A 6‐year‐old female with a history of Aicardi–Goutières syndrome (AGS) presented to dermatology clinic with hypopigmented and hyperpigmented macules and patches consistent with dyschromatosis ...symmetrica hereditaria (DSH). Previous genetic workup demonstrated a de novo, heterozygous mutation in the adenosine deaminase acting on RNA 1 (ADAR) gene. While the co‐occurrence of AGS and DSH has previously been described in mutations of the ADAR gene, our case highlights the potential association between these disorders that may aid in earlier future diagnosis of AGS.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of ...interferon (IFN) overproduction, and the development of PH has not been characterized to date.
We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001).
We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
Liquid chromatography–tandem mass spectrometry (LC-MS/MS) assays were developed to measure arylsulfatase A (ARSA) activity in leukocytes and dried blood spots (DBS) using deuterated natural sulfatide ...substrate. These new assays were highly specific and sensitive. Patients with metachromatic leukodystrophy (MLD) and multiple sulfatase deficiency (MSD) displayed a clear deficit in the enzymatic activity and could be completely distinguished from normal controls. The leukocyte assay reported here will be important for diagnosing MLD and MSD patients and for monitoring the efficacy of therapeutic treatments. ARSA activity was measured in DBS for the first time without an antibody. This new ARSA DBS assay can serve as a second-tier test following the sulfatide measurement in DBS for newborn screening of MLD. This leads to an elimination of most of the false positives identified by the sulfatide assay.
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IJS, KILJ, NUK, PNG, UL, UM
Aicardi-Goutières syndrome (AGS) is a monogenic type-I interferonopathy that results in neurologic injury. The systemic impact of sustained interferon activation is less well characterized. Liver ...inflammation is known to be associated with the neonatal form of AGS, but the incidence of AGS-related hepatitis across lifespan is unknown.We compared natural history data including liver enzyme levels with markers of inflammation, (liver-specific autoantibodies and interferon signaling gene expressionISG scores). Liver enzymes were classified as normal or elevated by the fold increase over the upper limit of normal (ULN). The highest increases were designated as hepatitis, defined as aspartate-aminotransferase or alanine-aminotransferase threefold ULN, or gamma-glutamyl transferase 2.5-fold ULN. A larger cohort was used to further characterize the longitudinal incidence of liver abnormalities and the association with age and genotype.Across the AGS cohort (
= 102), elevated liver enzymes were identified in 76 individuals (74.5%) with abnormalities at a level consistent with hepatitis in 29 individuals (28.4%). SAMHD1 mutations were less likely to be associated with hepatitis (log-rank test;
= 0.011). Hepatitis was associated with early-onset disease and microcephaly (log-rank test; microcephaly
= 0.0401, age onset
= 0.0355). While most subjects (
= 20/33) were found to have liver-specific autoantibodies, there was no association between the presence of autoantibodies or ISG scores with hepatitis-level enzyme elevations.In conclusion, all genotypes of AGS are associated with transient elevations of liver enzymes and the presence of liver-associated autoantibodies. This adds to our growing understanding of the systemic pathology AGS.
Abstract Exome sequencing (ES) has emerged as an essential tool in the evaluation of neurodevelopmental disorders (NDD) of unknown etiology. Genome sequencing (GS) offers advantages over ES due to ...improved detection of structural, copy number, repeat number and non‐coding variants. However, GS is less commonly utilized due to higher cost and more intense analysis. Here, we present nine cases of pediatric NDD that were molecularly diagnosed with GS between 2017 and 2022, following non‐diagnostic ES. All individuals presented with global developmental delay or regression. Other features present in our cohort included epilepsy, white matter abnormalities, brain malformation and dysmorphic features. Two cases were diagnosed on GS due to newly described gene‐disease relationship or variant reclassification ( MAPK8IP3, CHD3 ). Additional features missed on ES that were later detected on GS were: intermediate‐size deletions in three cases who underwent ES that were not validated for CNV detection, pathogenic variants within the non‐protein coding genes SNORD118 and RNU7‐1 , pathogenic variant within the promoter region of GJB1 , and a coding pathogenic variant within BCAP31 which was not sufficiently covered on ES. GS following non‐diagnostic ES led to the identification of pathogenic variants in this cohort of nine cases, four of which would not have been identified by reanalysis alone.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is a recently described autosomal recessive leukoencephalopathy caused by pathogenic variants in the
gene. ...ARLIAK is characterized by acute neurologic involvement, often precipitated by febrile illness, with largely reversible clinical symptoms and imaging findings. Three patients have been reported in the literature to date. Our objective is to report newly identified patients and their genetic variants and phenotypes and review published literature on ARLIAK.
This report contributes 4 additional patients to the literature; describes novel variants in
; and reviews genetic, biochemical, clinical, and radiologic features of all published patients with ARLIAK.
We provide additional genetic, imaging, and laboratory insights into ARLIAK, an atypical leukodystrophy with clinical and radiologic findings that can normalize.
Our case series highlights the importance of reanalysis of next-generation sequencing in the diagnostic workup.
Vanishing white matter (VWM) is a leukodystrophy caused by bi-allelic pathogenic variants in the eukaryotic initiation factor 2B (eIF2B). eIF2B orchestrates the integrated stress response (ISR), a ...physiological response to cellular stress. In VWM brain, the ISR is deregulated. The degree of ISR deregulation has been shown to correlate positively with disease severity in a representative VWM mouse model. Preclinical studies have shown that the ISR is a viable treatment target for VWM. Suitable biomarkers to assess disease activity and ISR-target engagement in patients are lacking. Therefore, the current study aimed to find potential blood mRNA biomarkers for VWM with nanoString technology. The technology confirmed ISR deregulation in the brains of VWM patients but did not identify a single ISR blood biomarker that can be readily used in clinical setting. A set of three mRNAs that are differentially expressed in blood between VWM patients and controls was detected.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
IFIH1 gain‐of‐function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten ...syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Metachromatic leukodystrophy is a lysosomal storage disorder with an estimated incidence of 1:40,000. Magnetic resonance imaging at time of diagnosis often shows symmetric white matter involvement, ...sparing the arcuate fibers. A 25-month-old female child presented with a cranial neuropathy, a spastic gait, decreased leukocyte arylsulfatase-A activity, and elevated urinary sulfatides. Magnetic resonance imaging revealed multiple cranial nerve enhancement, without intraparenchymal white matter involvement.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
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