David Pellerin

McGill University | McGill · Department of Neurology and Neurosurgery

Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits...

Objectives Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 ( FGF14 ) gene has recently been recognized as a common cause of late‐onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathol...

Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of...

Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA·TTC repeat expansion in FGF14 . Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibit...

The factors driving or preventing pathological expansion of tandem repeats remain largely unknown. Here, we assessed the FGF14 (GAA)·(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a common 5'-flanking variant in 70.34% of alleles analyzed (3,463/4,923) that represents the phylogenetically ancestral allele...

Background Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. Objective Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertia...

Background An intronic GAA repeat expansion in FGF14 was recently identified as a cause of GAA-FGF14 ataxia. We aimed to characterise the frequency and phenotypic profile of GAA-FGF14 ataxia in a large Chinese ataxia cohort. Methods A total of 1216 patients that included 399 typical late-onset cerebellar ataxia (LOCA), 290 early-onset cerebellar a...

Background GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA)≥250 and (GAA)...

Objectives The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients (“idiopathic”), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we hypothesized that biallelic RFC1 expansions may also represent a recurrent cause of DBN syndrome. Methods...

Background GAA- FGF14 ataxia (SCA27B) is a recently reported late-onset ataxia caused by a GAA repeat expansion in intron 1 of the FGF14 gene. Initial studies revealed cerebellar atrophy in 74-97% of patients. A more detailed brain imaging characterization of GAA- FGF14 ataxia is now needed to provide supportive diagnostic features and earlier dise...

Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic heterogeneity. Currently, up to 75% of such patients remain without a genetic diagnosis. In an era of emerging disease‐modifying gene‐stratified therapies, the identification of causative alle...

Whether spinocerebellar ataxia 27B (SCA27B) may present as a cerebellar multiple system atrophy (MSA-C) mimic remains undetermined. To assess the prevalence of FGF14 (GAA)≥250 expansions in patients with MSA-C, to compare SCA27B and MSA-C clinical presentation and natural history. FGF14 expansion screening combined with longitudinal deep-phenotypin...

A pathogenic GAA repeat expansion in the first intron of the fibroblast growth factor 14 gene (FGF14) has been recently identified as the cause of spinocerebellar ataxia 27B (SCA27B). We herein screened 160 Greek index cases with late‐onset cerebellar ataxia (LOCA) for FGF14 repeat expansions using a combination of long‐range PCR and bidirectional...

Background Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant ataxia with invariable sensory neuropathy originally described in a family with Swedish ancestry residing in Utah more than 25 years ago. Despite tight linkage to the 16q22 region, the molecular diagnosis has since remained elusive. Objectives Inspired by pathogenic structura...

Background SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10–60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. Me...

Leukodystrophies are a heterogeneous group of rare genetic disorders primarily affecting the white matter of the central nervous system. These conditions can present a diagnostic challenge, requiring a comprehensive approach that combines clinical evaluation, neuroimaging, metabolic testing, and genetic testing. While MRI is the main tool for diagn...

Ashton C et al report a retrospective multi-centre cohort of 34 patients from Canada, France, Austria and Australia with spinocerebellar ataxia 27B, describing the common feature of episodic ataxia and other episodic features, as well as the inefficacy of acetazolamide in these patients.

Objectives Intronic FGF14 GAA repeat expansions have recently been found to be a common cause of hereditary ataxia (GAA- FGF14 ataxia; SCA27B). The global epidemiology and regional prevalence of this newly reported disorder remain to be established. In this study, we investigated the frequency of GAA- FGF14 ataxia in a large cohort of Brazilian pat...

Background: Dominantly inherited GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene have recently been shown to cause spinocerebellar ataxia 27B (SCA27B). We aimed to study the frequency and phenotype of SCA27B in a cohort of patients with unsolved late-onset cerebellar ataxia (LOCA). We also assessed the frequency of SCA27B rel...

The cause of downbeat nystagmus (DBN) remains unknown in approximately 30% of patients (idiopathic DBN). Here, we hypothesized that: (i) FGF14 (GAA)≥250 repeat expansions represent a frequent genetic cause of idiopathic DBN syndromes, (ii) are treatable with 4-aminopyridine (4-AP), and (iii) FGF14 (GAA)200-249 alleles are potentially pathogenic. We...

Background: Heterozygous GAA expansions in the FGF14 gene have been related to autosomal dominant cerebellar ataxia (SCA27B-MIM:620174). Whether they represent a common cause of sporadic late-onset cerebellar ataxia (SLOCA) remains to be established. Objectives: To estimate the prevalence, characterize the phenotypic spectrum, identify discrimin...

Background Intronic GAA repeat expansions in the fibroblast growth factor 14 gene ( FGF14 ) have recently been identified as a common cause of ataxia with potential phenotypic overlap with RFC1 -related cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Our objective was to report on the frequency of intronic FGF14 GAA repeat...

Dominantly inherited GAA repeat expansions in FGF14 are a common cause of spinocerebellar ataxia (GAA-FGF14 ataxia; spinocerebellar ataxia 27B). Molecular confirmation of FGF14 GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. We developed and validated...

Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing...

The factors driving initiation of pathological expansion of tandem repeats remain largely unknown. Here, we assessed the FGF14 -SCA27B (GAA)·(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a 5′-flanking 17-bp deletion-insertion in 70.34% of alleles (3,463/4,923). This common sequence variation was present n...

Ataxia due to an autosomal dominant intronic GAA repeat expansion in FGF14 (GAA-FGF14 ataxia, Spinocerebellar ataxia 27B [SCA27B]) has recently been identified as one of the most common genetic late-onset ataxias. We here aimed to characterise its phenotypic profile, natural history progression, and 4-aminopyridine (4-AP) treatment response. We con...

Background Dominantly inherited GAA repeat expansions in FGF14 are a common cause of spinocerebellar ataxia (GAA- FGF14 ataxia; SCA27B, late-onset). Molecular confirmation of FGF14 GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. Methods We developed a...

BACKGROUND The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disea...

Background: Mutations in the slow skeletal muscle troponin T ( TNNT1 ) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic...

Background: Mutations in the slow skeletal muscle troponin T ( TNNT1 ) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic...

Multi-system proteinopathy associated with a VCP G156S mutation in a French Canadian family - David Pellerin, Benjamin Ellezam, Pat Korathanakhun, Mathilde Renaud, Marie-Josée Dicaire, Léo Pilote, Jake P. Levy, Jason Karamchandani, Simon Ducharme, Rami Massie, Bernard Brais

Objective: Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on four French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy. Method...

Background: Mutations of the slow skeletal muscle troponin-T1 (TNNT1) gene are a rare cause of nemaline myopathy. The phenotype is characterized by severe amyotrophy and contractures. Death from respiratory insufficiency occurs in infancy. We report on four French Canadians with a novel congenital TNNT1-related myopathy. Methods: Patients underwent...

Objective: To report on two adult siblings harbouring a novel missense homozygous mutation in the slow skeletal muscle troponin T (TNNT1) gene causing a mild phenotype of nemaline myopathy 5 (NEM5). Background: NEM5 is a rare congenital myopathy most often caused by homozygous nonsense mutations in the TNNT1 gene. The clinical phenotype is one of...

Rheumatoid meningitis is a rare complication of rheumatoid arthritis (RA). It is associated with substantial morbidity and mortality. The condition may present in a variety of ways and is therefore diagnostically challenging. Uncertainty still exists regarding the optimal treatment strategy. Herein, we describe the case of a 74-year-old man with a...

Rheumatoid meningitis is a rare complication of rheumatoid arthritis (RA). It is associated with substantial morbidity and mortality. The condition may present in a variety of ways and is therefore diagnostically challenging. Uncertainty still exists regarding the optimal treatment strategy. Herein, we describe the case of a 74-year-old man with a...

Mycophenolate Mofetil-Induced Status Epilepticus - Volume 45 Issue 5 - David Pellerin, Kelita Singh, Thomas Maniatis, Colin H. Chalk, Laurence Green

Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism spectrum disorders (ASD). Despite a large number of therapeutics developed in past years, there is currently no targeted treatment approved for FXS. In fact, translation of the positive and very promising preclinical findi...

Aim: To establish whether platelets from fragile X syndrome (FXS) individuals recapitulate FXS mouse neurons’ defects in ERK and Akt pathways, and to evaluate the effect of lovastatin on these pathways. Methods: ERK and Akt phosphorylation (pERK, pAkt) statuses were assessed with quantitative Western blotting before and after a 12-week lovastatin t...

Abstract Sample preparation is a crucial step for liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics. Sodium dodecyl sulfate (SDS) is a powerful denaturing detergent that allows for long-term preservation of protein integrity. However, as it inhibits trypsin and interferes with LC-MS/MS analyses, it must be removed from samp...

Fragile X syndrome (FXS) results from dynamic mutations leading ultimately to the absence of expression of the Fragile X Mental Retardation Protein (FMRP). It is characterized by synaptic upregulated protein synthesis and immature dendritic spines associated with altered brain plasticity and cognitive functions. Recent work in Fmr1 knockout mice ha...