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Biomedical subjects

T D Bird

Publications and source records attributed to T D Bird.

At least 19 recordsLinked to original sources
PubMed2001

Craniofacial and cutaneous findings expand the phenotype of hereditary neuralgic amyotrophy.

BACKGROUND: Hereditary neuralgic amyotrophy (HNA) is an autosomal-dominant disorder associated with recurrent, episodic, painful, brachial neuropathy. The gene for HNA has been mapped to chromosome 17q25. Characteristic features including hypotelorism, short stature, and cleft palate occur in some patients. OBJECTIVE: To further characterize the clinical, neurologic, and craniofacial features in 27 patients from seven families with HNA. METHODS: Medical history, physical examination, and facial measurements were obtained. Facial measurements were also made on 60 healthy controls. RESULTS: Twenty-five patients had an average of three attacks of brachial neuritis. The right arm was involved more frequently. Cleft palate was present in four individuals. Facial measurements showed significant hypotelorism in HNA patients versus controls. Unusual skin folds and creases were observed on the necks of several individuals as well as on the scalp of one man: cutis verticis gyrata. In three families, deep skin creases were present on the limbs of infants and toddlers who were subsequently affected with HNA. CONCLUSIONS: The phenotypic consequences of the mutant hereditary neuralgic atrophy gene may include a wider spectrum than previously appreciated and involve nonneural tissue.

Adolescent↗
PubMed2001

Parkinson's disease, CYP2D6 polymorphism, and age.

OBJECTIVE: PD may be caused by genetic susceptibility to neurotoxins. CYP2D6 is a candidate gene for PD because it regulates drug and toxin metabolism, but association studies have been inconsistent. The aim of this study was to test if the CYP2D6*4 allele (poor metabolizer phenotype) is associated with earlier age at onset. METHODS: Five hundred seventy-six patients with PD and 247 subjects without PD were studied using standard diagnostic, genotyping, and statistical techniques. RESULTS: Surprisingly, mean onset age was significantly later in *4-positive patients. Frequency of *4 was significantly higher in late-onset PD than early-onset PD. When early- and late-onset PD were analyzed separately, *4 had no effect on onset age; hence, the association with delayed onset was likely an artifact of an elevated *4 frequency in late-onset PD. Contrary to a common assumption that CYP2D6 frequencies do not change with age, *4 frequency rose significantly with advancing age, both in patients with PD (from 0.16 at mean age of 56.5 years to 0.21 at mean age of 72) and subjects without PD (from 0.09 at mean age of 45.5 years to 0.21 at mean age of 72). *4 Frequencies in patients with early- and late-onset PD, although different from each other, were in agreement with similarly aged subjects without PD, suggesting the elevated *4 frequency in late-onset PD was likely an age effect, unrelated to PD. CONCLUSION: The CYP2D6*4 allele is not associated with earlier PD onset. *4 May be associated with survival. Inconsistent results from allelic association studies may have been due to an unrecognized age effect.

Age of Onset↗
PubMed2001

Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia.

BACKGROUND: DNA testing of persons at risk for hereditary, degenerative neurologic diseases is relatively new. Only anecdotal reports of such testing in familial Alzheimer disease (FAD) exist, and little is know about the personal and social impact of such testing. METHODS: In a descriptive, observational study, individuals at 50% risk for autosomal dominant, early-onset FAD or frontotemporal dementia with parkinsonism linked to chromosome 17 underwent DNA testing for the genetic mutations previously identified in affected family members. Individuals were followed up for (1/2) to 3 years and were interviewed regarding attitudes toward the testing process and the impact of the results. RESULTS: Twenty-one (8.4%) of 251 persons at risk for FAD or frontotemporal dementia requested genetic testing. The most common reasons for requesting testing were concern about early symptoms of dementia, financial or family planning, and relief from anxiety. Twelve individuals had positive DNA test results, and 6 of these had early symptoms of dementia; 8 had negative results; and 1 has not yet received results. Of 14 asymptomatic individuals completing testing, 13 believed the testing was beneficial. Two persons reported moderate anxiety and 1 reported moderate depression. As expected, persons with negative test results had happier experiences overall, but even they had to deal with ongoing anxiety and depression. Thus far, there have been no psychiatric hospitalizations, suicide attempts, or denials of insurance. CONCLUSIONS: Genetic testing in early-onset FAD and frontotemporal dementia can be completed successfully. Most individuals demonstrate effective coping skills and find the testing to be beneficial, but long-term effects remain unknown.

Adult↗
PubMed2001

TAU as a susceptibility gene for amyotropic lateral sclerosis-parkinsonism dementia complex of Guam.

BACKGROUND: A Guam variant of amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia complex (PDC-G) are found in the Chamorro people of Guam. Both disorders have overlapping neuropathologic findings, with neurofibrillary tangles in spinal cord and brain. The cause of ALS-G-PDC-G is unknown, although inheritance and environment appear important. Because neurofibrillary tangles containing tau protein are present in ALS-G-PDC-G, and because mutations in the tau gene (TAU) cause autosomal dominant frontotemporal dementia, TAU was examined as a candidate gene for ALS-G-PDC-G. METHODS: TAU was evaluated by DNA sequence analysis in subjects with ALS-G-PDC-G, by linkage analysis of TAU polymorphisms in an extended pedigree from the village of Umatac, and by evaluation of linkage disequilibrium with polymorphic markers flanking and within TAU. RESULTS: Linkage disequilibrium between ALS-G-PDC-G and the TAU polymorphism CA3662 was observed. For this 2-allele system, PDC and ALS cases were significantly less likely than Guamanian controls to have the 1 allele (4.9% and 2% vs 11.5%, respectively; Fisher exact P =.007). DNA sequence analysis of TAU coding regions did not demonstrate a mutation responsible for ALS-G-PDC-G. Analysis of TAU genotypes in an extended pedigree of subjects from Umatac showed obligate recombinants between TAU and ALS-G-PDC-G. Linkage analysis of the Umatac pedigree indicates that TAU is not the major gene for ALS-G-PDC-G. CONCLUSIONS: The genetic association between ALS-G-PDC-G implicates TAU in the genetic susceptibility to ALS-G-PDC-G. TAU may be a modifying gene increasing risk for ALS-G-PDC-G in the presence of another, as yet, unidentified gene.

Adult↗
PubMed2001

Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia.

BACKGROUND: Mutations in the tau gene have been reported in families with frontotemporal dementia (FTD) linked to chromosome 17. It remains uncertain how commonly such mutations are found in patients with FTD or non-Alzheimer dementia with or without a positive family history. OBJECTIVE: To determine the frequency of tau mutations in patients with non-Alzheimer dementia. PATIENTS AND METHODS: One hundred one patients with non-Alzheimer, nonvascular dementia, most thought to have FTD. Of these, 57 had a positive family history of dementia. Neuropathologic findings were available in 32. The tau gene was sequenced for all exons including flanking intronic DNA, portions of the 3' and 5' untranslated regions, and at least 146 base pairs in the intron following exon 10. RESULTS: Overall, the frequency of the tau mutations was low, being 5.9% (6/101) in the entire group. No mutations were found in the 44 sporadic cases. However, 6 (10.5%) of the 57 familial cases and 4 (33%) of the 12 familial cases with tau pathologic findings had mutations in the tau gene. The most common mutation was P301L. CONCLUSIONS: We conclude that tau mutations are uncommon in a neurology referral population with non-Alzheimer dementia, even in those with a clinical diagnosis of FTD. However, a positive family history and/or tau pathologic findings increase the likelihood of a tau mutation. There must be other genetic and nongenetic causes of FTD and non-Alzheimer dementia, similar to the etiologic heterogeneity present in Alzheimer disease.

Chromosomes, Human, Pair 17↗
PubMed2001

Prion proteins with different conformations accumulate in Gerstmann-Sträussler-Scheinker disease caused by A117V and F198S mutations.

Gerstmann-Sträussler-Scheinker disease (GSS) is characterized by the accumulation of proteinase K (PK)-resistant prion protein fragments (PrP(sc)) of approximately 7 to 15 kd in the brain. Purified GSS amyloid is composed primarily of approximately 7-kd PrP peptides, whose N terminus corresponds to residues W(81) and G(88) to G(90) in patients with the A117V mutation and to residue W(81) in patients with the F198S mutation. The aim of this study was to characterize PrP in brain extracts, microsomal preparations, and purified fractions from A117V patients and to determine the N terminus of PrP(sc) species in both GSS A117V and F198S. In all GSS A117V patients, the approximately 7-kd PrP(sc) fragment isolated from nondigested and PK-digested samples had the major N terminus at residue G(88) and G(90), respectively. Conversely, in all patients with GSS F198S, an approximately 8-kd PrP(sc) fragment was isolated having the major N terminus start at residue G(74). It is possible that a further degradation of this fragment generates the amyloid subunit starting at W(81). The finding that patients with GSS A117V and F198S accumulate PrP(sc) fragments of different size and N-terminal sequence, suggests that these mutations generate two distinct PrP conformers.

Amyloid↗
PubMed2000

SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance.

We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetrance associated with paternal transmission.

Alleles↗
PubMed2000

Late-onset SCA2: 33 CAG repeats are sufficient to cause disease.

SCA-2 is an autosomal dominant inherited disorder characterized by ataxia, slow saccades, and hyporeflexia. The authors evaluated a patient with a mild balance problem with a SCA-2 allele sized at 33 CAG repeats. The authors then ascertained her 91 year-old mother, who showed disease onset at age 86 with an SCA-2 allele of identical size. Their study indicates that 33 CAG repeats can be pathogenic at the SCA-2 locus, though such an allele may produce an extremely late onset and gradual rate of disease progression.

Aged↗
PubMed2000

Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions.

OBJECTIVE: To describe the clinical features, neuropathology, and genetic studies in a family with autosomal dominant frontotemporal dementia (FTD). BACKGROUND: Clinical Pick's disease, or FTD with parkinsonism, has been described in several families linked to chromosome 17 (FTDP-17). Most of these have shown tau protein mutations. The clinical and pathologic variations in these families resemble the spectrum of sporadic FTD or "Pick complex." METHODS: Clinical and behavioral analysis of the affected members with extensive histochemical and neuropathologic description of three cases, genetic analysis of three clinically affected members and seven at risk members to assess linkage to chromosome 17, and sequencing of the tau gene in two patients were performed. RESULTS: The clinical pattern shows a highly stereotypic disinhibition dementia with late extrapyramidal features, progressive mutism, and terminal dysphagia in three generations of affected individuals. Neuropathology showed frontotemporal atrophy, and microscopically tau- and synuclein-negative and ubiquitin-positive neuronal inclusions, in the background of superficial cortical spongiosis, neuronal loss, and gliosis. Tau expression was restricted to oligodendroglia. All exons and surrounding introns of the tau gene were sequenced, and no mutation or disease-related polymorphisms were detected in either of two affected pedigree members. CONCLUSION: This family with autosomal dominant frontotemporal dementia (FTD) shows no tau expression in neurons. The ubiquitin-positive, tau-negative inclusions have been described before in FTD with and without motor neuron disease, but not in a familial form. The clinical and some pathologic features are similar to those of several of the families included in descriptions of FTD with parkinsonism linked to chromosome 17, but the linkage to tau has been excluded. The defect in this family, however, could be functionally related to tau mutations.

Adult↗
PubMed2000

Pro-apoptotic effects of tau mutations in chromosome 17 frontotemporal dementia and parkinsonism.

It was recently discovered that mutations of tau cause hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Here we report that cultured SH-SY5Y human neuroblastoma cells transfected with mutated tau genes are more vulnerable to apoptotic stimulus. Two kinds of mutations of tau causing FTDP-17 were examined in the present study: one was in exon 10 (N279K) and the other was in exon 12 (V337M). SH-SY5Y cells transfected with either mutated tau were more vulnerable to serum withdrawal, whereas cells transfected with the wild-type tau or vector alone showed no significant change in apoptotic vulnerability. The increase in the intracellular calcium concentration by the serum withdrawal was significantly greater in the SH-SY5Y cells transfected with mutated tau genes than in cells transfected with the wild-type tau or vector alone. These results suggest that mutations of tau might cause FTDP-17 by these pro-apoptotic functions by disrupting the intracellular calcium homeostasis.

Apoptosis↗
PubMed2000

Neuropathological heterogeneity in Alzheimer's disease: a study of 80 cases using principal components analysis.

Three hypotheses have been proposed to explain neuropathological heterogeneity in Alzheimer's disease (AD): the presence of distinct subtypes ('subtype hypothesis'), variation in the stage of the disease ('phase hypothesis') and variation in the origin and progression of the disease ('compensation hypothesis'). To test these hypotheses, variation in the distribution and severity of senile plaques (SP) and neurofibrillary tangles (NFT) was studied in 80 cases of AD using principal components analysis (PCA). Principal components analysis using the cases as variables (Q-type analysis) suggested that individual differences between patients were continuously distributed rather than the cases being clustered into distinct subtypes. In addition, PCA using the abundances of SP and NFT as variables (R-type analysis) suggested that variations in the presence and abundance of lesions in the frontal and occipital lobes, the cingulate gyrus and the posterior parahippocampal gyrus were the most important sources of heterogeneity consistent with the presence of different stages of the disease. In addition, in a subgroup of patients, individual differences were related to apolipoprotein E (ApoE) genotype, the presence and severity of SP in the frontal and occipital cortex being significantly increased in patients expressing apolipoprotein (Apo)E allele epsilon4. It was concluded that some of the neuropathological heterogeneity in our AD cases may be consistent with the 'phase hypothesis'. A major factor determining this variation in late-onset cases was ApoE genotype with accelerated rates of spread of the pathology in patients expressing allele epsilon4.

Age of Onset↗
PubMed2000

The number of trait loci in late-onset Alzheimer disease.

Although it is clear that apoE plays an important role in the genetics of late-onset Alzheimer disease (AD), evidence exists that additional genes may play a role in AD, and estimates of the total contribution of apoE to the variance in onset of AD vary widely. Unfortunately, little information is available on the number and contribution of additional genes. We estimated the number of additional quantitative-trait loci and their contribution to the variance in age at onset of AD, as well as the contribution of apoE and sex, in an oligogenic segregation analysis of 75 families (742 individuals) ascertained for members with late-onset AD. We found evidence that four additional loci make a contribution to the variance in age at onset of late-onset AD that is similar to or greater in magnitude than that made by apoE, with one locus making a contribution several times greater than that of apoE. Additionally, we confirmed previous findings of a dose effect for the apoE varepsilon4 allele, a protective effect for the varepsilon2 allele, evidence for allelic interactions at the apoE locus, and a small protective effect for males. Furthermore, although we estimate that the apoE genotype can make a difference of </=17 years in age at onset of AD, our estimate of the contribution of apoE (7%-9%) to total variation in onset of AD is somewhat smaller than that which has previously been reported. Our results suggest that several genes that have not yet been localized may play a larger role than does apoE in late-onset AD.

Adult↗
PubMed2000

Familial aggregation of psychotic symptoms in Huntington's disease.

OBJECTIVE: The mutation responsible for Huntington's disease is an elongated and unstable trinucleotide (CAG) repeat on the short arm of chromosome 4. Psychotic symptoms are more common in patients with Huntington's disease than in the general population. This study explored the relationship of psychosis in Huntington's disease patients with the number of CAG repeats and family history of psychosis. METHOD: Forty-four patients with Huntington's disease, 22 with and 22 without psychotic symptoms, were recruited from two university-affiliated medical genetics clinics in Seattle and Vancouver, B.C. Psychiatric assessments of the subjects were made through chart review, and diagnoses were validated by structured interviews in a subset of patients. The demographic and clinical characteristics of the psychotic and nonpsychotic patients were compared. RESULTS: The two groups did not differ in demographic and clinical characteristics, except that subjects with psychosis were significantly more likely than nonpsychotic subjects to have a first-degree relative with psychosis. In eight of nine families in which Huntington's disease probands with psychosis had a first-degree relative with psychosis, the relative's psychosis co-occurred with Huntington's disease. In the Huntington's disease probands with psychosis, the onset of psychosis correlated with the onset of the neurological symptoms of Huntington's disease, and the age at onset of psychosis was lower in probands with a higher number of CAG repeats. CONCLUSIONS: Patients with Huntington's disease and psychotic symptoms may have a familial predisposition to develop psychosis. This finding suggests that other genetic factors may influence susceptibility to a particular phenotype precipitated by CAG expansion in the Huntington's disease gene.

Adolescent↗