Jiri Vajsar

University of Toronto, Toronto, Ontario, Canada

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Publications (57)246.61 Total impact

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    ABSTRACT: Mutations in the fukutin-related protein gene account for a broad spectrum of phenotypes ranging from severe congenital muscular dystrophies to a much milder limb-girdle muscular dystrophy 2I. The involvement of the eyes is variable, with most patients having normal eye examination. We describe eye and brain abnormalities in a 16 month-old-boy with Walker-Warburg syndrome phenotype resulting from a novel fukutin-related protein gene mutation in exon 4 and compare these with other reported patients with fukutin-related protein gene mutation. All patients with reported fukutin-related protein gene mutations who had eye involvement were included. Their clinical features, brain magnetic resonance imaging, and eye findings were compared with our patient. Patients with fukutin-related protein gene mutation tend to have no or mild eye involvement (generally strabismus), with very few cases reported of moderate to severe eye involvement. Our patient with a novel mutation c.558dupC(p.Ala187fs) represents one of the most severe phenotypes described in regard to eye involvement.
    Pediatric Neurology 11/2013; 49(5):374-8. DOI:10.1016/j.pediatrneurol.2013.06.022 · 1.50 Impact Factor
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    ABSTRACT: OBJECTIVE:To evaluate the incidence, clinical features, diagnostic, and treatment trends of pediatric myasthenia in Canada.METHODS:Through established Canadian Pediatric Surveillance Program methodology, physicians were anonymously surveyed for cases of pediatric myasthenia using a standardized clinical questionnaire containing deidentified data. Inclusion criteria were any child <18 years old with ≥1 of the following: (1) fluctuating ptosis or extraocular weakness, (2) skeletal muscle weakness or fatigue, and (3) any of the following supportive tests: clinical response to acetylcholinesterase inhibitor, positive antibodies, abnormal slow repetitive nerve stimulation, or single-fiber electromyography.RESULTS:In 2 years of surveillance, 57 confirmed cases were reported. There were 34 generalized and 18 ocular reports of juvenile myasthenia gravis plus 5 congenital myasthenic syndrome cases. There were 14 incident cases in 2010 and 6 in 2011. Age of onset ranged from "birth" to 17 years for the generalized form compared with 18 months to 11 years for the ocular subtype. Positive acetylcholine receptor titers were found in 22 (67%) of 33 generalized cases and 8 (44%) of 18 ocular patients. Of patients started on pyridostigmine, improvement was noted in 33 (100%) of 33 generalized cases and 15 (88%) of 17 ocular cases.CONCLUSIONS:This study represents the largest descriptive series of pediatric myasthenia in North America and provides valuable information about clinical characteristics. A high index of suspicion is important for this treatable disease. Children generally respond promptly to readily available therapies.
    PEDIATRICS 09/2013; 132(4). DOI:10.1542/peds.2013-0814 · 5.30 Impact Factor
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    ABSTRACT: BACKGROUND: Thymectomy is a well-established treatment for generalized myasthenia gravis in adults, but predictors of long-term efficacy and the optimum timing for intervention in juvenile myasthenia remain controversial. PURPOSE: To review the preoperative presentation, surgical experience, and long-term neuromuscular follow-up in patients undergoing thoracoscopic thymectomy in a single institution. METHODS: A retrospective chart review of all patients undergoing thoracoscopic thymectomy for myasthenia gravis at a tertiary referral center between 2000 and 2010 and compared to an historical cohort of trans-sternal thymectomies performed between 1970 and 1995. Age at diagnosis, presurgical medications and hospitalizations, preoperative chest imaging, presence of acetylcholinesterase antibodies, Osserman Stage, time to operative intervention, length of follow-up, DeFillipi remission scale, as well as operative and post-operative data (length of surgery, blood loss, need for chest tube, length of intubation, length of hospital stay, pathology, and complications) were recorded. RESULTS: Fifteen patients undergoing thoracoscopic thymectomy were identified with a mean age of 11.3 years at time of diagnosis and average treatment duration of 12.5 months prior to operative intervention. Of these patients, most presented with Osserman Stage IIB (8) or III (5) disease. Two patients presented with Osserman Stage IIa disease. There were no reported complications, no conversions to an open approach, and an average length of stay of 2.6 days. Average length of follow-up was 37.5 months, available on 13 of 15 patients. Nine of 13 (69 %) were improved (DeFillippi Class 2 or 3) at 1-month follow-up, however, the pattern of remission waxed and waned, with only 50 % reporting improvement at 1 year, 86 % at 2 years and 75 % at 3 years. Only one patient was totally off medication. No patients required postoperative hospitalization for respiratory crisis. CONCLUSIONS: Thoracoscopic thymectomy offers a safe approach to thymic resection in children with JMG with little associated morbidity and a short hospital stay, but should not be considered curative. Rather it appears to make generalized JMG more amenable to long-term medical management.
    Pediatric Surgery International 02/2013; 29(6). DOI:10.1007/s00383-013-3284-x · 1.06 Impact Factor
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    ABSTRACT: Mutations in the FKRP gene account for a broad spectrum of patients ranging from CMD to a much milder LGMD2I. The involvement of the eyes can be variable with most patients having normal eye examination. We describe eye abnormalities in a child with Walker–Warburg phenotype due to a novel FKRP gene mutation in exon 3 and compare these with other reported cases with FKRP mutation. A boy was born to a G6P3L2 woman from Ghana. The couple was non-consanguineous and a previous pregnancy was interrupted for occipital encephalocele. Antenatal ultrasound showed severe hydrocephalus and delivery was by caesarian section at term. He had hypotonia, bilateral elbow contractures and very limited spontaneous movements. His creatine kinase was 6664 IU/L. Brain MRI showed massive hydrocephalus, diffuse cobblestone lissencephaly, hypomyelination, cerebellar cortical dysplasia, hypoplastic pons and deformed brainstem with fusion of colliculi. Eye examination revealed right micropthalmia, nonreactive pupils, absent red reflex, very deep anterior chamber with retrolental fibrovascular tissue. B scan showed closed funnel and total retinal unattachment. The left eye had shallow anterior chamber, tunica vasculosa lentis and clear lens, persistent vascular membrane, hypoplastic optic nerve, retinal pigmentary epithelium and vitreous hemorrhage. Fluorescein angiography revealed large areas of capillary dropouts and non perfusion ischemic retina. DNA testing showed two mutations in the FKRP gene: Exon 3:c.558dupC (p.Ala187fs) and Exon 3:c.1418T>G (p.Phe473cys).Patients with FKRP gene mutation have no or mild eye involvement (strabismus) with very few cases reported with moderate to severe eye involvement. Our patient represents one of the most severe phenotypes described in regards to eye involvement.
    Neuromuscular Disorders 10/2012; 22(s 9–10):815. DOI:10.1016/j.nmd.2012.06.046 · 3.13 Impact Factor
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    ABSTRACT: Walker–Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of alpha-dystroglycan posttranslational processing abnormalities, which share a defect in laminin binding glycan synthesis. Although six WWS causing genes have been described, only half of all patients can currently be diagnosed genetically. We now report that skin fibroblasts can be utilized to analyze the status of alpha-dystroglycan functional glycosylation, which is lost or reduced in dystroglycanopathy patient cells. To identify and validate the disease causing genes in dystroglycanopathy patients we developed a functional complementation assay based on adenoviral gene transfer into patient fibroblasts. We also examined cell fusion complementation assays using fibroblasts from undiagnosed WWS individuals and identified five novel complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the isoprenoid synthase domain containing (ISPD) gene. Confirmation of the pathogenicity of the identified ISPD mutations was demonstrated by complementation of fibroblasts with wild-type ISPD. Finally, we provide conclusive genetic and biochemical evidence that recessive mutations in ISPD abolish the initial step in laminin binding glycan synthesis by disrupting dystroglycan O-mannosylation. Further studies are needed to determine how defects in ISPD influence protein O-mannosylation, as this is the first WWS gene without proposed glycosyltransferase activity and direct role in α-DG glycosylation. This establishes a novel mechanism for WWS pathophysiology.
    Neuromuscular Disorders 10/2012; 22(9-10):805. DOI:10.1016/j.nmd.2012.06.014 · 3.13 Impact Factor
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    ABSTRACT: Troponins are the biomarkers of choice to diagnose acute cardiac injury. We present two cases of DMD with elevated serum Troponin. Case 1 is a 14 year old non-ambulatory male who presented to the ER with chest pain and diaphoresis. There were q waves in leads II, III and aVF with no ST elevation. Troponin I level was elevated at baseline and at 12 h. He was then transferred to a pediatric hospital. The chest pain resolved at 14 h. An echocardiogram was normal with good biventricuar function. No perfusion mismatch was detected on a lung ventilation perfusion scan. A CT of the coronary arteries was normal. The Troponin T remained elevated at 24 h (0.34 μg/L, N < 0.1) and 36 h (0.13 μg/L). The conclusion was that the chest pain was not cardiac in origin and the elevated troponin was thought to be secondary to DMD. The ECG findings remained unchanged for the past 6 years. Case 2 is a 4 year old boy who presented with abdominal pain and tachycardia (140–160 bpm). The CK was elevated (1068 U/L, N = 75–230 U/L) and Troponin T - high sensitivity was elevated (66 ng/L, N < 14 ng/L). He was diagnosed with ruptured appendicitis and query myocarditis. The Troponin T – high sensitivity continued to be elevated (59–177 ng/L) as was the CK (3824–11,456 U/L) over 1.5 months. He had a normal 24 h Holter monitor. He had 4 echocardiograms during this period showing normal left ventricular function (ejection fraction 68% and fractional shortening 37%). The first echocardiogram revealed a small pericardial effusion that resolved on subsequent echocardiograms. In both cases there were no acute changes noted on cardiac testing despite an elevated Troponin T. The second case may have had myocarditis however, there were no changes on the ECG and typically the elevated troponin will return to normal within a few days. If cardiac injury is suspected, a cardiac MRI could be considered to further evaluate the myocardium for injury.
    Neuromuscular Disorders 10/2012; 22(9-10):884-885. DOI:10.1016/j.nmd.2012.06.270 · 3.13 Impact Factor
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    ABSTRACT: Congenital muscular dystrophies (CMD) with hypoglycosylated α-dystroglycan due to POMT1 mutations are associated with clinical phenotypes that vary in severity. We describe a patient with congenital hypotonia, generalized weakness, elevated creatine kinase (CK), and normal brain imaging. Histochemical analysis of the index case's muscle showed deficiency of glycosylated α-dystroglycan and secondary merosin deficiency. Genetic testing revealed a novel mutation in exon 20 of the POMT1 gene. Our patient's milder form of CMD adds to the emerging evidence of an expanding phenotype caused by POMT1 mutations. The histopathological findings of the muscle biopsy in this case support the need for careful clinical, genetic, and histochemical diagnostic interpretation.
    Muscle & Nerve 05/2012; 45(5):752-5. DOI:10.1002/mus.23274 · 2.31 Impact Factor
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    ABSTRACT: Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy that is accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of diseases associated with abnormal post-translational processing of a-dystroglycan that share a defect in laminin-binding glycan synthesis1. Although mutations in six genes have been identified as causes of WWS, only half of all individuals with the disease can currently be diagnosed on this basis2. A cell fusion complementation assay in fibroblasts from undiagnosed individuals with WWS was used to identify five new complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the ISPD gene (encoding isoprenoid synthase domain containing). The pathogenicity of the identified ISPD mutations was shown by complementation of fibroblasts with wild-type ISPD. Finally, we show that recessive mutations in ISPD abolish the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O-mannosylation. This establishes a new mechanism for WWS pathophysiology.
    Nature Genetics 04/2012; 44(5):575-80. DOI:10.1038/ng.2252 · 29.65 Impact Factor
  • Neuromuscular Disorders 10/2011; 21(s 9–10):643. DOI:10.1016/j.nmd.2011.06.767 · 3.13 Impact Factor
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    ABSTRACT: To determine: (a) prevalence of clinically unsuspected nocturnal hypoventilation (NH) in a clinic population of children with progressive neuromuscular disease; (b) whether NH can be predicted from clinical/laboratory parameters; and (c) change over 1 year in pulmonary function decline, quality of life and attention in children with NH treated with non-invasive positive pressure ventilation (NPPV) compared with children without NH. Prospective cohort study. Two tertiary-care paediatric neuromuscular clinics. 46 children (6-17 years) with progressive neuromuscular disease without neurocognitive impairment or dystrophinopathy. Polysomnography, pulmonary function, manual muscle strength, quality of life (CHQ-PF50) and Conners questionnaires. (a) Prevalence of NH; (b) predictive value of surrogate clinical measures for NH; and (c) differences in change over 1 year in pulmonary function, muscle strength, quality of life and attention between children with and without NH. Prevalence of NH was 14.8%, 95% CI 8.0% to 25.7%. Maximal sensitivity and specificity for NH were achieved with thresholds of forced vital capacity <70% and forced expiratory volume in 1 s <65% predicted (sensitivities: 71.4, 71.4; specificities: 64.1, 79.5). Scoliosis also predicted NH (sensitivity 88.9; specificity 80.4). Over 1 year, those with NH had a greater increase in residual volume/total lung capacity (0.075 (-0.003 to 0.168) vs -0.03 (-0.065 to 0.028)), decline in muscle strength (-0.67 (-0.90 to 0.10) vs 0.53 (-0.05 to 0.90)) and worsened perception of health status. 15% of subjects had clinically unsuspected NH, predicted by moderate pulmonary function test impairment and scoliosis. Over 1 year those with NH had increased gas trapping, decline of muscle strength and worse perception of health status, despite NPPV.
    Archives of Disease in Childhood 12/2010; 95(12):998-1003. DOI:10.1136/adc.2010.182709 · 2.91 Impact Factor
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    ABSTRACT: Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. Advances in many areas of medical technology have not been adopted in clinical practice. The International Standard of Care Committee for Congenital Muscular Dystrophy was established to identify current care issues, review literature for evidence-based practice, and achieve consensus on care recommendations in 7 areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/ nutrition/speech/oral care, cardiology, and palliative care. To achieve consensus on the care recommendations, 2 separate online surveys were conducted to poll opinions from experts in the field and from congenital muscular dystrophy families. The final consensus was achieved in a 3-day workshop conducted in Brussels, Belgium, in November 2009. This consensus statement describes the care recommendations from this committee.
    Journal of child neurology 11/2010; 25(12):1559-81. DOI:10.1177/0883073810381924 · 1.67 Impact Factor
  • Neuromuscular Disorders 08/2010; 20(8):567-567. DOI:10.1016/j.nmd.2010.06.015 · 3.13 Impact Factor
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    Paediatrics & child health 04/2010; 15(4):226. · 1.55 Impact Factor
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    ABSTRACT: Cap myopathy is a congenital myopathy with cap-like structures under the sarcolemma. Mutations in TPM2 and TPM3 genes have been reported in cap myopathy so far. We report a newborn boy with persistent profound weakness who required gastro-jejunal tube feeding, tracheostomy and life-long ventilation until he died at 5 years of age. Muscle biopsy at 5 weeks of age was uninformative. Repeat biopsy at 4.5 years revealed subsarcolemmally located caps that were immunopositive for alpha-actinin, actin and to some extent, desmin. EM confirmed loosely arranged thin filaments and paucity of thick filaments. Molecular analysis of ACTA1 gene identified a novel de novo Met49Val [corrected] mutation. In addition to a new ACTA1 gene mutation, our case emphasizes the genetic heterogeneity of cap myopathy and its association with ACTA1 gene as well as the importance of repeat muscle biopsy in patients with undiagnosed muscle weakness.
    Neuromuscular Disorders 03/2010; 20(4):238-40. DOI:10.1016/j.nmd.2010.01.011 · 3.13 Impact Factor
  • Neuromuscular Disorders 09/2009; 19(8):638-638. DOI:10.1016/j.nmd.2009.06.294 · 3.13 Impact Factor
  • V. A. Harris, B. Alman, J. Vajsar
    Neuromuscular Disorders 10/2008; 18(9):825-825. DOI:10.1016/j.nmd.2008.06.348 · 3.13 Impact Factor
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    ABSTRACT: Walker-Warburg Syndrome (WWS) is an alpha-dystroglycan deficient congenital muscular dystrophy that is associated with brain and eye abnormalities. Patients present with hypotonia, weakness, developmental delay, mental retardation and occasional seizures. Other abnormalities were also described including cleft lip and palate. Mutations in POMT1, POMT2, fukutin, FKRP and LARGE genes are found in 20-30% of children with WWS. We report a novel mutation in POMT1 gene and provide further evidence that WWS with cleft lip and palate is associated with POMT1 mutations. We recommend POMT1 analysis in WWS cases associated with cleft lip and palate when considering which gene to sequence first.
    Neuromuscular Disorders 08/2008; 18(8):675-7. DOI:10.1016/j.nmd.2008.05.014 · 3.13 Impact Factor
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    ABSTRACT: The Western blot technique is currently the standard detection method for suspected limb girdle muscular dystrophy (LGMD) 2A (calpainopathy). This is the first report in the English literature of the successful application of immunohistochemical techniques to support a diagnosis of LGMD 2A. This approach is straightforward and appears to be reasonably specific. We propose that immunohistochemical methods should be re-evaluated for the screening of undiagnosed patients with suspected LGMD 2A.
    Neuropathology 07/2008; 28(3):264-8. DOI:10.1111/j.1440-1789.2007.00871.x · 1.80 Impact Factor
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    ABSTRACT: Mutations in protein-O-mannose-beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) have been found in muscle-eye-brain disease, a congenital muscular dystrophy with structural eye and brain defects and severe mental retardation. To investigate whether mutations in POMGnT1 could be responsible for milder allelic variants of muscular dystrophy. Screening for mutations in POMGnT1. Tertiary neuromuscular unit. A patient with limb-girdle muscular dystrophy phenotype, with onset at 12 years of age, severe myopia, normal intellect, and decreased alpha-dystroglycan immunolabeling in skeletal muscle. A homozygous POMGnT1 missense mutation (c.1666G>A, p.Asp556Asn) was identified. Enzyme studies of the patient's fibroblasts showed an altered kinetic profile, less marked than in patients with muscle-eye-brain disease and in keeping with the relatively mild phenotype in our patient. Our findings widen the spectrum of disorders known to result from mutations in POMGnT1 to include limb-girdle muscular dystrophy with no mental retardation. We propose that this condition be known as LGMD2M. The enzyme assay used to diagnose muscle-eye-brain disease may not detect subtle abnormalities of POMGnT1 function, and additional kinetic studies must be carried out in such cases.
    JAMA Neurology 01/2008; 65(1):137-41. DOI:10.1001/archneurol.2007.2 · 7.01 Impact Factor
  • Neuromuscular Disorders 10/2007; 17(9):775-775. DOI:10.1016/j.nmd.2007.06.050 · 3.13 Impact Factor