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Biomedical subjects

Thomas Bird

Publications and source records attributed to Thomas Bird.

14 recordsLinked to original sources
PubMed2006

Cambodian founder effect for spinocerebellar ataxia type 3 (Machado-Joseph disease).

Four families from the same region of Cambodia immigrated to the Pacific Northwest of the United States. All four families have been discovered to have spinocerebellar ataxia type 3 (SCA 3; Machado-Joseph disease) with a similar clinical phenotype. CAG repeat expansions in the ATXN3 gene range from 72 to 77. Mean age of onset has varied from 19 to 44 years and mean age at death of 4 individuals has been 60 years. The prevalence of the various subtypes of SCA varies worldwide from country to country. Neurologists should be alert to the possibility of SCA 3 in Cambodian patients with unexplained cerebellar ataxia.

Adult↗
PubMed2006

Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not alphaB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with alphaB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.

Adult↗
PubMed2006

Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.

OBJECTIVE: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive. METHODS: Here, we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients. Detailed clinical and genetic studies were performed. RESULTS: In each pedigree, we identified a unique mutation in the gene mitofusin 2 (MFN2). In three families, the MFN2 mutation occurred de novo; in two families the mutation was subsequently transmitted from father to son indicating autosomal dominant inheritance. INTERPRETATION: MFN2 is a mitochondrial membrane protein that was recently reported to cause axonal CMT type 2A. It is intriguing that MFN2 shows functional overlap with optic atrophy 1 (OPA1), the protein underlying the most common form of autosomal dominant optic atrophy, and mitochondrial encoded oxidative phosphorylation components as seen in Leber's hereditary optic atrophy. We conclude that autosomal dominant HMSN VI is caused by mutations in MFN2, emphasizing the important role of mitochondrial function for both optic atrophies and peripheral neuropathies.

Adolescent↗
PubMed2005

Proteomic determination of widespread detergent-insolubility including Abeta but not tau early in the pathogenesis of Alzheimer's disease.

Biochemical characterization of the major detergent-insoluble proteins that comprise hallmark histopathologic lesions initiated the molecular era of Alzheimer's disease (AD) research. Here, we reinvestigated detergent-insoluble proteins in AD using modern proteomic techniques. Using liquid chromatography (LC)-mass spectrometry (MS)-MS-based proteomics, we robustly identified 125 proteins in the detergent-insoluble fraction of late-onset AD (LOAD) temporal cortex that included several proteins critical to Abeta production, components of synaptic scaffolding, and products of genes linked to an increased risk of LOAD; we verified 15 of 15 of these proteins by Western blot. Following multiple analyses, we estimated that these represent ~80% of detergent-insoluble proteins in LOAD detectable by our method. Abeta, tau, and 7 of 8 other newly identified detergent-insoluble proteins were disproportionately increased in temporal cortex from patients with LOAD and AD derived from mutations in PSEN1 and PSEN2; all of these except tau were elevated in individuals with prodromal dementia, while none except Abeta were elevated in aged APPswe mice. These results are consistent with the amyloid hypothesis of AD and extend it to include widespread protein insolubility, not exclusively Abeta insolubility, early in AD pathogenesis even before the onset of clinical dementia.

Alzheimer Disease↗
PubMed2005

Gene expression in Huntington's disease skeletal muscle: a potential biomarker.

Huntington's disease (HD) is an incurable and fatal neurodegenerative disorder. Improvements in the objective measurement of HD will lead to more efficient clinical trials and earlier therapeutic intervention. We hypothesized that abnormalities seen in the R6/2 mouse, a greatly accelerated HD model, might highlight subtle phenotypes in other mouse models and human HD. In this paper, we identify common gene expression changes in skeletal muscle from R6/2 mice, Hdh(CAG(150)) homozygous knock-in mice and HD patients. This HD-triggered gene expression phenotype is consistent with the beginnings of a transition from fast-twitch to slow-twitch muscle fiber types. Metabolic adaptations similar to those induced by diabetes or fasting are also present but neither metabolic disorder can explain the full phenotype of HD muscle. The HD-induced gene expression changes reflect disease progression. This raises the possibility that muscle gene expression may be used as an objective biomarker to complement clinical HD-rating systems. Furthermore, an understanding of the molecular basis of muscle dysfunction in HD should provide insight into mechanisms involved in neuronal abnormalities and neurodegeneration.

Animals↗
PubMed2004

Coexistence of tuberous sclerosis and Friedreich ataxia.

Tuberous sclerosis (TS) is caused by point mutations in the TSC1 or TSC2 genes on chromosomes 9q33-34 or 16p13, respectively. Clinical manifestations can be quite variable but are primarily limited to cutaneous, neurologic, and cardiovascular abnormalities. Phenotypes range from neurologically devastated to those with silent lesions. A 34-year-old patient with genetically documented TSC1 developed progressive ataxia over a decade, without TS lesions to correlate with this finding. After evaluation of common causes including long-term antiepileptic regimens, DNA testing for hereditary ataxias was performed and revealed the presence of an additional mutation on chromosome 9. The patient was homozygous for the Friedreich ataxia (FA) mutation, with 500 and 700 GAA repeats in the FRDA gene on chromosome 9q13. There is no established relationship between these two disorders and the occurrence of two mutations on the same chromosome is probably coincidental but emphasizes the importance of searching for additional genetic causes when the phenotype does not fit with an established genetic diagnosis.

Adult↗
PubMed2004

Evidence of a founder effect in families with frontotemporal dementia that harbor the tau +16 splice mutation.

The +16 exon 10 splice mutation of the tau gene (microtubule-associated protein tau, MAPT) has been reported in numerous families with frontotemporal dementia (FTD). To date, the majority of these families are from England and Wales in the UK, although families with this mutation have been reported from Australia and the USA. Our own analysis has identified eight families with the +16 MAPT splice mutation from around the Manchester and North Wales areas of the UK. Given the proximity of the UK families to one another it is likely that they are related and represent a single extended pedigree. In order to investigate this possibility, and the possibility that the families with this mutation from London, the USA, and Australia are related, we genotyped 11 microsatellite markers around the tau locus. In most cases (20/25, 80%), a common haplotype, approximately 3 cM in size, was identified. In the remaining cases, this haplotype appears to have been varyingly reduced in size by recombination. We demonstrate that the +16 mutation is on the H1 tau haplotype and that H1 specific polymorphisms are also shared by these families. These data provide evidence that the MAPT +16 splice mutation cases from around the world analyzed in this study are indeed related and represent a single pedigree that probably originated in the North Wales area of the UK. Furthermore, this single large pedigree may be of use in the identification of disease modifying loci in FTD.

Australia↗
PubMed2004

Huntington's Disease-like 2 (HDL2) in North America and Japan.

Huntington's Disease-like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of r2=0.29, p=0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype.

Adult↗
PubMed2004

Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities.

Niemann-Pick type C disease (NPC) is characterized by neurodegeneration secondary to impaired cholesterol trafficking and excessive glycosphingolipid storage. Abnormal cholesterol and ganglioside metabolism may influence the generation and aggregation of amyloidogenic fragments (ie, C99 and Abeta) from amyloid-beta precursor protein (APP), crucial factors causing neurodegeneration in Alzheimer's disease. To reveal whether abnormal accumulation and aggregation of APP fragments also occurs in NPC, we studied their expression in cultured cortical neurons treated with U18666A, a compound widely used to induce NPC defects, and also in brain tissues from NPC patients. U18666A treatment resulted in increased intraneuronal levels of C99 and insoluble Abeta42, which were distributed among early and late endosomes, in compartments distinct from where endogenous cholesterol accumulates. Analyses of NPC brains revealed that C99 or other APP C-terminal fragments (APP-CTF), but not Abeta42, accumulated in Purkinje cells, mainly in early endosomes. In contrast, in hippocampal pyramidal neurons, the major accumulated species was Abeta42, in late endosomes. Similar to what has been shown in Alzheimer's disease, cathepsin D, a lysosomal hydrolase, was redistributed to early endosomes in NPC Purkinje cells, where it co-localized with C99/APP-CTF. Our results suggest that endosomal abnormalities related to abnormal lipid trafficking in NPC may contribute to abnormal APP processing and Abeta42/C99/APP-CTF deposition.

Adolescent↗
PubMed2003

SCA2 may present as levodopa-responsive parkinsonism.

Some kindreds with familial parkinsonism exhibit genetic anticipation, suggesting possible involvement of trinucleotide repeat expansion. Recent reports have shown trinucleotide repeat expansions in the spinocerebellar ataxia 2 (SCA2) gene in patients with levodopa-responsive parkinsonism. We tested 136 unrelated patients with familial parkinsonism for SCA2 mutations. Two probands had borderline mutations; the rest were normal. ( or=36 is pathogenic). The expanded allele segregated with neurological signs in one kindred. The absence of borderline mutations in the normal population, and the co-segregation of the expanded allele with neurological signs in one kindred suggest that SCA2 mutations may be responsible for a subset of familial parkinsonism.

Adult↗
PubMed2002

Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as "Nasu-Hakola disease," is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype.

Actins↗
PubMed2002

Age at onset of Parkinson disease and apolipoprotein E genotypes.

Several lines of evidence suggest that the variable age at onset of Parkinson disease (PD) is likely influenced by genes. The apolipoprotein E (APOE) gene is associated with onset of Alzheimer disease, and possibly other neurodegenerative disorders. APOE has been investigated in relation to onset of PD, but results have been inconsistent. The aim of the present study was to determine if APOE genotypes are associated with onset age of PD, using a patient population large enough to assure sufficient power. We studied 521 unrelated Caucasian patients with idiopathic PD from movement disorder clinics in Oregon and Washington. Genotyping and statistical analyses were carried out using standard methods. Age at onset of PD was significantly earlier in patients with the varepsilon3varepsilon4/varepsilon4varepsilon4 genotype than in patients with the varepsilon3varepsilon3 genotype (56.1 +/- 10.9 vs. 59.6 +/- 11.0, P = 0.003). The significantly earlier onset of PD was not influenced by the possible effects of recruitment site, family history and gender. The effect of the varepsilon2varepsilon3 genotype on onset of PD differed between the two recruitment sites. There was a trend for earlier onset of PD in varepsilon2varepsilon3 patients than in varepsilon3varepsilon3 patients only in the Oregon sample. In conclusion, APOE is associated with age at onset of PD.

Age of Onset↗
PubMed2002

Niemann-Pick disease type C yields possible clue for why cerebellar neurons do not form neurofibrillary tangles.

It is unknown why cerebellar neurons resist neurofibrillary tangle (NFT) formation. In Niemann-Pick disease Type C (NPC), NFT-mediated neurodegeneration occurs throughout brain, but the cerebellum degenerates conspicuously without NFT. To understand why, we have studied markers of NFT pathogenesis in cerebellum from 17 NPC cases, all having abundant NFT in forebrain. Remarkably, we found that NPC cerebella display several early markers of NFT formation, i.e., hyperphosphorylated tau and an array of cell cycle regulators, suggesting that cerebellar neurons in NPC undergo similar modifications as other neurons that develop NFT. However, cerebellar neurons are deficient in tau, the building block of NFT, and this may be one reason for their inability to form NFT. Even without NFT, cerebellar neurodegeneration may be triggered by the inappropriate activation of the cell cycle cdc2 kinase, and the npc-1 murine model provides an opportunity to test this hypothesis.

Adolescent↗