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T Klopstock,
G Metz,
P Yu-Wai-Man,
B Büchner,
C Gallenmüller,
M Bailie,
N Nwali,
P G Griffiths,
B von Livonius,
L Reznicek,
J Rouleau,
N Coppard,
T Meier, P F Chinnery
Brain 02/2013; · 9.46 Impact Factor
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ABSTRACT: Over the past year huge advances have been made in our ability to determine the genetic aetiology of many neurological diseases through the utilisation of next generation sequencing platforms. This technology is, on a daily basis, providing new breakthroughs in neurological disease. The aim of this article is to clearly describe the technological platforms, methods of data analysis, established breakthroughs, and potential future clinical and research applications of this innovative and exciting technique which has relevance to all those working within clinical neuroscience.
Clinical neurology and neurosurgery 11/2012; · 1.30 Impact Factor
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ABSTRACT: Background
McArdle disease, a common metabolic myopathy with autosomal recessive inheritance, is caused by a frequent R50X mutation and
many rare mutations in the myophosphorylase gene.
Objectives
To identify spectrum and frequencies of myophosphorylase gene mutations in a large cohort of patients with McArdle disease,
to discuss diagnostic implications, and to analyse genotype–phenotype relationship.
Methods
Molecular genetic analysis of 56 index patients with muscle biopsy-proven myophosphorylase deficiency from Germany (n = 35),
UK (n = 13), and several other countries (n = 8) was performed using direct sequencing.
Results
Allele frequency of the R50X mutation was 58%, and 71% of the patients carried this mutation at least on one allele. We detected
26 other less common mutations, 13 of which are novel: G157V, R161C, Q337R, E384K, S450L, G486D, R570W, K575E, IVS6-2A>T,
IVS10+1G>A, R650X, c.1354insC, c.1155_1156delGG. There was no genotype-phenotype correlation with respect to age of onset
and severity. R270X was the most frequent mutation among the less common mutations reaching an allele frequency of 5% followed
by R94W and G686R representing a frequency of 4% each.
Conclusions
The study further extends the genetic heterogeneity of myophosphorylase gene mutations showing no mutational hotspot and no
genotype–phenotype correlation. Most novel missense mutations were located in secondary structures or active sites of the
enzyme. Some of the less common mutations are recurrent with different frequencies within Europe. Ethnic origin and frequency
of less common mutations must be considered to establish efficient strategies in molecular genetic testing. Performing molecular
testing can avoid muscle biopsy.
Key words
genetic testing-McArdle disease-mutations-myophosphorylase deficiency
Journal of Neurology 04/2012; 254(6):797-802. · 3.47 Impact Factor
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ABSTRACT: Neuroferritinopathy is an autosomal dominant extrapyramidal movement disorder, caused by FTL gene mutations. Iron decreases the MR T2* decay time, therefore increasing the R2* (R2* = 1 /T2*), which correlates with brain tissue iron content. 3T structural and quantitative MR imaging assessment of R2* in 10 patients with neuroferritinopathy demonstrated a unique pattern of basal ganglia cavitation involving the substantia nigra in older patients and increasing thalamic R2* signal intensity detectable during 6 months. Increasing R2* signal intensity in the thalamus correlated with progression on a clinical rating scale measuring dystonia severity. Thalamic R2* signal intensity is a clinically useful method of objectively tracking disease progression in this form of neurodegeneration with brain iron accumulation.
American Journal of Neuroradiology 04/2012; 33(9):1810-3. · 2.93 Impact Factor
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ABSTRACT: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary small vessel brain disease, and is caused by mutations in NOTCH3. The disorder is often overlooked and misdiagnosed, and the population prevalences are generally not known. Over 100 families exist in France, with similar numbers in the United Kingdom,(1) and >200 in Germany.(2) In Finland, the reported prevalence is 2-4 per 100,000,(3) and in west Scotland, 1.98 per 100,000 have a definite diagnosis, and 4.14 per 100,000 are predicted mutation carriers.(4) However, both of these study populations include relative genetic isolates. We carried out a study to determine the prevalence of CADASIL in an outbred Western European population in the northeast of England.
Neurology 03/2012; 78(13):1025-7. · 8.31 Impact Factor
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ABSTRACT: Mutations affecting the nuclear gene encoding the mitochondrial OPA1 protein are the commonest causes of autosomal dominant optic atrophy (DOA). More recently OPA1 mutations have been shown to cause a disorder of mitochondrial DNA (mtDNA) maintenance, thus explaining the extraocular features observed in ∼20% of OPA1 mutation carriers with "DOA+," which include deafness, progressive external ophthalmoplegia (PEO), myopathy, ataxia, neuropathy, and spastic paraplegia.(1,2) However, it remains puzzling why, unlike other hereditary mtDNA maintenance disorders (e.g., POLG1(3)), most OPA1 mutation carriers only appear to develop isolated optic neuropathy. To determine whether this is actually the case, we looked for electrophysiologic evidence of subclinical multisystem disease in a sample of patients with clinically "pure" DOA. Because spasticity is an unusual clinical finding in mitochondrial disease, we were particularly interested to look for evidence of subclinical corticospinal tract (CST) disease in this clinically asymptomatic group, specifically to gain insight into the role of mitochondrial dysfunction in other more common neurodegenerative motor disorders.
Neurology 09/2011; 77(13):1309-12. · 8.31 Impact Factor
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ABSTRACT: X-linked Charcot-Marie-Tooth disease type 1 (CMTX1, MIM#302800) is the second most common cause of hereditary neuropathy and is due to mutations in GJB1, which codes for connexin 32 (Cx32). In most cases, GJB1 mutation only causes a progressive sensorimotor neuropathy that preferentially affects men. Transient neurologic features have been described infrequently in CMTX1, usually presenting in childhood.(1-5) Here we describe recurrent stroke-like episodes in a man with CMTX1.
Neurology 09/2011; 77(12):1205-6. · 8.31 Impact Factor
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C Fratter,
P Raman,
C L Alston,
E L Blakely,
K Craig,
C Smith,
J Evans,
A Seller,
B Czermin,
M G Hanna,
J Poulton,
C Brierley,
T G Staunton,
P D Turnpenny,
A M Schaefer, P F Chinnery,
R Horvath,
D M Turnbull,
G S Gorman,
R W Taylor
Neurology 06/2011; 76(23):2032-4. · 8.31 Impact Factor
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ABSTRACT: A 39-year-old woman presented to the neurology clinic with an abnormal gait. Subsequent investigations confirmed a rare neurodegenerative disease. This case highlights the key clinical features and diagnostic approach to neuroferritinopathy, and describes the discovery of the disease in a family from Cumbria in the north west of England.
Practical Neurology 04/2011; 11(2):81-4.
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ABSTRACT: The majority of patients with autosomal dominant optic atrophy (DOA) harbour pathogenic OPA1 mutations. Although DOA is characterised by the preferential loss of retinal ganglion cells (RGCs), about 20% of patients with OPA1 mutations will develop a more severe disease variant (DOA+), with additional neuromuscular features. In this prospective, observational case series, optical coherence tomography (OCT) was used to define the pattern of retinal nerve fibre layer (RNFL) loss in patients with both the pure and syndromal forms of DOA.
Forty patients with a molecular diagnosis of DOA due to OPA1 mutations were prospectively recruited from our neuro-ophthalmology clinic: 26 patients with isolated optic atrophy and 14 patients manifesting DOA+ features. Peripapillary RNFL thickness was measured with the Fast RNFL (3.4) acquisition protocol on a Stratus OCT.
There was a statistically significant reduction in average RNFL thickness in the OPA1 group compared with normal controls (P<0.0001). The percentage decrease was greatest in the temporal quadrant (59.0%), followed by the inferior (49.6%), superior (41.8%), and nasal (25.9%) quadrants. Patients with DOA+ features had worse visual outcomes compared with patients with pure DOA. Except in the temporal quadrant, RNFL measurements were significantly thinner for the DOA+ group. There was an inverse correlation between average RNFL thickness and logarithm of the minimum angle of resolution (LogMAR) visual acuity (P<0.0001).
RGC loss in DOA is characterised by severe involvement of the temporal papillomacular bundle, with relative sparing of the nasal fibres. RNFL thinning is more pronounced in patients with DOA+ phenotypes.
Eye (London, England) 03/2011; 25(5):596-602. · 1.97 Impact Factor
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J. D. Stewart,
S. Schoeler,
K. S. Sitarz,
R. Horvath,
K. Hallmann,
A. Pyle,
P. Yu-Wai-Man,
R. W. Taylor,
D. C. Samuels,
W. S. Kunz, P. F. Chinnery
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ABSTRACT: Disorders of mitochondrial DNA (mtDNA) maintenance have emerged as an important cause of human genetic disease, but demonstrating the functional consequences of de novo mutations remains a major challenge. We studied the rate of depletion and repopulation of mtDNA in human fibroblasts exposed to ethidium bromide in patients with heterozygous POLG mutations. POLG2 and TK2 mutations. Ethidium bromide induced mtDNA depletion occurred at the same rate in human fibroblasts from patients and healthy controls. By contrast, the restoration of mtDNA levels was markedly delayed in fibroblasts from patients with compound heterozygous POLG mutations. Specific POLG2 and TK2 mutations did not delay mtDNA repopulation rates. These observations are consistent with the hypothesis that mutations in POLG impair mtDNA repopulation within intact cells, and provide a potential method of demonstrating the functional consequences of putative pathogenic alleles causing a defect of mtDNA synthesis. (C) 2010 Elsevier B.V. All rights reserved.
Biochimica Et Biophysica Acta-Molecular Basis of Disease. 01/2011; 1812(3):321-325.
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Debbie Hicks,
A Sarkozy,
N Muelas,
K Koehler,
A Huebner,
G Hudson, P F Chinnery,
R Barresi,
M Eagle,
T Polvikoski, [......],
J Miller,
A Radunovic,
P J Hughes,
R Roberts,
S Krause,
M C Walter,
S H Laval,
V Straub,
H Lochmüller,
K Bushby
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ABSTRACT: The limb-girdle muscular dystrophies are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, limb-girdle muscular dystrophy 2L and non-dysferlin Miyoshi muscular dystrophy. We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic single nucleotide polymorphism and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised serum creatine kinase values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20 s to 50 s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100,000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high serum creatine kinase and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult limb-girdle muscular dystrophy patients.
Brain 01/2011; 134(Pt 1):171-82. · 9.46 Impact Factor
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C Fratter,
G S Gorman,
J D Stewart,
M Buddles,
C Smith,
J Evans,
A Seller,
J Poulton,
M Roberts,
M G Hanna, [......],
B Schoser,
C Kornblum,
B Czermin,
B Lecky,
E L Blakely,
K Craig, P F Chinnery,
D M Turnbull,
R Horvath,
R W Taylor
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ABSTRACT: Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome c oxidase (COX)-deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease.
We reviewed the clinical, histochemical, and molecular genetics analysis of 33 unreported patients from 26 families together with all previous cases described in the literature to define the clinical phenotype associated with PEO1 mutations.
Ptosis and ophthalmoparesis were almost universal clinical features among this cohort, with 52% (17/33) reporting fatigue and 33% (11/33) having mild proximal myopathy. Features consistent with CNS involvement were rarely described; however, in 24% (8/33) of the patients, cardiac abnormalities were reported. Mitochondrial histochemical changes observed in muscle showed remarkable variability, as did the secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Moreover, we report 7 novel PEO1 variants.
Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of adPEO may well be underestimated. Direct sequencing of the PEO1 gene should be considered in adPEO patients prior to muscle biopsy.
Neurology 05/2010; 74(20):1619-26. · 8.31 Impact Factor
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P Yu-Wai-Man,
P G Griffiths,
G S Gorman,
C M Lourenco,
A F Wright,
M Auer-Grumbach,
A Toscano,
O Musumeci,
M L Valentino,
L Caporali, [......],
R McFarland,
R W Taylor,
D M Turnbull,
M Votruba,
M Zeviani,
V Carelli,
L A Bindoff,
R Horvath,
P Amati-Bonneau, P F Chinnery
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ABSTRACT: Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.
Brain 02/2010; 133(Pt 3):771-86. · 9.46 Impact Factor
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Trends in Genetics. 01/2010; 26(6):242-243.
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ABSTRACT: Primary open angle glaucoma is a progressive optic neuropathy characterised by the selective loss of retinal ganglion cells, pathological optic disc cupping and visual field defects. The OPA1 gene encodes an inner mitochondrial membrane protein crucial for normal mitochondrial function, and pathogenic mutations cause autosomal dominant optic atrophy by specifically targeting retinal ganglion cells. This raises the distinct possibility that more subtle genetic variations in OPA1 could alter the risk of developing glaucoma.
137 patients with primary open angle glaucoma (67 patients with high-tension glaucoma (HTG), 70 patients with normal-tension glaucoma (NTG)) and 75 controls from the North East of England were studied. Three single-nucleotide polymorphisms in intron 8 (IVS8+4c-->t and IVS8+32t-->c) and exon 4 (c.473A-->G) of the OPA1 gene were genotyped in the study group. In addition, the entire OPA1 coding region was sequenced in 24 individuals with the CT/TT compound genotype using standard BigDye chemistries.
There was no difference in either allele or genotype frequency for the IVS8+32t-->c single-nucleotide polymorphisms between patients and controls, but there was a significant association between the T allele at IVS8+4c-->t and the risk of developing NTG (OR=2.04, 95% CI=1.10 to 3.81, p=0.004), but not HTG. Logistic regression analysis also confirmed a strong association between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (OR=29.75, 95% CI=3.83 to 231.21, p=0.001).
The CT/TT compound genotype at IVS8+4 and IVS8+32 is a strong genetic risk determinant for NTG but not HTG.
Journal of Medical Genetics 08/2009; 47(2):120-5. · 6.36 Impact Factor
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Neurology 03/2009; 72(6):568-9. · 8.31 Impact Factor
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ABSTRACT: Mitochondrial DNA mutations cause disease in >1 in 5000 of the population, and approximately 1 in 200 of the population are asymptomatic carriers of a pathogenic mtDNA mutation. Many patients with these pathogenic mtDNA mutations present with a progressive, disabling neurological syndrome that leads to major disability and premature death. There is currently no effective treatment for mitochondrial disorders, placing great emphasis on preventing the transmission of these diseases. An empiric approach can be used to guide genetic counseling for common mtDNA mutations, but many families transmit rare or unique molecular defects. There is therefore a pressing need to develop techniques to prevent transmission based on a solid understanding of the biological mechanisms. Several recent studies have cast new light on the genetics and cell biology of mtDNA inheritance, but these studies have also raised new controversies. Here we compare and contrast these findings and discuss their relevance for the transmission of human mtDNA diseases.
Biochimica et Biophysica Acta 03/2009; 1792(12):1097-102. · 4.66 Impact Factor
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J D Stewart,
S Tennant,
H Powell,
A Pyle,
E L Blakely,
L He,
G Hudson,
M Roberts,
D du Plessis,
D Gow,
L D Mewasingh,
M G Hanna,
S Omer,
A A Morris,
R Roxburgh,
J H Livingston,
R McFarland,
D M Turnbull, P F Chinnery,
R W Taylor
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ABSTRACT: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease.
We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers-Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids.
The addition of these substitutions-including the first report of a dinucleotide mutation (c.1814_1815TT>GC)-to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations.
Journal of Medical Genetics 03/2009; 46(3):209-14. · 6.36 Impact Factor
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E Matthews,
R Labrum,
M G Sweeney,
R Sud,
A Haworth, P F Chinnery,
G Meola,
S Schorge,
D M Kullmann,
M B Davis,
M G Hanna
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ABSTRACT: Several missense mutations of CACNA1S and SCN4A genes occur in hypokalemic periodic paralysis. These mutations affect arginine residues in the S4 voltage sensors of the channel. Approximately 20% of cases remain genetically undefined.
We undertook direct automated DNA sequencing of the S4 regions of CACNA1S and SCN4A in 83 cases of hypokalemic periodic paralysis.
We identified reported CACNA1S mutations in 64 cases. In the remaining 19 cases, mutations in SCN4A or other CACNA1S S4 segments were found in 10, including three novel changes and the first mutations in channel domains I (SCN4A) and III (CACNA1S).
All mutations affected arginine residues, consistent with the gating pore cation leak hypothesis of hypokalemic periodic paralysis. Arginine mutations in S4 segments underlie 90% of hypokalemic periodic paralysis cases.
Neurology 01/2009; 72(18):1544-7. · 8.31 Impact Factor
