global translation in the intestinal epithelium are needed for APC-driven malignant transformation.

Imaging Patterns Characterizing Mitochondrial Leukodystrophies.

Background And Purpose: Achieving a specific diagnosis in leukodystrophies is often difficult due to clinical and genetic heterogeneity. Mitochondrial defects cause 5%-10% of leukodystrophies. Our objective was to define MR imaging features commonly shared by mitochondrial leukodystrophies and to distinguish MR imaging patterns related to specific genetic defects.

MRI Natural History of the Leukodystrophy Vanishing White Matter.

Background In vanishing white matter (VWM), a form of leukodystrophy, earlier onset is associated with faster clinical progression. MRI typically shows rarefaction and cystic destruction of the cerebral white matter. Information on the evolution of VWM according to age at onset is lacking.

LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations.

Objective: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in , encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described.

Efficient lentiviral transduction method to gene modify cord blood CD8 T cells for cancer therapy applications.

Adoptive T cell therapy utilizing tumor-specific autologous T cells has shown promising results for cancer treatment. However, the limited numbers of autologous tumor-associated antigen (TAA)-specific T cells and the functional aberrancies, due to disease progression or treatment, remain factors that may significantly limit the success of the therapy. The use of allogeneic T cells, such as umbilical cord blood (CB) derived, overcomes these issues but requires gene modification to induce a robust and specific anti-tumor effect.

Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations.

Background: Vanishing white matter (VWM) is a leukodystrophy, caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B)-subunit genes (EIF2B1-EIF2B5); 80% are missense mutations. Clinical severity is highly variable, with a strong, unexplained genotype-phenotype correlation.

Materials And Methods: With information from a recent natural history study, we severity-graded 97 missense mutations.

Isocaloric low protein diet in a mouse model for vanishing white matter does not impact ISR deregulation in brain, but reveals ISR deregulation in liver.

Vanishing white matter (VWM) is a genetic brain white matter disorder caused by mutations in eIF2B. eIF2B is central in the integrated stress response (ISR), during which its activity is inhibited by various cellular stresses. VWM is a chronic progressive disease with episodes of rapid neurological deterioration provoked by stresses.

Vanishing white matter: deregulated integrated stress response as therapy target.

Objective: Vanishing white matter (VWM) is a fatal, stress-sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation during the integrated stress response (ISR). Mutations reduce eIF2B activity.