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M G Sweeney

Publications and source records attributed to M G Sweeney.

At least 19 recordsLinked to original sources
PubMed2004

Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India.

OBJECTIVE: Spinocerebellar ataxia type 2 (SCA2) has been reported as the commonest dominant hereditary ataxia in India. However, India is an ethnically and religiously diverse population. Previous studies have not clearly indicated exact ethnic and religious origins, and must therefore be interpreted with caution. The purpose of this study was to determine the prevalence of different SCA mutations in a relatively homogeneous population from eastern India. METHODS: We identified 28 families with autosomal dominant cerebellar ataxia from eastern India. Each underwent full clinical evaluation and were analysed for the presence of SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and SCA17 mutations. In addition, haplotype analysis was carried out in seven of the 16 families with SCA2. RESULTS: Seven patients from four (14%) families were positive for an expansion in SCA1 and 26 patients from 16 (57%) families were positive for an expansion in SCA2. No mutations were detected in the remaining eight families (29%). Most of the SCA1 and SCA2 families were Hindu from the state of Bihar. Five out of 26 SCA2 patients in this study did not have slow saccades. In addition, four of seven SCA1 patients had slow saccades. We found an association between the SCA2 CAG repeat expansion and the 285 base pair (bp) allele of microsatellite marker D12S1672, and also data supportive of the association between the expansion and the 225 bp allele of D12S1333, which has been previously described. CONCLUSIONS: We conclude that (1) although slow ocular saccades are highly suggestive of SCA2, that they are not universal, nor are they exclusive to this disorder and (2) SCA2 is likely to be the commonest dominant ataxia in eastern India, with further evidence for a founder effect.

Adolescent↗
PubMed2003

Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type 1A due to the 17p11.2-p12 duplication.

The Thr(118)Met substitution in the peripheral myelin protein 22 (PMP22) gene has been detected in a number of families with demyelinating Charcot-Marie-Tooth (CMT1) neuropathy or with the hereditary neuropathy with liability to pressure palsy, but in none of them has it consistently segregated with the peripheral neuropathy. We describe here a CMT1 family (a 63-year-old man, his brother and his niece) in which two mutations on different chromosomes were found in the PMP22 gene, the 17p duplication, detected by fluorescent semiquantitative polymerase chain reaction (PCR) of microsatellite markers localized within the duplicated region on chromosome 17p11.2-p12, and the Thr(118)Met substitution, detected by direct sequencing the four coding exons of the PMP22 gene. A genotype/phenotype correlation study showed that the neuropathy segregates with the duplication and that the amino acid substitution does not seem to modify the clinical characteristics or the severity of the peripheral neuropathy. We did not find any evidence to characterize this substitution as a polymorphism in the population studied and we propose that the high frequency reported for this point mutation in the literature suggests that the Thr(118)Met substitution may be a hotspot for mutations in the PMP22 gene.

Amino Acid Substitution↗
PubMed2003

Severe infantile hyperkalaemic periodic paralysis and paramyotonia congenita: broadening the clinical spectrum associated with the T704M mutation in SCN4A.

The authors describe an Italian kindred with nine individuals affected by hyperkalaemic periodic paralysis associated with paramyotonia congenita (hyperPP/PMC). Periodic paralysis was particularly severe, with several episodes a day lasting for hours. The onset of episodes was unusually early, beginning in the first year of life and persisting into adult life. The paralytic episodes were refractory to treatment. Patients described minimal paramyotonia, mainly of the eyelids and hands. All affected family members carried the threonine to methionine substitution at codon 704 (T704M) in exon 13 of the skeletal muscle voltage gated sodium channel gene (SCN4A). The association between T704M and the hyperPP/PMC phenotype has been only recently revealed. Nevertheless, such a severe phenotype has never been reported so far in families with either hyperPP or hyperPP/PMC. These data further broaden the clinical spectrum of T704M and support the evidence that this mutation is a common cause of hyperPP/PMC.

Adolescent↗
PubMed2002

Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease.

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.

Adolescent↗
PubMed2000

Increased risk of stroke in patients with the A12308G polymorphism in mitochondria.

Factors which increase the risk of stroke in patients with the A3243G (mitochondrial encephalomyopathy, lactic acidosis, and stroke [MELAS]) mutation in human mitochondrial DNA are unclear. Previous work on lung-cancer cells with an A3243G mutation showed that a mutation in the mitochondrial transfer gene for leucine tRNA(Leu(CUN)) was able to ameliorate the A3243G-induced biochemical phenotype. We analysed the tRNA(Leu(CUN)) gene in 48 unrelated A3243G cases. We showed that a polymorphism, A12308G, in tRNA(Leu(CUN)) increases the risk of developing stroke in patients with the A3243G mutation (relative risk=2.17). This may have implications for genetic counselling.

DNA Mutational Analysis↗
PubMed1999

Phenotypic variation of a new P0 mutation in genetically identical twins.

We have identified a new point mutation in the myelin protein zero (P0) gene in two genetically identical twins with a demyelinating neuropathy. The G to A transition at nucleotide position 382 caused an aspartic acid to asparagine substitution in exon 3. Moreover, we found clear clinical differences which were most evident at an early age. These observations suggest that the expression of this P0 mutation may be susceptible to external, non-genetic influences that may act early in the course of the disease to alter the phenotype.

Adult↗
PubMed1998

Dejerine-Sottas neuropathy and PMP22 point mutations: a new base pair substitution and a possible "hot spot" on Ser72.

The occurrence of mutations in peripheral myelin protein 22 is one of the genetic mechanisms associated with Dejerine-Sottas neuropathy (DSN). On direct sequencing 2 of such patients we have found the first mutation in the third transmembrane domain associated with this neuropathy and the fourth Ser72Leu. We propose that the Ser72 may be a "hot spot" for DSN and that this should be considered for molecular analysis.

Adult↗
PubMed1998

Generalized chorea in two patients harboring the Friedreich's ataxia gene trinucleotide repeat expansion.

Recently, a trinucleotide repeat expansion in intron 1 of the frataxin gene on chromosome 9p13 has been identified as the genetic defect in Friedreich's ataxia (FA). We have identified two patients exhibiting generalized chorea in the absence of cerebellar signs who were homozygous for this intron 1 expansion. Chorea as a rare manifestation of FA has previously been controversial. This is the first report of chorea in patients confirmed to have the FA genetic abnormality and broadens further the clinical phenotype associated with the FA genotype.

Adolescent↗
PubMed1998

The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates.

The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47 isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were analysed for this mutation. The identification of the SCA2 mutation in 31 out of 38 families with the ADCA I phenotype, but in none of those with ADCA II, ADCA III or ILOCA confirms the specificity of this mutation. A clinical comparison of the ADCA I patients with the three known mutations (SCA1, -2 or -3) highlights significant differences between the groups; SCA2 patients tended to have a longer disease duration, a higher frequency of slow saccades and depressed tendon reflexes. However, these neurological signs were also seen in an ADCA I family in which the SCA2 mutation was not identified, illustrating the importance of a direct genetic test. The SCA2 families were from different geographical and ethnic backgrounds. However, haplotype analysis failed to show evidence of a founder mutation, even in families from the same geographical origin. The range of normal alleles varied from 17 to 30 CAG repeats and from 35 to 51 repeats for the pathological alleles. Similar to the other diseases caused by unstable trinucleotide repeats, a significant inverse correlation has been found between the number of repeats and age of onset, and there is a significantly higher paternal instability of repeat length on transmission to offspring. The SCA2 mutation is the most frequent amongst ADCA I patients, accounting for 40%, compared with SCA1 and SCA3 which account for 35% and 15%, respectively.

Adolescent↗
PubMed1997

Mitochondrial DNA polymorphisms in pathologically proven Parkinson's disease.

To date, five single base pair changes of the mitochondrial DNA have been reported to occur either exclusively or with increased frequency in Caucasian patients with Parkinson's disease (PD) and it has been postulated that these mutations might be casually related to the observed inhibition of mitochondrial respiratory chain function in PD. To evaluate these findings, we analysed the frequency of all five polymorphisms in 100 cases of pathologically proven cases of PD. We were either unable to detect the previously described polymorphisms in our series or found them to be present with the same frequency among controls. Our data do not support the hypothesis of an involvement of the mitochondrial DNA in the pathogenesis of PD.

Adult↗
PubMed1997

The phenotypic manifestations of chromosome 17p11.2 duplication.

Clinical and electrophysiological investigations and nerve biopsies were carried out on 61 patients shown to have a chromosome 17p11.2 duplication (hereditary motor and sensory neuropathy-HMSN Ia). Of these, 50 showed a Charcot-Marie-Tooth (CMT) phenotype and eight could be classified as having the Roussy-Lévy syndrome. Of the patients with a CMT phenotype, three had associated pyramidal signs and of these one had 'complicated' HMSN and also signs of cerebellar and bulbar involvement. Diaphragmatic weakness was present in three severely affected cases, one of whom also had denervation of the anal sphincter associated with faecal incontinence. One unusual case presented in middle life with incapacitating muscle cramps associated with calf hypertrophy and only mild clinical signs of neuropathy. Prominent distal sensory loss was a consistent feature in one family, resulting in acrodystrophic changes in several members. Concurrent focal peripheral nerve lesions were seen with both the CMT and Roussy-Lévy phenotypes, in seven patients. Upper limb motor nerve conduction velocity was 19.9 m/s +/- 1.3 (SEM), range 5-34 m/s. This corresponds to values previously obtained for autosomal dominant HMSN I. This series consisted mainly of older patients with more advanced disease. In contrast to the findings in younger patients, in their nerve biopsies, myelin thickness tended to be relatively reduced for axon size, indicating remyelination and/or hypomyelination; there was also regression of the onion bulbs. It is concluded that the possession of two copies of the peripheral myelin protein 22 gene within the duplicated region on chromosome 17p gives rise to a range of phenotypes and not solely to a CMT syndrome, and that the pattern of histological change in the peripheral nerves alters with advance of the disease.

Adolescent↗
PubMed1997

Multiple-system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration.

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown cause. The only case-control study conducted in MSA patients to date suggested a possible contributory genetic component in the pathogenesis of this disorder. The aim of this study was to evaluate a possible overlap between clinically or pathologically well-defined MSA and other conditions with an identified genetic defect causing spinocerebellar degeneration in humans or mutant mice strains. The spinocerebellar ataxia type 1 and 3 genes (SCA1 and SCA3) were analyzed for a pathologic expansion in 80 patients with MSA to evaluate a possible overlap between MSA and SCA1 or SCA3. Weaver mice and lurcher mice are animal models for spinocerebellar degeneration; both share pathologic features with MSA. We sequenced the H5 pore region of the human homologue of the weaver mouse gene, hiGIRK2, in all our patients. In lurcher mice, previous biochemical studies have shown a decreased intracellular response to insulin-like growth factor 1 (IGF-1) in the cerebellar cortex, and we thus investigated the possibility of an allelic association between MSA and the receptor for IGF-1. In addition, we evaluated a possible involvement of the ciliary neurotrophic factor gene (CNTF) and examined the role of HLA-A32 to clarify the conflicting data from previous studies. No changes were detected in any of the analyzed genes. Our studies strongly suggest that MSA is an autonomous syndrome distinct from identified genetic causes for spinocerebellar degeneration.

Alleles↗
PubMed1996

Evidence against an X-linked visual loss susceptibility locus in Leber hereditary optic neuropathy.

Pedigree analysis of British families with Leber hereditary optic neuropathy (LHON) closely fits a model in which a pathogenic mtDNA mutation interacts with an X-linked visual loss susceptibility locus (VLSL). This model predicts that 60% of affected females will show marked skewing of X inactivation. Linkage analysis in British and Italian families with genetically proven LHON has excluded the presence of such a VLSL over 169 cM of the X chromosome both when all families were analyzed together and when only families with the bp 11778 mutation were studied. Further, there was no excess skewing of X inactivation in affected females. There was no evidence for close linkage to three markers in the pseudoautosomal region of the sex chromosomes. The mechanism of incomplete penetrance and male predominance in LHON remains unclear.

DNA, Mitochondrial↗
PubMed1995

Mitochondrial DNA (mtDNA) diseases: correlation of genotype to phenotype.

This study examines the relationship of genotype to phenotype in 14 unselected patients who were found to harbour the A3243G transition in the mitochondrial transfer RNALeu(UUR) gene commonly associated with the syndrome of mitochondrial encephalopathy, lactic acidosis and strokes (MELAS). Only 6 of the 14 cases (43%) had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. Of the remaining cases, four had an encephalomyopathy with deafness, ataxia and dementia, two had syndromes with progressive external ophthalmoplegia and two had limb weakness alone. Even within the MELAS subgroup, the majority of patients had one or more clinical manifestations considered to be atypical of the MELAS syndrome. They included developmental delay, ophthalmoparesis, pigmentary retinopathy and intestinal pseudo-obstruction. The proportion of mutant mitochondrial DNA (mtDNA) in muscle was generally higher in patients with recurrent strokes than in those without strokes, the highest levels being observed in MELAS cases with early onset disease. Studies of isolated muscle mitochondria identified a range of respiratory chain abnormalities mostly involving Complex I; immunoblots of Complex I in 3 of 10 cases showed selective loss of specific subunits encoded by nuclear genes. In the group as a whole, however, no clear correlations were observed between the severity or extent of the respiratory chain abnormality and clinical phenotype or the proportion of mutant mtDNA in biopsied skeletal muscle. These discrepancies suggest that, in patients harbouring the common MELAS3243 mutation, differences in heteroplasmy and the proportions of mutant mtDNA may not be the sole determinants of disease expression and that additional genetic mechanisms are involved in defining the range of clinical and biochemical phenotypes associated with this aberrant mitochondrial genome.

Adolescent↗
PubMed1995

Kearns-Sayre syndrome associated with mitochondrial DNA deletion or duplication: a molecular genetic and pathological study.

The neuropathological findings in 2 patients with Kearns-Sayre syndrome and mitochondrial DNA (mtDNA) rearrangements, one a predominant deletion and the other a predominant duplication, were remarkably similar, showing diffuse vacuolation of white matter. There were some of the pathological features of Leigh's syndrome in the spinal cord of the patient with a duplication. In the patient with a predominant deletion, rearranged mtDNA was undetectable in blood, spleen, and testis, and present in highest amounts in muscle and the brain, but relatively low in cerebellum, reflecting the ratio seen, albeit in much smaller amounts, in normal aged brains. MtDNA rearrangements in this patient were largely deletions or deletion dimers; duplicated mtDNA was present in only trace amounts in some tissues and there was none in skeletal muscle. The patient with a predominant duplication of mtDNA had higher amounts of rearranged mtDNA in blood (mainly duplicated) than muscle (mainly deleted). Correlation of these data with tissue dysfunction is probably complicated by the replicative behaviour of deleted, duplicated and normal mtDNA.

Adolescent↗
PubMed1995

The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation.

One hundred and seven patients from 79 families were defined as having Leber's hereditary optic neuropathy (LHON) by the presence of one of the mitochondrial DNA (mtDNA) mutations at positions 11778 (60 families), 3460 (seven families) or 14484 (12 families). Only half of the 11778 index patients had a history of similarly affected relatives; this proportion was higher with the 3460 (71%) and 14484 (100%) mutations. The ratios of affected male to female patients were 2.5:1 (11778), 2:1 (3460), and 5.7:1 (14484). Detailed clinical data were available for 79 patients from 55 families. Visual loss developed between the ages of 11 and 30 years in 69%, with a range of 6-62 years, and no significant differences between mutation groups or males and females. It was bilateral in all but two patients, to a median of counting fingers with a central scotoma, developing simultaneously in 22% and sequentially in 78%, with a median inter-eye delay of 8 weeks, and progressing in each eye over a period of 4-6 weeks. Nineteen patients had pain in an affected eye or on eye movements, and four experienced Uhthoff's phenomenon. Retinal microangiopathy was uncommon after 6 months from onset and was not detected in 36% of patients examined within 3 months of visual loss; the microangiopathy was particularly uncommon in the 14484 group. There was no difference in the overall visual outcome between the 11778 and 3460 groups with median final visual acuities of 1/60 and 3/60, respectively. Particularly severe visual loss occurred in one-third of women with the 11778 mutation, to vague perception of light or no perception of light in at least one eye. A multiple sclerosis-like illness was observed in 45% of females with the 11778 mutation. Prognosis was substantially better in the 14484 patients, with recovery to a final visual acuity of at least 6/24, in 71% of patients. Good visual outcome was strongly correlated with age at onset, all those with onset before 20 years having a final visual acuity better than 6/24 as opposed to only 2 out of 6 with later onset. Improvement in vision occurred as long as 4 years after onset. High alcohol and tobacco consumption, cranial or ocular trauma, young or old age at presentation, co-existing neurological disease, and recent childbirth with post-partum haemorrhage, all contributed to diagnostic difficulties in this series, usually in the absence of a family history. These problems were resolved by mtDNA analysis.

Adolescent↗