Annarita Scardamaglia
A5014962879- Genetics and Neurodevelopmental Disorders
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Hereditary Neurological Disorders
- Genetic Neurodegenerative Diseases
- Peptidase Inhibition and Analysis
- Cellular Mechanics and Interactions
- Cellular transport and secretion
- RNA regulation and disease
- Ubiquitin and proteasome pathways
- RNA and protein synthesis mechanisms
- Neurogenetic and Muscular Disorders Research
- RNA Research and Splicing
- Fetal and Pediatric Neurological Disorders
- Connective tissue disorders research
- Nuclear Receptors and Signaling
- Lipid metabolism and biosynthesis
- Endoplasmic Reticulum Stress and Disease
- Cancer-related gene regulation
- Signaling Pathways in Disease
- Protein Tyrosine Phosphatases
- Pluripotent Stem Cells Research
- Cardiac Structural Anomalies and Repair
- Neurological diseases and metabolism
- Epigenetics and DNA Methylation
National Hospital for Neurology and Neurosurgery
2023-2025
University College London
2023-2025
Abstract Background Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant with invariable sensory neuropathy originally described in a family Swedish ancestry residing Utah more than 25 years ago. Despite tight linkage to the 16q22 region, molecular diagnosis has since remained elusive. Objectives Inspired by pathogenic structural variation implicated other 16q‐ataxias same locus, we revisited index SCA4 cases from using novel technologies investigate within candidate region. Methods...
Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC a heterogeneous disorder currently linked to variants six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 ten individuals from seven families with autosomal recessive PFBC. The lead loss-of-function lack of protein N-terminal (Nt)-acetylation activity. We...
FITM2 encodes fat-storage inducing transmembrane protein 2 (FIT2), a lipid diphosphatase in the ER that cleaves acyl-CoAs and is crucial for homeostasis. In humans, homozygous null mutations are associated with syndrome characterized by deafness dystonia. Here, we report two families hereditary spastic paraplegia (HSP) whom exome sequencing revealed compound heterozygosity mutations. each family, affected probands carry one putative allele G100R missense allele. Functional analyses...
Abstract Partial phenotypic overlap has been suggested between multiple system atrophy (MSA) and spinocerebellar ataxia 27B, the autosomal dominant caused by an intronic GAA•TTC repeat expansion in FGF14. This study investigated frequency of FGF14 clinically diagnosed pathologically confirmed cases. We screened 657 cases (193 464 confirmed) 1,003 controls. The locus was genotyped using long-range PCR bidirectional repeat-primed PCRs, expansions were with targeted long-read Oxford Nanopore...
The post-transcriptional modification of tRNAs plays a crucial role in tRNA structure and function. Pathogenic variants tRNA-modification enzymes have been implicated wide range human neurodevelopmental neurological disorders. However, the molecular basis for many these disorders remains unknown. Here, we describe comprehensive cohort 43 individuals from 31 unrelated families with bi-allelic methyltransferase 1 (TRMT1). These present disorder universally characterized by developmental delay...
Abstract Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent A2 enzymes, is involved in various physiological processes through maintenance membrane phospholipids. Biallelic variants PNPLA8 have been associated with a range paediatric neurodegenerative disorders. However, phenotypic spectrum, genotype–phenotype correlations and underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families biallelic...
Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes identification potential biomarkers therapeutic targets. Here, we identify
Abstract The post-transcriptional modification of tRNAs plays a key role in tRNA folding and function to ensure proper levels protein synthesis during growth development. Pathogenic variants enzymes have been implicated diverse human neurodevelopmental neurological disorders. However, the molecular basis for many these disorders remains unknown, thereby limiting our understanding potential treatment pathologies linked modification. Here, we describe an extensive cohort 31 individuals from 24...
The mediator (MED) multisubunit-complex modulates the activity of transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated neurologic diseases. In this study, we identified a recurrent homozygous variant MED11 (c.325C>T; p.Arg109Ter) 7 affected individuals from 5 unrelated families.To investigate cause disease, exome or genome sequencing were performed families via research networks Matchmaker Exchange. Deep clinical brain imaging evaluations...
The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 2, which are involved in ribosomal homeostasis. Pathogenic variants were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked GTPBP1. Here, we describe individuals carrying bi-allelic that display identical with characterize the overall spectrum protein (1/2)-related disorders. In this study, 20 from 16 families distinct NDDs...
<title>Abstract</title> We describe eighteen individuals from twelve families with an autosomal recessive neurodevelopmental disorder and variable leukodystrophy harbouring biallelic variants in <italic>SUPV3L1</italic>. <italic>SUPV3L1</italic> encodes the RNA helicase SUV3 (also known as SUPV3L1), previous studies demonstrating a role for protein part of mitochondrial degradosome. Patient mutations result accumulation double stranded RNAs human cells. An assessment <italic>supv3l1</italic>...
Abstract Charcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies, with over 100 causative genes identified to date. Despite progress in genetic sequencing, around quarter patients remain unsolved. Through international collaborations, we 16 recessive variants Rho GTPase activating protein 19 ( ARHGAP19 ) causing motor-predominant neuropathy conduction slowing 25 individuals from 20 unrelated multi-ancestry families. GTPase-activating...
ABSTRACT Autophagy is a fundamental and evolutionary conserved biological pathway with vital roles in intracellular quality control homeostasis. The process of autophagy involves the engulfment targets by autophagosomes their delivery to lysosome for digestion recycling. We have previously reported recessive variants EPG5 , encoding ectopic P-granules 5 protein crucial role autophagosome-lysosome fusion, as cause Vici syndrome (VS), severe multisystem neurodevelopmental disorder defined...
Myotubularin-Related Protein 5 (MTMR5) is an inactive, poorly characterized D3-phosphatidylinositol phosphatase. Mutations in MTMR5 have been linked to Charcot-Marie-Tooth Disease Type 4B3 (CMT4B3), a rare, early-onset, recessive peripheral neuropathy. Here, we describe the establishment and validation of three human induced pluripotent stem cell (iPSC) lines derived from unrelated CMT4B3 patients, each harboring homozygous MTMR5/Sbf1 mutations. Current
Abstract Background The identification of a heterozygous exonic GGC repeat expansion in ZFHX3 underlying spinocerebellar ataxia type 4 (SCA4) has solved 25‐year diagnostic conundrum. We used adaptive long‐read sequencing to decipher the pathogenic index Utah family and an unrelated from Iowa Swedish ancestry. Contemporaneous our discovery, other groups identified same affected individuals Utah, Sweden, Germany, highlighting current pivotal time for detection novel disorders. Methods Given...
Abstract Joubert syndrome (JS) is a rare autosomal recessive disease characterized by peculiar brain malformation, hypotonia, ataxia, developmental delay, abnormal eye movements, and neonatal breathing abnormalities. This picture often associated with variable multiorgan involvement, mainly of the retina, kidneys liver, defining group conditions termed syndrome-related disorders (JSRD). Currently, more than 30 causative genes have been identified, involved in development stability primary...
Abstract PNPLA8, one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through maintenance membrane phospholipids. However, little known about its role brain development. Here, we report 12 individuals from 10 unrelated families with biallelic ultra-rare variants PNPLA8 presenting a wide spectrum clinical features ranging developmental and epileptic-dyskinetic encephalopathy (DEDE) to progressive movement disorders. Complete loss was...
Mutations or multiplications of the SNCA (Synuclein Alpha) gene cause rare autosomal dominant Parkinson's disease (PD). The G51D missense mutation is associated with a synucleinopathy that shares PD and multiple system atrophy (MSA) characteristics. We generated induced pluripotent stem cell (iPSC) lines from two individuals mutations at risk PD. Dermal fibroblasts were reprogrammed to pluripotency using non-integrating mRNA-based protocol. resulting human iPSCs displayed normal morphology,...