Publications by authors named "Mary B Davis"

21 Publications

  • Page 1 of 1

Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17.

Front Cell Neurosci 2018 23;12:429. Epub 2018 Nov 23.

Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom.

Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington's disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0.38%). Phenotype-genotype correlation was performed on 30 individuals and the repeat structure of their genes was examined. We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset. We were unable to identify any particular phenotypic trait that segregated with particular CAG/CAA repeat tract structures or repeat lengths. One individual within the cohort was homozygous for variable penetrance range SCA17 alleles. This patient had a similar age at onset to heterozygotes with the same repeat sizes, but also presented with a rapidly progressive dementia. A pair of monozygotic twins within the cohort presented 3 years apart with the sibling with the earlier onset having a more severe phenotype with dementia and chorea in addition to the ataxia observed in their twin. This appears to be a case of variable expressivity, possibly influenced by other environmental or epigenetic factors. Finally, there was an asymptomatic father with a severely affected child with an age at onset in their twenties. Despite this, they share the same expanded allele repeat sizes and sequences, which would suggest that there is marked difference in the penetrance of this 51-repeat allele. We therefore propose that the variable penetrance range extend from 48 repeats to incorporate this allele. This study shows that there is variability in the presentation and penetrance of the SCA17 phenotype and highlights the complexity of this disorder.
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http://dx.doi.org/10.3389/fncel.2018.00429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265347PMC
November 2018

PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption.

Front Cell Neurosci 2018 31;12:200. Epub 2018 Jul 31.

Ataxia Centre, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine tract within the gene. Normal alleles have been reported to range from 6 to 35 repeats, intermediate alleles from 36 to 38 repeats and fully penetrant pathogenic alleles have at least 39 repeats. This distribution was based on relatively few samples and the narrow intermediate range makes the accuracy of the repeat sizing crucial for interpreting and reporting diagnostic tests, which can vary between laboratories. Here, we examine the distribution of 6378 SCA1 chromosomes and identify a very late onset SCA1 family with a fully penetrant uninterrupted pathogenic allele containing 38 repeats. This finding supports the theory that polyQ toxicity is related to the increase of the length of the inherited tracts and not as previously hypothesized to the structural transition occurring above a specific threshold. In addition, the threshold of toxicity shifts to a shorter polyQ length with the increase of the lifespan in SCA1. Furthermore, we show that SCA1 intermediate alleles have a different behavior compared to the other polyglutamine disorders as they do not show reduced penetrance when uninterrupted. Therefore, the pathogenic mechanism in SCA1 is distinct from other cytosine-adenine-guanine (CAG) repeat disorders. Accurately sizing repeats is paramount in precision medicine and can be challenging particularly with borderline alleles. We examined plasmids containing cloned CAG repeat tracts alongside a triplet repeat primed polymerase chain reaction (TP PCR) CAG repeat ladder to improve accuracy in repeat sizing by fragment analysis. This method accurately sizes the repeats irrespective of repeat composition or length. We also improved the model for calculating repeat length from fragment analysis sizing by fragment analyzing 100 cloned repeats of known size. Therefore, we recommend these methods for accurately sizing repeat lengths and restriction enzyme digestion to identify interruptions for interpretation of a given allele's pathogenicity.
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http://dx.doi.org/10.3389/fncel.2018.00200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080413PMC
July 2018

The role of interruptions in polyQ in the pathology of SCA1.

PLoS Genet 2013 25;9(7):e1003648. Epub 2013 Jul 25.

MRC NIMR, London, United Kingdom.

At least nine dominant neurodegenerative diseases are caused by expansion of CAG repeats in coding regions of specific genes that result in abnormal elongation of polyglutamine (polyQ) tracts in the corresponding gene products. When above a threshold that is specific for each disease the expanded polyQ repeats promote protein aggregation, misfolding and neuronal cell death. The length of the polyQ tract inversely correlates with the age at disease onset. It has been observed that interruption of the CAG tract by silent (CAA) or missense (CAT) mutations may strongly modulate the effect of the expansion and delay the onset age. We have carried out an extensive study in which we have complemented DNA sequence determination with cellular and biophysical models. By sequencing cloned normal and expanded SCA1 alleles taken from our cohort of ataxia patients we have determined sequence variations not detected by allele sizing and observed for the first time that repeat instability can occur even in the presence of CAG interruptions. We show that histidine interrupted pathogenic alleles occur with relatively high frequency (11%) and that the age at onset inversely correlates linearly with the longer uninterrupted CAG stretch. This could be reproduced in a cellular model to support the hypothesis of a linear behaviour of polyQ. We clarified by in vitro studies the mechanism by which polyQ interruption slows down aggregation. Our study contributes to the understanding of the role of polyQ interruption in the SCA1 phenotype with regards to age at disease onset, prognosis and transmission.
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http://dx.doi.org/10.1371/journal.pgen.1003648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723530PMC
January 2014

Prevalence study of genetically defined skeletal muscle channelopathies in England.

Neurology 2013 Apr 20;80(16):1472-5. Epub 2013 Mar 20.

Medical Research Council Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery and University College London Institute of Neurology, Queen Square, London, UK.

Objectives: To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders.

Methods: Analysis of demographic, clinical, electrophysiologic, and genetic data of all patients assessed at our national specialist channelopathy service. Only patients living in the United Kingdom with a genetically defined diagnosis of nondystrophic myotonia or periodic paralysis were eligible for the study. Prevalence rates were estimated for England, December 2011.

Results: A total of 665 patients fulfilled the inclusion criteria, of which 593 were living in England, giving a minimum point prevalence of 1.12/100,000 (95% confidence interval [CI] 1.03-1.21). Disease-specific prevalence figures were as follows: myotonia congenita 0.52/100,000 (95% CI 0.46-0.59), paramyotonia congenita 0.17/100,000 (95% CI 0.13-0.20), sodium channel myotonias 0.06/100,000 (95% CI 0.04-0.08), hyperkalemic periodic paralysis 0.17/100,000 (95% CI 0.13-0.20), hypokalemic periodic paralysis 0.13/100,000 (95% CI 0.10-0.17), and Andersen-Tawil syndrome (ATS) 0.08/100,000 (95% CI 0.05-0.10). In the whole sample (665 patients), 15 out of 104 different CLCN1 mutations accounted for 60% of all patients with myotonia congenita, 11 out of 22 SCN4A mutations for 86% of paramyotonia congenita/sodium channel myotonia pedigrees, and 3 out of 17 KCNJ2 mutations for 42% of ATS pedigrees.

Conclusion: We describe for the first time the overall prevalence of genetically defined skeletal muscle channelopathies in England. Despite the large variety of mutations observed in patients with nondystrophic myotonia and ATS, a limited number accounted for a large proportion of cases.
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http://dx.doi.org/10.1212/WNL.0b013e31828cf8d0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662361PMC
April 2013

Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology.

Brain 2011 Oct 29;134(Pt 10):2982-3010. Epub 2011 Jun 29.

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, UCL, Queen Square, London WC1N 3BG, UK.

Dravet syndrome is an epilepsy syndrome 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 of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20-66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy.
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http://dx.doi.org/10.1093/brain/awr129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187538PMC
October 2011

An intragenic duplication in guanosine triphosphate cyclohydrolase-1 gene in a dopa-responsive dystonia family.

Mov Disord 2011 Apr 1;26(5):905-9. Epub 2011 Feb 1.

Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, London, United Kingdom.

Background: Autosomal dominant dopa-responsive dystonia is commonly caused by mutations in the guanosine triphosphate cyclohydrolase-1 gene.

Methods: We report a British family that has been followed for more than 20 years in which no mutations were previously identified.

Results: Reanalysis of this pedigree detected a duplication of guanosine triphosphate cyclohydrolase-1 exon 2 in affected family members. mRNA analysis showed a mutant transcript with a tandem exon 2 duplication. Four family members developed dopa-responsive dystonia, with onset in their late teens, and subsequently developed restless leg syndrome and migraine.

Conclusions: This is the first report of an intragenic guanosine triphosphate cyclohydrolase-1 duplication in a dopa-responsive dystonia family.
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http://dx.doi.org/10.1002/mds.23593DOI Listing
April 2011

Endothelial, sympathetic, and cardiac function in inherited (6R)-L-erythro-5,6,7,8-tetrahydro-L-biopterin deficiency.

Circ Cardiovasc Genet 2010 Dec 11;3(6):513-22. Epub 2010 Oct 11.

Centre for Clinical Pharmacology, University College London, 5 University St., London, UK.

Background: (6R)-5,6,7,8-Tetrahydro-l-biopterin (BH4) is a cofactor for enzymes involved in catecholamine and nitric oxide generation whose synthesis is initiated by GTP cyclohydrolase I (GTPCH-1), encoded by GCH1. In the absence of a potent, specific GTPCH-1 inhibitor, natural BH4 deficiency caused by mutations in GCH1 in the rare movement disorder, DOPA-responsive dystonia (OMIM DYT5), offers the opportunity to study the role of endogenous BH4 in humans.

Methods And Results: In 16 DOPA-responsive dystonia patients with mutations predicted to affect GTPCH-1 expression or function and in age- and sex-matched control subjects, we measured plasma biopterin and nitrogen oxides by high-performance liquid chromatography and the Griess reaction, respectively, endothelial function by brachial artery flow-mediated dilation (FMD), sympathetic function by measurement of plasma norepinephrine, epinephrine, and heart rate and blood pressure in response. Cardiac function and structure were assessed by echocardiography. Plasma biopterin was lower in patients (5.76±0.53 versus 8.43±0.85 nmol/L, P=0.03), but plasma NO(2)(-)/NO(3)(-) (NOx) (median, 9.06 [interquartile range, 5.35 to 11.04] versus 8.40 [interquartile range, 5.28 to 11.44] μmol/L, P=1) and FMD were not lower (7.7±0.8% versus 7.9±0.9%, P=0.91). In patients but not control subjects, FMD was insensitive to nitric oxide synthase inhibition (FMD at baseline, 6.7±2.1%; FMD during l-NMMA infusion, 6.2±2.5, P=0.68). The heart rate at rest was higher in patients, but the heart rate and blood pressure response to sympathetic stimulation did not differ in patients and control subjects despite lower concentrations of norepinepherine (264±8 pg/mL versus 226±9 pg/mL, P=0.006) and epinephrine (33.8±5.2 pg/mL versus 17.8±4.6 pg/mL, P=0.03) in patients. There was also no difference in cardiac function and structure.

Conclusions: Sympathetic, cardiac, and endothelial functions are preserved in patients with GCH1 mutations despite a neurological phenotype, reduced plasma biopterin, and norepinepherine and epinephrine concentrations. Lifelong endogenous BH4 deficiency may elicit developmental adaptation through mechanisms that are inaccessible during acquired BH4 deficiency in adulthood.
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http://dx.doi.org/10.1161/CIRCGENETICS.110.957605DOI Listing
December 2010

An ITPR1 gene deletion causes spinocerebellar ataxia 15/16: a genetic, clinical and radiological description.

Mov Disord 2010 Oct;25(13):2176-82

Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, London, UK.

The purpose of this study was to characterise a novel family with very slowly progressive pure spinocerebellar ataxia (SCA) caused by a deletion in the inositol 1,4,5-triphosphate receptor 1 (ITPR1) gene on chromosome 3. This is a detailed clinical, genetic, and radiological description of the genotype. Deletions in ITPR1 have been shown to cause SCA15/SCA16 in six families to date. A further Japanese family has been identified with an ITPR1 point mutation. The exact prevalence is as yet unknown, but is probably higher than previously thought. The clinical phenotype of the family is described, and videotaped clinical examinations are presented. Serial brain magnetic resonance imaging studies were carried out on one affected individual, and genetic analysis was performed on several family members. Protein analysis confirmed the ITPR1 deletion. Affected subjects display a remarkably slow, almost pure cerebellar syndrome. Serial magnetic resonance imaging shows moderate cerebellar atrophy with mild inferior parietal and temporal cortical volume loss. Genetic analysis shows a deletion of 346,487 bp in ITPR1 (the second largest ITPR1 deletion reported to date), suggesting SCA15 is due to a loss of ITPR1 function. Western blotting of lymphoblastoid cell line protein confirms reduced ITPR1 protein levels. SCA15 is a slowly or nonprogressive pure cerebellar ataxia, which appears to be caused by a loss of ITPR1 function and a reduction in the translated protein. Patients with nonprogressive or slowly progressive ataxia should be screened for ITPR1 defects.
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http://dx.doi.org/10.1002/mds.23223DOI Listing
October 2010

Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy.

J Physiol 2010 Jun 15;588(Pt 11):1905-13. Epub 2010 Feb 15.

MRC Centre for Neuromuscular Diseases, Department of Molecular Neuroscience, University College London, Institute of Neurology, London WC1N 3BG, UK.

Mutations in CACNA1A, which encodes the principal subunit of the P/Q calcium channel, underlie episodic ataxia type 2 (EA2). In addition, some patients with episodic ataxia complicated by epilepsy have been shown to harbour CACNA1A mutations, raising the possibility that P/Q channel dysfunction may be linked to human epilepsy. We undertook a review of all published CACNA1A EA2 cases and this showed that 7% have epilepsy--representing a sevenfold increased epilepsy risk compared to the background population risk (P<0.001). We also studied a series of 17 individuals with episodic ataxia accompanied by epilepsy and/or clearly epileptiform electroencephalograms (EEGs). We screened the entire coding region of CACNA1A for point mutations and rearrangements to determine if genetic variation in the gene is associated with the epilepsy phenotype, and measured the functional impact of all missense variations on heterologously expressed P/Q channels. We identified two large scale deletions and two new missense mutations in CACNA1A. When expressed, L621R had little detectable effect on P/Q channel function, while the other missense change, G540R, caused an approximately 30% reduction in current density. In nine patients we also identified the previously reported non-synonymous coding variants (E921D and E993V) which also resulted in impairment of P/Q channel function. Taken together, 12 of the 17 patients have genetic changes which decrease P/Q channel function. We conclude that variants in the coding region of CACNA1A that confer a loss of P/Q-type channel function are associated with episodic ataxia and epilepsy. Our data suggest that functional stratification of all variants, including common polymorphisms, rare variants and novel mutations, may provide new insights into the mechanisms of channelopathies.
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http://dx.doi.org/10.1113/jphysiol.2009.186437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901979PMC
June 2010

Macular dystrophy associated with the A3243G mitochondrial DNA mutation. Distinct retinal and associated features, disease variability, and characterization of asymptomatic family members.

Arch Ophthalmol 2008 Mar;126(3):320-8

Moorfields Eye Hospital, London, England.

Objectives: To determine (1) detailed retinal and audiological features of probands harboring the A3243G mitochondrial DNA mutation (m.3243A>G) and their asymptomatic maternal relatives, (2) intrafamilial and interfamilial phenotypic variability, and (3) the presence of other systemic features.

Methods: Seven probands harboring the A3243G mitochondrial DNA mutation and 36 asymptomatic maternal relatives were ascertained. Participants underwent ophthalmologic examination, fundus photography, autofluorescence imaging, and audiological evaluation and completed a questionnaire. Blood samples were taken to test for diabetes, determine renal function, and screen relatives for the A3243G mutation.

Results: The A3243G mutation was associated with both intrafamilial and interfamilial variable expressivity regarding retinal appearance, hearing loss, diabetes, and other systemic features. The most common macular appearance in maternal relatives (one-third of those positive for the mutation) was mild abnormalities of the retinal pigment epithelium (more clearly identified using autofluorescence), which may therefore be a useful clinical indicator suggesting positive mutation status. Four probands and 13 mutation-positive relatives were found to have evidence of significant bilateral, cochlear, symmetrical age-adjusted hearing loss, predominantly affecting high frequencies.

Conclusions: Hearing loss and macular disturbance were the most frequent findings in mutation-positive participants, with 95% of mutation-positive relatives having hearing loss. Diabetes was the least frequent finding. Patients with progressive hearing loss may merit ophthalmologic assessment to detect retinal abnormalities consistent with the A3243G mutation. Conversely, patients with macular features in keeping with the A3243G mutation should have audiological testing, even in the absence of diabetes or a positive family history.
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http://dx.doi.org/10.1001/archopht.126.3.320DOI Listing
March 2008

Huntington's disease phenocopies are clinically and genetically heterogeneous.

Mov Disord 2008 Apr;23(5):716-20

Department of Neurodegenerative Disease, UCL Institute of Neurology/National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom.

Huntington's disease (HD) classically presents with movement disorder, cognitive dysfunction and behavioral problems but is phenotypically variable. One percent of patients with HD-like symptoms lack the causative mutation and are considered HD phenocopies. Genetic diseases known to cause HD phenocopies include HD-like syndromes HDL1, HDL2, and HDL4 (SCA17). HD has phenotypic overlap with dentatorubral-pallidoluysian atrophy, the spinocerebellar ataxias and neuroferritinopathy. Identifying the genetic basis of HD phenocopies is important for diagnosis and may inform the search for HD genetic modifiers. We sought to identify neurogenetic diagnoses in the largest reported cohort of HD phenocopy patients. Two hundred eighty-five patients with syndromes consistent with HD, who were HD expansion-negative, were screened for mutations in PRNP, JPH3, TBP, DRPLA, SCA1, SCA2, SCA3, FTL and FRDA. Genetic diagnoses were made in 8 subjects: we identified 5 cases of HDL4, 1 of HDL1 and 1 of HDL2. One patient had Friedreich's ataxia. There were no cases of DRPLA, SCA1, SCA2, SCA3, or neuroferritinopathy. HD phenocopies are clinically and genetically diverse and a definitive genetic diagnosis is currently possible in only a minority of cases. When undertaken, it should be clinically directed and patients and clinicians should be prepared for the low probability of reaching a genetic diagnosis in this group of patients.
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http://dx.doi.org/10.1002/mds.21915DOI Listing
April 2008

Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11.

Nat Genet 2007 Dec 25;39(12):1434-6. Epub 2007 Nov 25.

Department of Molecular Neuroscience, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.

The microtubule-associated protein tau (encoded by MAPT) and several tau kinases have been implicated in neurodegeneration, but only MAPT has a proven role in disease. We identified mutations in the gene encoding tau tubulin kinase 2 (TTBK2) as the cause of spinocerebellar ataxia type 11. Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration.
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http://dx.doi.org/10.1038/ng.2007.43DOI Listing
December 2007

Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia.

Muscle Nerve 2006 Dec;34(6):731-9

Department of Neurology, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes, 3900 Ribeirão Preto, São Paulo, 14049-900, Brazil.

The phenotype of 16 members of a family affected by a late-onset, dominant, progressive, motor and autonomic disorder is described. The VAPB (Pro56Ser) mutation was detected in Brazilian families with different phenotypes of motor neuron disorders. In this family, proximal and axial muscle weakness and atrophy, associated with abdominal protrusion, defined the motor phenotype. Death occurred in 10-15 years due to respiratory insufficiency. Tone and tendon reflexes were decreased and a distal tremor was common. Sensation was preserved. Autonomic abnormalities were also present, including choking, chronic intestinal constipation, sexual dysfunction, and sudomotor abnormalities, and on nerve morphology there was involvement of unmyelinated fibers. Electromyography disclosed ongoing denervation and reinnervation. Isolated dysfunction of motor and autonomic neurons is unusual among the spinal muscular atrophies. On this basis, this condition seems to represent a new category of disease.
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http://dx.doi.org/10.1002/mus.20657DOI Listing
December 2006

Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data.

Brain 2005 Dec 4;128(Pt 12):2786-96. Epub 2005 Nov 4.

Department of Molecular Neuroscience, Institute of Neurology, London, UK.

We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awh667DOI Listing
December 2005

Spinocerebellar ataxia type 17: extension of phenotype with putaminal rim hyperintensity on magnetic resonance imaging.

Mov Disord 2005 Nov;20(11):1521-3

National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom.

We report on a 50-year-old woman who presented with an 8-year history of involuntary movements, unsteadiness, and cognitive decline. Examination revealed multidomain cognitive deficits, jerky ocular pursuit movements, hypometric saccades, gaze impersistence, dysarthria, upper limb dystonia, and widespread chorea. TATA-binding protein gene test revealed trinucleotide expansion allele sizes of 47 and 39 repeats, confirming the diagnosis of spinocerebellar ataxia type 17 (SCA-17). Magnetic resonance imaging (MRI) showed marked cerebellar atrophy and putaminal rim hyperintensity. This is the first case of SCA-17 reported to show MRI signal change in the basal ganglia, and extends the phenotypic manifestation of SCA-17.
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http://dx.doi.org/10.1002/mds.20529DOI Listing
November 2005

Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease.

Hum Mol Genet 2004 Jun 28;13(12):1219-24. Epub 2004 Apr 28.

MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology UCL, Queen Square, London, UK.

Alzheimer's disease (AD) is the commonest neurodegenerative disease worldwide. Rare familial cases may be caused by mutations in one of three genes-amyloid precursor protein, presenilin-1 and presenilin-2; however, the molecular basis of >99% of AD cases is unknown. Somatic mutation has been considered to be a mechanism that may account for a proportion of sporadic cases of AD, but to date there has been no evidence for this. We now report a sporadic early-onset patient with AD, and show that this individual is a somatic mosaic for a mutation in the presenilin-1 gene, suggesting a novel molecular mechanism for AD. Quantification of the mosaicism demonstrated the degree of mosaicism at 8% in peripheral lymphocytes and 14% in cerebral cortex in the index patient; a clear gene dosage effect on age of presentation and clinical phenotypic presentation is demonstrated. This finding has important implications for the aetiology of sporadic AD, and for other apparently sporadic neurodegenerative diseases such as Parkinson's disease, motor neuron disease and Creutzfeldt-Jakob disease.
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http://dx.doi.org/10.1093/hmg/ddh134DOI Listing
June 2004

Coexistent hereditary and inflammatory neuropathy.

Brain 2004 Jan 7;127(Pt 1):193-202. Epub 2003 Nov 7.

University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, and Department of Neurology, Royal Free Hospital,UK.

Classically, the course of Charcot-Marie-Tooth (CMT) disease is gradually progressive. We describe eight atypical patients who developed acute or subacute deterioration. Seven of these had genetically proven CMT disease type 1A (CMT1A) due to chromosome 17p11.2-12 duplication, and one had X-linked disease (CMTX) due to a mutation in the GJB1 gene. In this group there was sufficient clinical, electrophysiological and neuropathological information to indicate a diagnosis of a superimposed inflammatory polyneuropathy. The age range of the patients was 18-69 years, with a mean of 39 years. A family history of a similar neuropathic condition was present in only four patients. All eight had an acute or subacute deterioration following a long asymptomatic or stable period. Seven had neuropathic pain or prominent positive sensory symptoms. Nerve biopsy demonstrated excess lymphocytic infiltration in all eight patients. Five patients were treated with steroids and/or intravenous immunoglobulin, with variable positive response; three patients received no immunomodulatory treatment. Inflammatory neuropathy has previously been recognized in patients with hereditary neuropathy, with uncharacterized genetic defects and with CMT1B. We present detailed assessments of patients with CMT1A and CMTX, including nerve biopsy, and conclude that coexistent inflammatory neuropathy is not genotype-specific in hereditary motor and sensory neuropathy. Although this was not a formal epidemiological study, estimates of the prevalence of CMT disease and chronic inflammatory demyelinating polyneuropathy indicate that the association is more frequent than would be expected by chance. This has implications for understanding the pathogenesis of inflammatory neuropathies and raises important considerations in the management of patients with hereditary neuropathies. If a patient with CMT disease experiences an acute or subacute deterioration in clinical condition, treatment of a coexistent inflammatory neuropathy with steroids or immunoglobulin should be considered.
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http://dx.doi.org/10.1093/brain/awh017DOI Listing
January 2004

Hereditary sensory neuropathy is caused by a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4 ) gene.

Hum Mol Genet 2003 Aug;12(15):1917-25

Division of Clinical Neurology and Department of Molecular Pathogenesis, Institute of Neurology, Queen Square, London, WC1N 3BG, UK

A spontaneous autosomal recessive mutation was identified in the Sprague-Dawley rat strain with an early onset sensory neuropathy. The main clinical features of the mutation (mutilated foot, mf ), detectable shortly after birth, include ataxia, insensitivity to pain and foot ulceration. The pathological features include a severe reduction in the number of sensory ganglia and fibres. This mutant is therefore an excellent model for human hereditary sensory neuropathies. Here, we demonstrate that the mf locus maps to the distal end of rat chromosome 14, a region syntenic to human 2p13-p16 and proximal mouse 11. Sequence analysis of four candidate genes in this interval revealed a 1349G>A mutation in the chaperonin (delta) subunit 4 (Cct4) gene associated with the mf mutant. This change resulted in the substitution of a highly conserved cysteine for tyrosine at amino acid 450. Although we did not identify a mutation in the human CCT4 gene in a set of HSN patients, this result clearly demonstrates the pathological consequences of a defect in Cct4, a subunit of CCT (cytosolic chaperonin-containing t-complex peptide-1), involved in folding tubulin, actin and other cytosolic proteins. This is the first report of a mutation in a molecular chaperonin causing a hereditary neuropathy and raises the possibility that mis-folding proteins may be a cause of this group of neuropathies.
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http://dx.doi.org/10.1093/hmg/ddg198DOI Listing
August 2003

Genetic and clinical heterogeneity in paroxysmal kinesigenic dyskinesia: evidence for a third EKD gene.

Mov Disord 2002 Jul;17(4):717-25

Department of Molecular Pathogenesis, Institute of Neurology, University College London, London, United Kingdom.

Paroxysmal kinesigenic dyskinesia (PKD) is characterised by paroxysms of choreic, dystonic, ballistic, or athetoid movements. The attacks typically last seconds to minutes in duration and are induced by sudden voluntary movement. PKD loci have been identified on chromosome 16. We present the clinical and genetic details of two British and an Indian family with PKD. Linkage to the PKD loci on chromosome 16 has been excluded in one of these families, providing evidence for a third loci for PKD. Detailed clinical descriptions highlight the presence of both adolescent and infantile seizures in some of the PKD families. This study attempts to clarify the relationship of adolescent and infantile seizures to PKD and provides evidence that PKD is both genetically and clinically heterogeneous.
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http://dx.doi.org/10.1002/mds.10126DOI Listing
July 2002

Partial epilepsy with pericentral spikes: a new familial epilepsy syndrome with evidence for linkage to chromosome 4p15.

Ann Neurol 2002 Jun;51(6):740-9

Department of Molecular Pathogenesis, Institute of Neurology, Queen Square, London WC1N 3BG, UK.

The genetic analysis of simple Mendelian epilepsies remains a key strategy in advancing our understanding of epilepsy. In this article, we describe a new family epilepsy syndrome, partial epilepsy with pericentral spikes, which we map to chromosome 4p15. We distinguish it clinically, electrophysiologically, and genetically from previously described Mendelian epilepsies. The family described is a large Brazilian kindred of Portuguese extraction in which affected family members manifest a variety of seizure types, including hemiclonic, hemitonic, generalized tonic-clonic, simple partial (stereotyped episodes of epigastric pain), and complex partial seizures consistent with temporal lobe epilepsy. The syndrome is benign, either requiring no treatment or responding to a single antiepileptic medication. Seizure onset is in the first or second decades of life, with seizures in individuals up to the age of 71 years and documented encephalogram changes up to the age of 30 years. A key feature of partial epilepsy with pericentral spikes is a characteristic encephalogram abnormality of spikes or sharp waves in the pericentral region (centroparietal, centrofrontal, or centrotemporal). This distinctive encephalogram abnormality of pericentral spikes unites these several seizure types into a discrete family epilepsy syndrome. As with other familial epilepsies, the inherited nature of this new syndrome may be overlooked because of the variability in penetrance and seizure types among affected family members.
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http://dx.doi.org/10.1002/ana.10221DOI Listing
June 2002

PARK6-linked parkinsonism occurs in several European families.

Ann Neurol 2002 Jan;51(1):14-8

Institute for Medical Genetics C.S.S. Mendel, Rome, Italy.

The Parkin gene on 6q25.2-27 is responsible for about 50% of autosomal recessive juvenile parkinsonism and less than 20% of sporadic early-onset cases. We recently mapped a novel locus for early-onset parkinsonism (PARK6) on chromosome 1p35-p36 in a large family from Sicily. We now confirm linkage to PARK6 in eight additional families with Parkin-negative autosomal recessive juvenile parkinsonism from four different European countries. The maximum cumulative pairwise LOD score was 5.39 for marker D1S478. Multipoint linkage analysis gave the highest cumulative LOD score of 6.29 for marker D1S478. Haplotype construction and determination of the smallest region of homozygosity in one consanguineous family has reduced the candidate interval to a 9cM region between markers D1S483 and D1S2674. No common haplotype could be detected, excluding a common founder effect. These families share some clinical features with the phenotype reported for European Parkin-positive cases, with a wide range of ages at onset (up to 68 yrs) and slow progression. However, features typical of autosomal recessive juvenile parkinsonism, including dystonia at onset and sleep benefit, were not observed in PARK6-linked families, thus making the clinical presentation of late-onset cases indistinguishable from idiopathic Parkinson's disease. PARK6 appears to be an important locus for early-onset parkinsonism in European Parkin-negative patients.
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January 2002