Isabella Peixoto de Barcelos

IntroductionAicardi Goutières Syndrome (AGS) is a genetically heterogeneous interferonopathy caused by disruptions in RNA and DNA metabolism. Biallelic pathogenic variants in Sterile alpha motif (SAM) and histidine-aspartate (HD) domain containing protein 1 (SAMHD1) are particularly associated with moyamoya syndrome (MMS) and stroke in this rare subtype of AGS. In this report, we describe the clinical course and unique cerebrovascular features in a cohort of patients with SAMHD1-related AGS.MethodologyIndividuals with genetically confirmed SAMHD1-related AGS enrolled under the Myelin Disorders Biorepository Project protocol were included (n=32). Clinical data, including age at evaluation, genotype, functional level, and AGS Severity Scale Scores, were extracted from medical records. Available cerebral imaging studies were reviewed, and the composite cerebrovascular stenosis score (CVSS) was applied. Prospective functional outcomes, including the Gross Motor Function Measure (GMFM-88) and Vineland Adaptive Behavior Scale (VABS-3), were collected. Interferon signaling gene (ISG) scores were calculated as a biomarker of disease activity. Descriptive statistics were performed in R.ResultsIn this cohort, 46.9% (15/32) had evidence of cerebrovascular disease, identified through medical records (n=8) or neuroimaging review (n=7). Axial hypotonia and hypertension were more frequently observed in the subcohort with cerebrovascular disease (p = 0.02 and 0.02, respectively). Neuroimaging demonstrated arterial ischemic changes, abnormal collateral vessel formation, and arterial stenosis, as quantified by CVSS scoring, consistent with moyamoya syndrome in a subset of cases. Individuals without cerebrovascular disease were more likely to develop cortical visual impairment (p = 0.03). They had a lower GMFM total percentile score (median = 3.99, IQR = 3.27) than those with cerebrovascular disease (median = 61.2, IQR = 82.3; p = 0.03). Children with SAMHD1-related AGS were more likely to develop cerebrovascular disease compared to non-SAMHD1 genotypes (p < 0.001).ConclusionIn this study, we described a cohort of patients with SAMHD1-related AGS, representing a distinct clinical subtype within AGS. In this cohort, impaired communication function and the presence of hypertension were associated with an increased risk of cerebrovascular disease, including moyamoya syndrome, but were not sufficient predictors of risk. Based on these findings, periodic cerebrovascular imaging may be considered for surveillance in affected individuals; however, the evidence presented here is insufficient to support a specific screening interval such as annual imaging.

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF–expressing) and anti-inflammatory (IL-10–expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a “fourth signal” that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

Paroxysmal exercise-induced movement disorders may be caused by energy metabolism disorders, such as Glut 1 deficiency, pyruvate dehydrogenase deficiency or mitochondrial respiratory chain disorders. A 4-year-old boy with a history of febrile seizures presented with paroxysmal dystonia, triggered by exercise, or occurring at rest. Additional investigations demonstrated pallidal hyperintensities on brain MRI and low CSF glucose. Pyruvate and lactate were elevated. The clinical presentation, combined with neuroimaging abnormalities and biochemical profile (the lactate/pyruvate ratio) were clues to pyruvate dehydrogenase deficiency, a treatable metabolic disorder with neurological presentations.

Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

We report a 20-year-old female, adopted Indian patient with over 662 Mb regions of homozygosity who presented with variants associated with symptoms in BBS6, STRC, and DUOX2 genes. And a VUS in the TNNT2 gene, so far without clinical correlation. Symptoms are not explained by only one gene.

BACKGROUND AND PURPOSE: Little is known about imaging features of spinal cord lesions in mitochondrial disorders. The aim of this research was to assess the frequency, imaging features, and pathogenic variants causing primary mitochondrial disease in children with spinal cord lesions. MATERIALS AND METHODS: This retrospective analysis included patients seen at Children’s Hospital of Philadelphia between 2000 and 2019 who had a confirmed diagnosis of a primary (genetic-based) mitochondrial disease and available MR imaging of the spine. The MR imaging included at least both sagittal and axial fast spin-echo T2-weighted images. Spine images were independently reviewed by 2 neuroradiologists. Location and imaging features of spinal cord lesions were correlated and tested using the Fisher exact test. RESULTS: Of 119 children with primary mitochondrial disease in whom MR imaging was available, only 33 of 119 (28%) had available spine imaging for reanalysis. Nineteen of these 33 individuals (58%) had evidence of spinal cord lesions. Two main patterns of spinal cord lesions were identified: group A (12/19; 63%) had white ± gray matter involvement, and group B (7/19; 37%) had isolated gray matter involvement. Group A spinal cord lesions were similar to those seen in patients with neuromyelitis optica spectrum disorder, multiple sclerosis, anti–myelin oligodendrocyte glycoprotein-IgG antibody disease, and leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Group B patients had spinal cord findings similar to those that occur with ischemia and viral infections. Significant associations were seen between the pattern of lesions (group A versus group B) and the location of lesions in cervical versus thoracolumbar segments, respectively (P < .01). CONCLUSIONS: Spinal cord lesions are frequently observed in children with primary mitochondrial disease and may mimic more common causes such as demyelination and ischemia.

The aging process includes impairment in mitochondrial function, a reduction in anti-oxidant activity, and an increase in oxidative stress, marked by an increase in reactive oxygen species (ROS) production. Oxidative damage to macromolecules including DNA and electron transport proteins likely increases ROS production resulting in further damage. This oxidative theory of cell aging is supported by the fact that diseases associated with the aging process are marked by increased oxidative stress. Coenzyme Q10 (CoQ₁₀) levels fall with aging in the human but this is not seen in all species or all tissues. It is unknown whether lower CoQ₁₀ levels have a part to play in aging and disease or whether it is an inconsequential cellular response to aging. Despite the current lay public interest in supplementing with CoQ₁₀, there is currently not enough evidence to recommend CoQ₁₀ supplementation as an anti-aging anti-oxidant therapy.

In recent years, several studies have examined the potential associations between mitochondrial dysfunction and neurodegenerative diseases such as multiple sclerosis (MS), Parkinson’s disease and Alzheimer’s disease. In MS, neurological disability results from inflammation, demyelination, and ultimately, axonal damage within the central nervous system. The sustained inflammatory phase of the disease leads to ion channel changes and chronic oxidative stress. Several independent investigations have demonstrated mitochondrial respiratory chain deficiency in MS, as well as abnormalities in mitochondrial transport. These processes create an energy imbalance and contribute to a parallel process of progressive neurodegeneration and irreversible disability. The potential roles of mitochondria in neurodegeneration are reviewed. An overview of mitochondrial diseases that may overlap with MS are also discussed, as well as possible therapeutic targets for the treatment of MS and other neurodegenerative conditions.