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T T Warner

Publications and source records attributed to T T Warner.

34 records · Page 2Linked to original sources
PubMed2000

Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy.

We studied in vivo muscle energy metabolism in patients with Huntington's disease (HD) and dentatorubropallidoluysian atrophy (DRPLA) using 31P magnetic resonance spectroscopy (MRS). Twelve gene-positive HP patients (4 presymptomatic patients) and 2 gene-positive DRPLA patients (1 presymptomatic patient) were studied. 31P-MRS at rest showed a reduced phosphocreatine-to-inorganic phosphate ratio in the symptomatic HD patients and DRPLA patient. Muscle adenosine triphosphate/(phosphocreatine + inorganic phosphate) at rest was significantly reduced in both groups of symptomatic and presymptomatic HD subjects and was below the normal range in the 2 DRPLA subjects. During recovery from exercise, the maximum rate of mitochondrial adenosine triphosphate production was reduced by 44% in symptomatic HD patients and by 35% in presymptomatic HD carriers. The maximum rate of mitochondrial adenosine triphosphate production in muscle was also reduced by around 46% in the 2 DRPLA subjects. Our findings show that HD and DRPLA share a deficit of in vivo mitochondrial oxidative metabolism, supporting a role for mitochondrial dysfunction as a factor involved in the pathogenesis of these polyglutamine repeat-mediated neurodegenerative disorders. The identification of 31P-MRS abnormalities may offer a surrogate biochemical marker by which to study disease progression and the effects of treatment in HD and DRPLA.

Adenosine Triphosphate↗
PubMed1999

Detailed haplotype analysis in Ashkenazi Jewish and non-Jewish British dystonic patients carrying the GAG deletion in the DYT1 gene: evidence for a limited number of founder mutations.

The DYT1 gene on human chromosome 9q34 appears to be responsible for most cases of early onset primary torsion dystonia (PTD) both in Ashkenazi Jewish (AJ) and in non-Jewish patients. Previous haplotype analysis in a 2 cM region surrounding the DYT1 gene showed that a single founder mutation (DYT1AJ) was responsible for most cases of early onset PTD in the North American AJ population and refined the most likely location of the gene to a 150 kb interval between the marker loci D9S2161 and D9S63. Recently, the majority of cases of early onset PTD in both AJ and non-Jewish patients were found to carry a unique 3-bp (GAG) deletion in the coding region of the DYT1 gene. This deletion appears to have arisen more than once, suggesting independent mutational events. In this study, we analysed the haplotypes surrounding DYT1 in 9 AJ and 15 non-Jewish British patients carrying the GAG deletion in the DYT1 gene. We found that all AJ British patients carried the same haplotype as the North American Jews, sustaining the theory that the current British AJ community descends from the same small group of individuals as the North American Jewry. Furthermore, in the non-Jewish British patients, only a limited number of distinct founder mutations was observed. This supports the hypothesis that the GAG deletion in the DYT1 gene is not a very frequent mutation, and that it has arisen only a limited number of times throughout the centuries.

Alleles↗
PubMed1998

The role of DYT1 in primary torsion dystonia in Europe.

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous movement disorder. DYT1 on chromosome 9q34 was the first PTD gene to be mapped. A 3-bp (GAG) deletion in this gene was reported to account for almost all early limb-onset generalized PTD. No relationship has been found with DYT1 in patients with prominent craniocervical involvement. To elucidate the DYT1-associated phenotype, we analysed the DYT1 mutation in 150 PTD patients, either sporadic or index cases from small PTD families. Twenty-two patients were positive for the GAG deletion in the DYT1 gene. Fifteen of them presented with the typical DYT1 phenotype (early, limb-onset generalized dystonia without spread to craniocervical muscles), four had limb-onset dystonia with spread to craniocervical muscles, two patients had arm-onset segmental dystonia and one had focal right-arm dystonia. One-hundred and twenty-eight patients were negative for the DYT1 mutation. Forty-six of them had segmental dystonia and 59 had focal dystonia. The other 23 patients presented with generalized dystonia, either with craniocervical involvement (13 patients) or without spread to the craniocervical region (typical DYT1 phenotype-10 patients). These data confirm the importance of the GAG deletion in European cases of PTD, and indicate phenotypic and genotypic heterogeneity.

Adolescent↗
PubMed1998

The dystonias.

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Diagnosis, Differential↗
PubMed1998

The role of the alpha-synuclein gene mutation in patients with sporadic Parkinson's disease in the United Kingdom.

Parkinson's disease is a common neurodegenerative disorder of unknown aetiology. A pathogenic point mutation within the a-synuclein gene has recently been identified in one Italian-American kindred and three families of Greek origin with parkinsonism. DNA from 70 patients with Parkinson's disease was screened for this G209A mutation. No samples were positive for the mutation, suggesting that it is not relevant for most patients with sporadic idiopathic Parkinson's disease.

DNA Mutational Analysis↗
PubMed1997

Genetic counselling in mitochondrial diseases.

Mitochondrial disorders may be caused by mutations either in mitochondrial or in nuclear genes involved in the synthesis or regulation of respiratory chain subunits. The unique nature of the mitochondrial genome calls for a different approach to genetic counselling and risk analysis.

DNA Mutational Analysis↗
PubMed1996

Exclusion of the DYT1 locus in familial torticollis.

Clinical-genetic studies of idiopathic torsion dystonia (ITD) indicate that the DYT1 gene on chromosome 9q34 is responsible for most childhood limb-onset disease. The genetic basis of adult-onset ITD is less well studied. In most multiplex adult-onset ITD families, dystonia is limited to the cervical, cranial, or brachial muscles; in a few rare families, dystonia also involves the legs and trunk. Previous linkage studies have excluded the DYT1 locus in these atypical families. We studied two large non-Jewish families with adult-onset ITD limited to the cervical and brachial muscles and excluded the DYT1-containing region. This study further restricts the role of DYT1 to childhood limb-onset ITD and suggests that other genes are responsible for focal adult-onset ITD.

Adolescent↗
PubMed1995

A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families.

Dentatorubropallidoluysian atrophy is a neurodegenerative disorder with characteristic pathology, chiefly described in reports from Japan, and is associated with an unstable CAG trinucleotide repeat in a gene on chromosome 12. We describe four European families, three British and one Maltese, with this mutation. All exhibited autosomal dominant inheritance, and there was evidence for anticipation associated with an increase of the expansion with paternal transmission in two families. Affected chromosomes from patients with dentatorubropallidoluysian atrophy had CAG expansions of 58 to 74 repeats, compared to 7 to 26 in control chromosomes, and the size of repeat was significantly inversely correlated with age of onset. The clinical features were diverse, even within individual families, and comprised a combination of a movement disorder (chorea, myoclonus, dystonia, or parkinsonism), cerebellar ataxia, epilepsy, psychosis, and dementia. A clinical diagnosis of Huntington's disease had been made in affected individuals from all families. Neuropathological examination of 2 patients showed no specific abnormality in one and degenerative changes predominantly affecting the spinal cord in the other. Investigation of 55 patients who might represent sporadic examples of dentatorubropallidoluysian atrophy did not detect any expanded alleles. Dentatorubropallidoluysian atrophy is likely to be more common than previously recognized in non-Japanese populations, and should be considered in any patient with a dominantly inherited neurodegenerative disorder with the above-mentioned clinical features.

Adolescent↗
PubMed1994

Autosomal-dominant dentatorubropallidoluysian atrophy in the United Kingdom.

Dentatorubropallidoluysian atrophy (DRPLA) has been described chiefly in Japan and appears to be rare in Europe. It is of autosomal dominant inheritance. We report the first British family with DRPLA, which contains four affected individuals in two generations. The diagnosis was made at autopsy in one case. The age of onset of symptoms ranged from 15 to 38 years, and clinical features included ataxia, dementia, chorea, and dystonia; three patients had generalized seizures. The three living patients resemble those with early Huntington's disease clinically. Three main phenotypes of DRPLA have been proposed: an ataxo-choreoathetoid type, a pseudo-Huntington type, and a myoclonic epilepsy type. The variation in clinical presentation in our family demonstrates the difficulty in applying such classifications to this and other dominantly inherited disorders with phenotypic variation. DRPLA is likely to be confused with Huntington's disease in European families.

Adult↗
PubMed1994

DRPLA in Europe.

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Atrophy↗
PubMed1993

Linkage analysis with chromosome 9 markers in hereditary essential tremor.

Hereditary essential tremor (ET) is an autosomal dominant disorder with variable expression and reduced penetrance. A tremor indistinguishable from ET may be observed in patients with autosomal dominant idiopathic torsion dystonia (ITD), in which the disease locus has been mapped to 9q32-34 in some kindreds, tightly linked to the argininosuccinate synthetase (ASS) locus. We performed linkage analysis in 15 families with ET containing 60 definitely affected individuals, using dinucleotide repeat polymorphisms at the ASS locus and the Abelson locus (ABL). Cumulative lod scores were -19.5 for ASS and -10.8 for ABL at a recombination fraction of 0.01, and tight linkage to ASS was excluded individually in 11 of the families. These data indicate that the ET gene is not allelic to that causing ITD.

Adolescent↗
PubMed1993

Linkage analysis in British and French families with idiopathic torsion dystonia.

Idiopathic torsion dystonia is most commonly caused by an autosomal dominant gene or genes with reduced penetrance. An idiopathic torsion dystonia locus has been mapped to chromosome 9q34 in one large non-Jewish and several Jewish kindreds in the USA. Linkage analysis was performed in 27 (26 British, one French) small families with idiopathic torsion dystonia, three of which were Ashkenazi Jewish, using the highly polymorphic loci argininosuccinate synthetase (ASS) and Abelson oncogene (ABL) which map to 9q34. The cumulative lod score for the more informative ASS locus at a recombination fraction of 0.001 was -6.72. A large component of this score was derived from three non-Jewish families, indistinguishable clinically from the others, in which individual lod scores excluded a disease locus tightly linked to ASS. Analysis of all the data using HOMOG showed significant heterogeneity, but evidence for linkage of an idiopathic torsion dystonia gene to 9q34 in a subset of families. The allelic association observed between ASS/ABL and idiopathic torsion dystonia in Ashkenazi families in the USA was also present in British Jewish kindreds. These data suggest genetic heterogeneity in idiopathic torsion dystonia but indicate the existence of a locus for idiopathic torsion dystonia at 9q34 in both Jewish and non-Jewish kindreds in the UK.

Argininosuccinate Synthase↗
PubMed1992

Reactivation of tuberculous lymphadenitis during pregnancy.

Three patients presenting with tuberculous lymphadenitis during pregnancy are described. By suppressing cell-mediated immunity, pregnancy predisposes the mother to infections of the type in which cellular immunity is important in defence. In this setting, self-healed primary pulmonary or extra-pulmonary tuberculosis may reactivate.

Adult↗