A5090151246- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Neurological disorders and treatments
- Parkinson's Disease Mechanisms and Treatments
- Neurological diseases and metabolism
- Central Venous Catheters and Hemodialysis
- Hereditary Neurological Disorders
- Ion channel regulation and function
- Metabolism and Genetic Disorders
- Botulinum Toxin and Related Neurological Disorders
- Genetics and Neurodevelopmental Disorders
- Mechanical Circulatory Support Devices
- Cardiac Arrest and Resuscitation
- Cardiac electrophysiology and arrhythmias
- Nuclear Receptors and Signaling
- Pediatric Pain Management Techniques
- RNA modifications and cancer
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- DNA Repair Mechanisms
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Cancer-related Molecular Pathways
- Genetic factors in colorectal cancer
- Muscle Physiology and Disorders
- Cardiac Structural Anomalies and Repair
University of Iowa Stead Family Children’s Hospital
2013-2024
University of Iowa
2020-2024
University of Iowa Hospitals and Clinics
2023
Tennessee Department of Health
2021
Griffith University
2020
National Hospital for Neurology and Neurosurgery
2005-2018
University College London
2005-2018
Vanderbilt University
2015-2016
Vanderbilt Health
2016
Medical Research Council
2007-2013
Although many recessive loci causing parkinsonism dystonia have been identified, these do not explain all cases of the disorder.We used homozygosity mapping and mutational analysis in three individuals from two unrelated families who presented with adult-onset levodopa-responsive dystonia-parkinsonism, pyramidal signs cognitive/psychiatric features, cerebral cerebellar atrophy on magnetic resonance imaging but absent iron basal ganglia.We identified areas chromosome 22 and, subsequently,...
Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims this study were to determine the frequency in large cohort patients CMT devise guidelines for genetic testing practice.The known cause sequenced 1607 (425 attending an inherited neuropathy clinic 1182 whose DNA was sent authors testing) proportion subtypes UK population.A molecular diagnosis achieved 62.6% clinic; 80.4% CMT1...
We have established that the frequency of LRRK2 mutations in a series 118 cases familial Parkinson's disease is 5.1%. In largest family with autosomal dominant, late-onset where affected subjects share Y1699C missense mutation we provide detailed clinical, pathological and imaging report. The phenotype this large British kindred included asymmetrical, levodopa-responsive parkinsonism unilateral leg tremor at onset foot dystonia were prominent features. There was no significant abnormality...
Charcot-Marie-Tooth disease type 2A (CMT2A), the most common form of CMT2, is caused by mutations in mitofusin 2 gene (MFN2), a nuclear encoded essential for mitochondrial fusion and tethering endoplasmic reticulum to mitochondria. Published CMT2A phenotypes have differed widely severity.To determine prevalence within our clinics we performed genetic testing on 99 patients with CMT2 evaluated at Wayne State University Detroit 27 National Hospital Neurology Neurosurgery London. We then...
Dravet syndrome is an epilepsy of infantile onset, frequently caused by SCN1A mutations or deletions.Its prevalence, long-term evolution in adults and neuropathology are not well known.We identified a series 22 adult patients, including three post-mortem cases with syndrome.For all we reviewed the clinical history, seizure types frequency, antiepileptic drugs, cognitive, social functional outcome results investigations.A systematic study was performed, material from syndrome, comparison...
Several missense mutations of CACNA1S and SCN4A genes occur in hypokalemic periodic paralysis. These affect arginine residues the S4 voltage sensors channel. Approximately 20% cases remain genetically undefined.We undertook direct automated DNA sequencing regions 83 paralysis.We identified reported 64 cases. In remaining 19 cases, or other segments were found 10, including three novel changes first channel domains I (SCN4A) III (CACNA1S).All affected residues, consistent with gating pore...
<h3>Background:</h3> An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is most common cause of dopa-responsive dystonia (DRD). A classic phenotype young-onset lower-limb dystonia, diurnal fluctuations and excellent response to levodopa has been well recognised association with mutations, rare atypical presentations have reported. However, a number clinical issues remain unresolved including phenotypic variability,...
Dystonia type 4 (DYT4) was first described in a large family from Heacham Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and characteristic hobby horse ataxic gait. We carried out genetic linkage analysis the extended DYT4 that spanned 7 generations England Australia, revealing single LOD score peak of 6.33 on chromosome 19p13.12-13. Exome sequencing 2 cousins identified cosegregating mutation (p.R2G) β-tubulin 4a (TUBB4a) gene absent number...
<h3>Objectives:</h3> To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate frequency distribution of mutations associated with these disorders. <h3>Methods:</h3> Analysis demographic, clinical, electrophysiologic, genetic data all patients assessed at our national specialist channelopathy service. Only living in United Kingdom a genetically defined diagnosis nondystrophic myotonia or periodic paralysis were eligible study. Prevalence estimated...
Huntington's disease (HD) classically presents with movement disorder, cognitive dysfunction and behavioral problems but is phenotypically variable. One percent of patients HD-like symptoms lack the causative mutation are considered HD phenocopies. Genetic diseases known to cause phenocopies include syndromes HDL1, HDL2, HDL4 (SCA17). has phenotypic overlap dentatorubral-pallidoluysian atrophy, spinocerebellar ataxias neuroferritinopathy. Identifying genetic basis important for diagnosis may...
Myotonia congenita (MC) is the commonest genetic skeletal muscle ion channelopathy. It caused by mutations in CLCN1 on chromosome 7q35, which alter function of major voltage-gated chloride channel. Dominant and recessive forms disease exist. We have undertaken a clinical, molecular expression study based upon large cohort over 300 UK patients. In an initial 22 families, we sequenced DNA entire coding region identified 11 novel known allowing us to undertake detailed genotype–phenotype...
Acetazolamide has been the most commonly used treatment for hypokalemic periodic paralysis since 1968. However, its mechanism of efficacy is not fully understood, and it known whether therapy response relates to genotype. We undertook a clinical genetic study evaluate rate patients treated with acetazolamide investigate possible correlations between genotype.We identified total 74 genotyped this study. These included who were referred over 15-year period only U.K. referral center or Chinese...
Mutations in CACNA1A, which encodes the principal subunit of P/Q calcium channel, underlie episodic ataxia type 2 (EA2). In addition, some patients with complicated by epilepsy have been shown to harbour CACNA1A mutations, raising possibility that channel dysfunction may be linked human epilepsy. We undertook a review all published EA2 cases and this showed 7% epilepsy--representing sevenfold increased risk compared background population (P<0.001). also studied series 17 individuals...
At least nine dominant neurodegenerative diseases are caused by expansion of CAG repeats in coding regions specific genes that result abnormal elongation polyglutamine (polyQ) tracts the corresponding gene products. When above a threshold is for each disease expanded polyQ promote protein aggregation, misfolding and neuronal cell death. The length tract inversely correlates with age at onset. It has been observed interruption silent (CAA) or missense (CAT) mutations may strongly modulate...
Mutations in mitofusin 2 (MFN2) are the most common cause of axonal Charcot-Marie-Tooth disease (CMT2). Over 50 mutations have been reported, mainly causing autosomal dominant disease, though families with homozygous or compound heterozygous described. We present 3 early-onset CMT2 associated MFN2 mutations. Transcriptional analysis was performed to investigate effects mutations.Patients were examined clinically and electrophysiologically; parents also where available. Genetic investigations...
Abstract Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion with reduced penetrance. The DYT1 gene on chromosome 9q34 responsible for most cases early limb‐onset PTD. Two other PTD loci have been mapped to date. DYT6 locus 8 associated mixed phenotype, whereas the DYT7 18p adult onset focal cervical dystonia. Several families described which linkage known excluded. We identified large...
Abstract The Parkin gene on 6q25.2–27 is responsible for about 50% of autosomal recessive juvenile parkinsonism and less than 20% sporadic early‐onset cases. We recently mapped a novel locus (PARK6) chromosome 1p35–p36 in large family from Sicily. now confirm linkage to PARK6 eight additional families with Parkin‐negative four different European countries. maximum cumulative pairwise LOD score was 5.39 marker D1S478. Multipoint analysis gave the highest 6.29 Haplotype construction...