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Clinical Genetics 07/2012; 9999(9999). · 3.13 Impact Factor
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ABSTRACT: Huntington's disease (HD) is an autosomal dominant disorder characterized by a triad of chorea, psychiatric disturbance and cognitive decline. Around 1% of patients with HD-like symptoms lack the causative HD expansion and are considered HD phenocopies. Genetic diseases that can present as HD phenocopies include HD-like syndromes such as HDL1, HDL2 and HDL4 (SCA17), some spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA). In this study we screened a cohort of 21 Greek patients with HD phenocopy syndromes for mutations causing HDL2, SCA17, SCA1, SCA2, SCA3, SCA8, SCA12 and DRPLA. Fifteen patients (71%) had a positive family history. We identified one patient (4.8% of the total cohort) with an expansion of 81 combined CTA/CTG repeats at the SCA8 locus. This falls within what is believed to be the high-penetrance allele range. In addition to the classic HD triad, the patient had features of dystonia and oculomotor apraxia. There were no cases of HDL2, SCA17, SCA1, SCA2, SCA3, SCA12 or DRPLA. Given the controversy surrounding the SCA8 expansion, the present finding may be incidental. However, if pathogenic, it broadens the phenotype that may be associated with SCA8 expansions. The absence of any other mutations in our cohort is not surprising, given the low probability of reaching a genetic diagnosis in HD phenocopy patients.
Journal of Neurology 02/2012; · 3.47 Impact Factor
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G L Davidson,
S M Murphy,
J M Polke,
M Laura,
M A M Salih,
F Muntoni,
J Blake,
S Brandner,
N Davies,
R Horvath, [......],
M Donaghy,
M Roberts,
N Foulds,
G Ramdharry,
D Soler,
M P Lunn,
H Manji,
M B Davis, H Houlden,
M M Reilly
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ABSTRACT: The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.
Journal of Neurology 02/2012; 259(8):1673-85. · 3.47 Impact Factor
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ABSTRACT: NBIA characterizes a class of neurodegenerative diseases that feature a prominent extrapyramidal movement disorder, intellectual deterioration, and a characteristic deposition of iron in the basal ganglia. The diagnosis of NBIA is made on the basis of the combination of representative clinical features along with MR imaging evidence of iron accumulation. In many cases, confirmatory molecular genetic testing is now available as well. A number of new subtypes of NBIA have recently been described, with distinct neuroradiologic and clinical features. This article outlines the known subtypes of NBIA, delineates their clinical and radiographic features, and suggests an algorithm for evaluation.
American Journal of Neuroradiology 09/2011; 33(3):407-14. · 2.93 Impact Factor
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J M Polke,
M Laurá,
D Pareyson,
F Taroni,
M Milani,
G Bergamin,
V S Gibbons, H Houlden,
S C Chamley,
J Blake,
C Devile,
R Sandford,
M G Sweeney,
M B Davis,
M M Reilly
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ABSTRACT: 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 mutations have been described. We present 3 families with early-onset CMT2 associated with compound heterozygous MFN2 mutations. Transcriptional analysis was performed to investigate the effects of the mutations.
Patients were examined clinically and electrophysiologically; parents were also examined where available. Genetic investigations included MFN2 DNA sequencing and dosage analysis by multiplex ligation-dependent probe amplification. MFN2 mRNA transcripts from blood lymphocytes were analyzed in 2 families.
Compound heterozygosity for MFN2 mutations was associated with early-onset CMT2 of varying severity between pedigrees. Parents, where examined, were unaffected and were heterozygous for the expected mutations. Four novel mutations were detected (one missense, one nonsense, an intragenic deletion of exons 7 + 8, and a 3-base pair deletion), as well as 2 previously reported missense mutations. Transcriptional analysis demonstrated aberrant splicing of the exonic deletion and indicated nonsense-mediated decay of mutant alleles with premature truncating mutations.
Our findings confirm that MFN2 mutations can cause early-onset CMT2 with apparent recessive inheritance. Novel genetic findings include an intragenic MFN2 deletion and nonsense-mediated decay. Carrier parents were asymptomatic, suggesting that MFN2 null alleles can be nonpathogenic unless coinherited with another mutation.
Neurology 06/2011; 77(2):168-73. · 8.31 Impact Factor
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M Russo,
M Laurá,
J M Polke,
M B Davis,
J Blake,
S Brandner,
R A C Hughes, H Houlden,
D L H Bennett,
M P T Lunn,
M M Reilly
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ABSTRACT: Charcot-Marie-Tooth disease (CMT) is the commonest hereditary neuropathy encompassing a large group of clinically and genetically heterogeneous disorders. The commonest form of CMT, CMT1A, is usually caused by a 1.4 megabase duplication of chromosome 17 containing the PMP22 gene. Mutations of PMP22 are a less common cause of CMT. We describe clinical, electrophysiological and molecular findings of 10 patients carrying PMP22 missense mutations. The phenotype varied from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe CMT1. We identified six different point mutations, including two novel mutations. Three families were also found to harbour a Thr118Met mutation. Although PMP22 point mutations are not common, our findings highlight the importance of sequencing the PMP22 gene in patients with variable CMT phenotypes and also confirm that the PMP22 Thr118Met mutation is associated with a neuropathy albeit with reduced penetrance.
Neuromuscular Disorders 02/2011; 21(2):106-14. · 2.80 Impact Factor
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Handbook of Clinical Neurology 01/2011; 103:521-34.
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ABSTRACT: An ITPR1 gene deletion causes spinocerebellar ataxia 15/16: a genetic, clinical and radiological description of a novel kindred. Spinocerebellar ataxia (SCA) 15/16 is an autosomal dominantly inherited, almost pure cerebellar ataxia, which shows slow or no progression. (It has been designated variably SCA15 and SCA 16; we refer to it here as SCA15/16 to avoid confusion). Deletions in the inositol 1,4,5-triphosphate receptor 1 (ITPR1) on chromosome 3 have been shown to cause SCA15/16 in six families worldwide to date, with one further Japanese family identified as having an ITPR1 point mutation. We present a previously unreported SCA15/16 kindred. We describe the clinical phenotype of the family in detail; affected subjects display a remarkably slow, almost pure cerebellar syndrome. We also present genetic analyses for all subjects and longitudinal MRI data for one affected subject. 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, and western blotting of lymphoblastoid cell line protein confirms reduced ITPR1 protein levels. Serial MRIs show midline cerebellar atrophy with mild inferior parietal and temporal cortical volume loss. We believe that genetic testing for SCA15/16 should become a routine DNA screen available in all neurogenetics clinics, which is likely to lead to an increased rate of the diagnosis. Familiarity with the phenotype is therefore important for all neurologists.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e32. · 4.87 Impact Factor
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ABSTRACT: CMTX1 is the second most common cause of Charcot-Marie-Tooth disease (CMT), usually caused by mutations in the Cx32 gene. Cx32 has two tissue-specific promoters: P1, specific for liver and pancreas, and P2 which is nerve specific. Over 300 mutations have been described in Cx32, spread throughout the coding region. However, 10% of CMTX1 families do not have mutations in the coding region. To date, 5 noncoding region mutations have been reported. We describe two families with X-linked inheritance and a phenotype consistent with CMTX1 who did not have mutations in the Cx32 coding region. Family 1 were negative for mutations in PMP22, MPZ, SPTLC1 and GDAP1 Family 2 were negative for mutations in MPZ and rearrangements at chromosome 17p11.2. The noncoding region of Cx32 was sequenced and an upstream exon-splicing variant found at c.-373G>A which segregated with the disease in both families. This variant is located at the last base of the nerve-specific 5'UTR exon and thus may disrupt splicing of the nerve-specific transcript. Online consensus splice-site programs predict a reduced score for the mutant sequence vs the normal sequence. Two other mutations have previously been described within the 5'UTR region, which created a potential donor splice site and were shown to prevent translation of mutant mRNA. It is likely that other mutations within the Cx32 noncoding regions account for the CMTX1 families who do not have coding region mutations.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e50. · 4.87 Impact Factor
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ABSTRACT: The clinical phenotype of DYT6 consists mainly of primary craniocervical dystonia. Recently, the THAP1 gene was identified as the cause of DYT6, where a total of 13 mutations have been identified in Amish-Mennonite and European families.
We sequenced the THAP1 gene in a series of 362 British, genetically undetermined, primary dystonia patients (78 with focal, 186 with segmental, and 98 with generalized dystonia) and in 28 dystonia-manifesting DYT1 patients and 176 normal control individuals.
Nine coding mutations were identified in the THAP1 gene. Two were small deletions, 2 were nonsense, and 5 were missense. Eight mutations were heterozygous, and 1 was homozygous. The main clinical presentation of cases with THAP1 mutations was early-onset (<30 years) dystonia in the craniocervical region or the limbs (8 of 9 patients). There was phenotypic variability with laryngeal or oromandibular dystonia present in 3 cases. Four of 9 THAP1 cases developed generalized dystonia.
The number of THAP1 mutations has been significantly expanded, indicating an uncommon but important cause of dystonia. Coding mutations account for 9 of 362 dystonia cases, indicating a mutation frequency of 2.5% of dystonia cases in the population that we have screened. The majority of cases reported here with THAP1 mutations had craniocervical- or limb-onset segmental dystonia, but we also identified 1 homozygous THAP1 mutation, associated initially with writer's dystonia and then developing segmental dystonia. Three of our patients had a nonsense or frameshift THAP1 mutation and the clinical features of laryngeal or oromandibular dystonia. These data suggest that early-onset dystonia that includes the involvement of the larynx or face is frequently associated with THAP1 mutations.
Neurology 03/2010; 74(10):846-50. · 8.31 Impact Factor
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A W Michell,
M Laura,
J Blake,
M P Lunn,
A Cox,
V S Gibbons,
M B Davis,
N W Wood,
H Manji, H Houlden,
N M F Murray,
M M Reilly
Journal of neurology, neurosurgery, and psychiatry 07/2009; 80(6):699-700. · 4.87 Impact Factor
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B Segarane,
A Li,
R Paudel,
S Scholz,
J Neumann,
A Lees,
T Revesz,
J Hardy,
C J Mathias,
N W Wood,
J Holton, H Houlden
Neurology 04/2009; 72(13):1185-6. · 8.31 Impact Factor
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ABSTRACT: To investigate and correlate the frequency and types of pupil abnormalities that are associated with hereditary peripheral neuropathy in a large cohort of patients prospectively examined.
A prospective study between 1998 and 2007. Patients were enrolled and examined after being seen in the neurology clinic. Data were collected on demographics, family and medical history. Patients had eye and pupillography testing carried out as well as being neurologically and genetically investigated.
A consecutive series of 131 cases of inherited peripheral neuropathy were seen and categorized into five groups: familial amyloid polyneuropathy (FAP), Charcot Marie Tooth disease (CMT), hereditary neuropathywith liability to pressure palsies (HNPP), Refsum's disease, and hereditary sensory and autonomic neuropathy. A number of unreported mutations were identified in these patient groups. Pupil abnormalities were common in the Refsum's group, with frequent abnormally small pupils. The inherited neuropathies commonly associated with autonomic abnormalities were frequently found to have developed bilateral Horner's syndrome, which was particularly prevalent in our FAP series. Abnormalities were rare in HNPP and CMT type 1, but CMT type 2 showed frequent and varied pupil defects. The results describe the pupil abnormalities that were frequently associated with the particular group of inherited neuropathy patients, but we could not predict the genetic defect or the neuropathy severity.
This is the first study of the pupil abnormalities found in the inherited neuropathies and provides an overview of the frequency and type of defects seen in a large number of cases. This series along with the detailed tables will act as an important diagnostic aid in assessing these patients.
Eye (London, England) 04/2009; 23(4):966-74. · 1.97 Impact Factor
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ABSTRACT: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder and is characterized by significant clinical and genetic heterogeneity. Recently, mutations in both the small heat shock protein 27 (HSP27 or HSPB1) and 22 (HSP22 or HSPB8) genes have been reported to cause autosomal dominant CMT with minimal sensory involvement (CMT 2F/CMT2L) and autosomal dominant distal hereditary motor neuropathy type II (dHMN II).
We analyzed the HSPB1 and HSPB8 genes in a large clinically well-characterized series of dHMN and CMT type 2 (CMT2) cases and families using linkage analysis and direct sequencing of these genes.
We identified a novel homozygous mutation in the alpha-crystallin domain of HSPB1 segregating in an autosomal recessive fashion in a family with distal HMN/CMT2. A further four heterozygous HSPB1 mutations were identified in four autosomal dominant families dHMN/CMT2, and two sporadic cases were identified with probable de novo mutations. In the autosomal dominant and autosomal recessive families, there were no clinical sensory findings, but reduced sural nerve action potential amplitudes were found in some affected individuals, indicating that long sensory axons are mildly affected in this predominantly motor disorder.
This extends the clinical and electrophysiologic spectrum of HSPB1 mutations and identifies four unreported dominant HSPB1 mutations and the first family where the HSPB1 mutation acts in a recessive way to cause distal HMN.
Neurology 11/2008; 71(21):1660-8. · 8.31 Impact Factor
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ABSTRACT: Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum is a distinct and usually severe form of complex hereditary spastic paraplegia classified as SPG11. Recently mutations on SPG11 gene (KIAA1840), which is localized to chromosome 15q13-q15, were shown to cause the majority of SPG11 cases.
We analysed the 40 coding exons of this gene in the probands from eight families with complex ARHSP, four of these families had a thin corpus callosum and two has mild thinning.
Three families were identified with novel mutations in the SPG11 gene. One family was of Asian origin with a homozygous nonsense mutation and had a very severe phenotype but only very mild thinning of the corpus callosum. In the other two English families the parents were unrelated and the mutations were compound heterozygotes. In these two families the phenotype was mild and both probands had a thin corpus callosum.
Given the probable mechanism of action of the mutations in the Spatacsin gene, we discuss the probable genotype phenotype correlations in these families. This study confirms the frequent occurrence of Spatacsin mutations in complex ARHSP with genotype phenotype effects and exposes the spectrum of clinical heterogeneity in SPG11.
European Journal of Neurology 09/2008; 15(10):1065-70. · 3.69 Impact Factor
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ABSTRACT: Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common form of complex hereditary spastic paraplegia. The genetic lesion underlying ARHSP-TCC was localized to chromosome 15q13-q15 and given the designation SPG11. Recently, the gene encoding spatacsin (KIAA1840) has been shown to contain mutations that underlie the majority of ARHSP-TCC cases.
We present a complete analysis of the 40 coding exons of this gene in patients with sporadic (n = 25) or familial (20 probands) complex hereditary spastic paraplegia with and without thinning of the corpus callosum.
We identified seven mutations, including deletions, insertions, and nonsense mutations, which were all predicted to lead to premature truncation of the protein.
We conclude that mutations on KIAA1840 are frequent in complex autosomal recessive hereditary spastic paraplegia but an infrequent cause of sporadic complex hereditary spastic paraplegia.
Neurology 05/2008; 70(16 Pt 2):1384-9. · 8.31 Impact Factor
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ABSTRACT: The authors describe a patient with hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) who has two compound heterozygote mutations of the PANK2 gene. IVS4-1 G>T segregates with the lipid and erythrocyte changes in the mother and sister. No other family members have the lipid, erythrocyte, or clinical abnormalities. The father and two brothers are heterozygous for Met327Thr. One other mutation has been found in this PANK2 region associated with the HARP phenotype, suggesting a local genotype effect.
Neurology 11/2003; 61(10):1423-6. · 8.31 Impact Factor
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ABSTRACT: Three causative genes have been identified for autosomal dominant AD.
To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes.
A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years.
The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001).
Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.
Neurology 01/2003; 60(2):235-9. · 8.31 Impact Factor
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ABSTRACT: X-linked Charcot-Marie-Tooth disease (CMTX) is a clinically heterogeneous hereditary motor and sensory neuropathy with X-linked transmission. Common clinical manifestations of CMTX, as in other forms of Charcot-Marie-Tooth disease (CMT), are distal muscle wasting and weakness, hyporeflexia, distal sensory disturbance, and foot deformities. Motor nerve conduction velocity is reduced. In male patients it is often less than 38 m/s in the median nerve (a value often used to distinguish between "demyelinating" and "axonal" forms of CMT), but in female patients conduction velocity may be faster than this or normal. Mutations in the connexin32 (gap junction protein beta 1 (GJB1)) gene are responsible for the majority of CMTX cases. This report describes six British CMTX families with six novel mutations (four missense, one nonsense, and one frame shift) of the GJB1 gene. Affected members in these six families had typical signs of CMT but in some affected members of three families there was additional central nervous system involvement or deafness in the absence of any other explanation other than CMT.
Journal of Neurology Neurosurgery & Psychiatry 10/2002; 73(3):304-6. · 4.76 Impact Factor
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H R Morris,
M Baker,
K Yasojima, H Houlden,
M N Khan,
N W Wood,
J Hardy,
M Grossman,
J Trojanowski,
T Revesz,
E H Bigio,
C Bergeron,
J C Janssen,
P L McGeer,
M N Rossor,
A J Lees,
P L Lantos,
M Hutton
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ABSTRACT: Pick's disease (PiD) is characterized by the deposition of tau protein as three-repeat tau Pick bodies, whereas progressive supranuclear palsy (PSP) involves the deposition of four-repeat tau neurofibrillary tangles. PSP is associated with the tau H1 haplotype. The authors investigated a possible association between PiD and the tau H1 or H2 haplotype. There was no difference between the tau H2 haplotype or H2H2 genotype frequency in PiD cases and control subjects. No tau mutations were identified in pathologically typical cases of PiD, with antibody 12-E8-negative Pick bodies.
Neurology 09/2002; 59(3):443-5. · 8.31 Impact Factor
