Jodi Warman Chardon

The Ottawa Hospital · Department of Neurology

Background and Objectives Coenzyme Q10 (CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10 biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A...

An 83-year-old male developed horizontal diplopia immediately following elective transfemoral transcatheter aortic valve implantation (TAVI). On right gaze, left eye adduction was impaired while there was horizontal nystagmus of the abducting right eye, representative of internuclear ophthalmoplegia (INO). The remainder of the neurological examinat...

We examined the utility of clinical and research processes in the reanalysis of publicly‐funded clinical exome sequencing data in Ontario, Canada. In partnership with 8 sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from 7 laboratories was reanalyzed with the referring clinicians. Reanalysis...

Objective: The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement. Methods: Clinical features of 6 patients with SMA-PME were assessed by retrosp...

Oculopharyngeal muscular dystrophy (OPMD) is a genetic muscle disease causing eyelid ptosis, severe swallowing difficulties and progressive limb weakness, although atypical presentations may be difficult to diagnose. Sensitive biomarkers of disease progression in OPMD are needed to enable more effective clinical trials. This study was designed to t...

Background Myotonic dystrophy type 1 (DM1) is a hereditary muscular dystrophy affecting ∼2.1–14.3/100,000 adults. Cardiac manifestations of DM1 include conduction disorders and rarely cardiomyopathies. DM1 increases the risk of obstetric complications, however, little is known about the relationship between pregnancy and cardiomyopathy in DM1 due t...

Introduction Laryngospasm is an involuntary sustained closure of sphincter musculature that leads to an unpleasant subjective experience of dyspnea and choking. It is an underreported symptom in amyotrophic lateral sclerosis (ALS). This study aimed to better characterize the prevalence and clinical characteristics of laryngospasm in ALS patients....

Myasthenia gravis is a treatable autoimmune disease caused by autoantibodies directed against membrane proteins at the neuromuscular junction. While acetylcholine receptor antibodies are most common, a minority of patients have antibodies directed against muscle-specific kinase (MuSK-antibody). Differentiating features often include subacute onset...

Background and Purpose Elevation of total protein level in cerebrospinal fluid (CSF-TP) in diabetic patients is often disregarded by clinicians. However, existing studies on the topic have significant limitations, and therefore we aimed to explore the relationship between diabetes and CSF-TP in a large database of CSF samples. Methods Retrospectiv...

Background Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) refractory to conventional therapy can lead to marked disability and represents a therapeutic challenge. Objective To report five cases of treatment-refractory disabling CIDP treated with autologous hematopoietic stem cell transplantation (AHSCT). Methods This was a retro...

Introduction A distal‐predominant demyelinating symmetric pattern is most frequent in patients with neuropathy associated with anti‐myelin‐associated glycoprotein (MAG) antibodies. The literature however lacks longitudinal data to describe whether this is consistent over time. Methods From the Ottawa Neuromuscular Center database, we identified 23...

[This corrects the article DOI: 10.1371/journal.pone.0231502.].

Advances in DNA sequencing technologies have resulted in a near doubling, in under 10 years, of the number of causal genes identified for inherited neuromuscular disorders. However, around half of patients, whether children or adults, do not receive a molecular diagnosis after initial diagnostic workup. Massively parallel technologies targeting RNA...

Purpose To assess whether there is a measurable impairment of median nerve conduction study parameters with uncomplicated distal radius fracture. Methods Patients were assessed prospectively at the time of cast removal (visit 1) after a standard 6–8 week immobilization for uncomplicated distal radius fracture. Patients with prior entrapment neurop...

A 76-year-old man with a 5-year history of gait difficulties was suspected to have length-dependent sensorimotor polyneuropathy. Electrodiagnostic results pointed to a foot drop of neurogenic etiology, except for the prominence of myotonic discharges on needle EMG. Tests for acquired and genetic causes of polyneuropathy were unrevealing. The patien...

The discriminative value of CSF total protein (CSF-TP) in subtypes of Guillain–Barré syndrome has not been well documented in North-American patients. We reviewed 173 cases from a single institution, comprising the following clinical categories of neuropathy: 134 Sensorimotor (SM) GBS, 13 Motor (M) GBS, 8 Localized (L) GBS, and 18 Miller Fisher syn...

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...

Monomelic pure motor amyotrophy may seem to be an ominous syndrome as it leads to consideration of motor neuron disease. We present a series of 3 very similar cases where unilateral pure distal lower motor neuron paresis and atrophy was limited to the C8-T1 myotomes, without long-tract signs. Electrodiagnostic studies were in keeping with a restric...

Background: Neurolymphomatosis (NL) is a direct process of invasion of peripheral nerves by lymphoma. It occurs in roughly 5% of patients with lymphoma and represents a particularly difficult diagnostic dilemma when it is the presenting focal manifestation of occult lymphoma. Case presentation: We present 3 examples of invasion of the lumbosacra...

Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure change...

Polyneuropathies are amongst the most common neurological conditions worldwide affecting over 20 million people. However, 40% of patients with primary polyneuropathies have no disease-causing mutation identified. We investigated patients with gene-negative primary polyneuropathies using a combination of whole genome sequencing, homozygosity mapping...

Introduction: Disuse atrophy from immobilization is the result of decreased neural activity and muscle unloading. Methods: We studied the impact of disuse on hand intrinsic compound muscle action potentials (CMAP) in a cohort of 39 patients with unilateral 6-week immobilization of the hand in a cast, after distal radius fracture. We excluded pat...

Whole-body magnetic resonance imaging has emerged as a useful imaging tool in diagnosing and characterizing the progression of myopathies and muscular dystrophies. Whole-body MRI indications and diagnostic efficacy are becoming better defined with the increasing number of cases, publications and discussions within multidisciplinary working groups....

Objective: We conducted a retrospective review of patients with a diagnosis of Guillain-Barré syndrome (GBS) to assess the diagnostic impact of applying age-adjusted upper limits for CSF total protein (CSF-TP) supported by a systematic literature review. Methods: Cases coded as GBS or inflammatory neuropathy for the period 2001-2016 at The Ottaw...

Objective: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse...

Objective To identify disease‐causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods We performed genome‐wide sequencing, homozygosity mapping, and segregation analysis for novel disease‐causing gene discovery. We used circular dichroism to show secondary structure changes...

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 identify disease‐causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods We performed genome‐wide sequencing, homozygosity mapping and segregation analysis for novel disease‐causing gene discovery. We used circular dichroism to show secondary structure changes...

LGMD1D is an autosomal dominant limb girdle muscular dystrophy caused by variants in the DNAJB6 gene. This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement; however phenotypic variability is often observed with some individuals having earlier onset and mo...

Background: The antiquated standard reference range of 0.15-0.45 g/L for cerebrospinal fluid total protein (CSF-TP) is well entrenched in medical literature and laboratory operating procedures across the world. Methods: We conducted a web-based survey with a response rate of 34.9% through the listserv of the Canadian Neurological Sciences Federa...

This article reports data pertaining to a worldwide web-based survey referenced in the publication “Adult CSF Total Protein: Higher upper reference limits should be considered worldwide ” (P.R. Bourque, et al., 2019). This survey was distributed to corresponding authors of the journal Neurology and the Journal of neurological sciences for the perio...

Erythrokeratodermia (EK) is a rare skin disorder, likely genetic and usually present from infancy.¹ There is patchy symmetrical involvement over the body surface, manifested in progressive figurate plaques of hyperkeratosis and more transient areas of erythema. There is significant overlap in the clinical and genetic features of the "variabilis" an...

Intraneural Ganglion Cysts of the Fibular Nerve: A Cause of Fluctuating Painful Foot Drop - Pierre R. Bourque, Kirsty U. Boyd, Gerard H. Jansen, Jodi Warman-Chardon, Jocelyn Zwicker, Elizabeth B. Pringle, Kawan Rakhra, Ari Breiner

Purpose: To examine the impact of a targeted exome approach for the molecular diagnosis of patients nationwide with a wide range of ataxia-related phenotypes. Methods: One hundred and seventy patients with ataxia of unknown etiology referred from clinics throughout the United States and Canada were studied using a targeted exome approach. Patien...

Background: Neurolymphomatosis is a process of neoplastic endoneurial invasion, most strongly associated with non-Hodgkin's lymphoma. It must be distinguished from paraneoplastic, metabolic, nutritional and treatment-related causes of neuropathy that are common in this patient population. Methods: This brief case series illustrates the protean m...

Spinal muscular atrophy (SMA) is caused by homozygous mutation of the survival motor neuron 1 (SMN1) gene. Disease severity inversely correlates to the amount of SMN protein produced from the homologous SMN2 gene. We show that SMN protein is naturally released in exosomes from all cell types examined. Fibroblasts from patients or a mouse model of S...

The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes kn...

Muscle magnetic resonance imaging (MRI) and ultrasound (US) are emerging tools to assist in the diagnosis of children with genetic muscle disease. Increasing number of studies demonstrate that these imaging techniques can identify selective patterns of muscle atrophy, fatty degeneration, and muscle edema that help to distinguish between different e...

At least 15% of disease-causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in non-coding regions. Whole transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease...

We report on a 45 year-old man with rapidly progressive cardiac amyloidosis, requiring heart transplantation within two years of symptomatic onset. Hematologic testing and initial tissue biopsies confirmed amyloid infiltration but were inconclusive for the amyloidogenic protein source. Mass spectroscopy and transthyretin (TTR) sequencing were requi...

Objective: To describe the clinical, genetic, and epidemiologic features of hereditary spastic paraplegia (HSP) in Canada and to determine which clinical, radiologic, and genetic factors determine functional outcomes for patients with HSP. Methods: We conducted a multicenter observational study of patients who met clinical criteria for the diagnos...

Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- moto...

Objective: Autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) is an emerging syndrome caused by mutations in the C-terminus end of the TS domain of the DNMT1 gene. ADCA-DN is also associated with sensorimotor polyneuropathy, extrapyramidal, and dysautonomic signs, as well as dementia. Little has been reported about the pro...

Perineural invasion is a targeted cellular proliferation guided by neurotrophins, rather than a simple diffusion of tumor in a path of least resistance. Invasion of cranial nerves by squamous cell carcinoma can represent an important diagnostic dilemma. It commonly presents as a distinct clinical neurological syndrome of combined isolated trigemina...

BackgroundDNA methylation is an essential epigenetic mark, controlled by DNA methyltransferase (DNMT) proteins, which regulates chromatin structure and gene expression throughout the genome. In this study, we describe a family with adult-onset autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) caused by mutations in the mai...

Report on the 3rd Ottawa International Conference on Neuromuscular Biology, Disease and Therapy – September 24–26, 2015, Ottawa, Canada The second session devoted to basic NMD research focused on muscle stem cells, and was moderated by Dr. Alexander Blais (uOttawa, CAN). Dr. Emanuela Gussoni (Boston Children’s Hospital/Harvard Medical School, USA)...

Background: Immunoglobulin therapy has become a major treatment option in several autoimmune neuromuscular disorders. For patients with Myasthenia Gravis (MG), intravenous immunoglobulin (IVIg) has been used for both crisis and chronic management. Subcutaneous Immunoglobulins (SCIg), which offer the advantage of home administration, may be a pract...

Painless enlargement of the neck is most often due to adiposity, goiter, or lymphadenopathy. The figure, A, demonstrates how diffuse hypertrophy of cervical spinal nerves and trunks can also produce a clinically obvious increase in neck circumference.

Introduction: The clinical characteristics of unilateral hypoglossal neuropathy have not been systematically analyzed. Methods: We documented subjective abnormalities of speech and swallowing, and photographed 9 specific tongue movements and positions. Objective deficits were scored independently by 2 examiners. Results: Eight patients were an...

Objective. The ability to correctly identify chronic demyelinating neuropathy can have important therapeutic and prognostic significance. The stimulus intensity value required to obtain a supramaximal compound muscle action potential amplitude is a commonly acquired data point that has not been formally assessed as a diagnostic tool in routine nerv...

In 1987 Fitzsimmons and Guilbert described identical male twins with progressive spastic paraplegia, brachydactyly with cone shaped epiphyses, short stature, dysarthria, and "low-normal" intelligence. In subsequent years, four other patients, including one set of female identical twins, a single female child, and a single male individual were descr...

This case report describes possible stabilization of liver transplant–acquired amyloid neuropathy with diflunisal.The transmission of systemic transthyretin amyloidosis through domino liver transplantation, using a donor liver graft from a patient with familial amyloid neuropathy (FAP), was first described in 2005.1 This complication had not been e...

Neurological disorders secondary to single gene mutations are an extremely heterogeneous group of diseases, individually rare, and often associated with progressive and severe disability. Given the degree of both clinical and genetic heterogeneity, next-generation sequencing (NGS) has become an important diagnostic tool. Multi-gene panel testing ba...

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), is identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is likely influenced by when in the diagnostic process WES is used. The Finding Of R...

Peripheral nervous system axons and myelin have unique potential protein, proteolipid, and ganglioside antigenic determinants. Despite the existence of a blood–nerve barrier, both humoral and cellular immunity can be directed against peripheral axons and myelin. Molecular mimicry may be triggered at the systemic level, as was best demonstrated in t...

Limb Girdle Muscular Dystrophy (LGMD) is a heterogeneous group of genetic disorders leading to progressive muscle degeneration and often associated with cardiac complications. We present two adult siblings with childhood-onset of weakness progressing to a severe quadriparesis with the additional features of triangular tongues and biventricular card...

OBJECTIVE: Present a case of spinocerebellar ataxia 28 (SCA28) secondary to de novo deletion of AFG3L2.BACKGROUND: SCA28 is one of the less common autosomal dominant progressive spinocerebellar ataxias. The clinical phenotype is juvenile-onset, slowly progressive ataxia with associated ophthalmoplegia and gaze-evoked nystagmus. The causative gene i...

Whole-exome sequencing (WES) has transformed our ability to detect mutations causing rare diseases. FORGE (Finding Of Rare disease GEnes) and Care4Rare Canada are nation-wide projects focused on identifying disease genes using WES and translating this technology to patient care. Rare forms of epilepsy are well-suited for WES and we retrospectively...

OBJECTIVE: Present a case of spinocerebellar ataxia 28 (SCA28) secondary to de novo deletion of AFG3L2. BACKGROUND: SCA28 is one of the less common autosomal dominant progressive spinocerebellar ataxias. The clinical phenotype is juvenile-onset, slowly progressive ataxia with associated ophthalmoplegia and gaze-evoked nystagmus. The causative gene...

Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease...

Despite remarkable advances in genetic testing, many adults with syndromic epilepsy remain without a molecular diagnosis. The challenge in providing genetic testing for this patient population lies in the extensive genetic heterogeneity associated with epilepsy. Even for the subset of epilepsy patients that present with a defining feature, such as...

Table S1. Molecular Genetic Testing Prior to Exome Sequencing for Selected Projects*

In the past few years, the increasing accessibility of next-generation sequencing technology has translated to a number of significant advances in our understanding of brain malformations. Genes causing brain malformations, previously intractable due to their complex presentation, rarity, sporadic occurrence, or molecular mechanism, are being ident...