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Biomedical subjects

Susan L Perlman

Publications and source records attributed to Susan L Perlman.

8 recordsLinked to original sources
PubMed2006

Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia.

Expansion of GAA x TTC triplets within an intron in FXN (the gene encoding frataxin) leads to transcription silencing, forming the molecular basis for the neurodegenerative disease Friedreich's ataxia. Gene silencing at expanded FXN alleles is accompanied by hypoacetylation of histones H3 and H4 and trimethylation of histone H3 at Lys9, observations that are consistent with a heterochromatin-mediated repression mechanism. We describe the synthesis and characterization of a class of histone deacetylase (HDAC) inhibitors that reverse FXN silencing in primary lymphocytes from individuals with Friedreich's ataxia. We show that these molecules directly affect the histones associated with FXN, increasing acetylation at particular lysine residues on histones H3 and H4 (H3K14, H4K5 and H4K12). This class of HDAC inhibitors may yield therapeutics for Friedreich's ataxia.

Acetylation↗
PubMed2006

Genome-wide significance for a modifier of age at neurological onset in Huntington's disease at 6q23-24: the HD MAPS study.

BACKGROUND: Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD. METHODS: In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs. RESULTS: Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci. CONCLUSION: In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.

Adolescent↗
PubMed2006

Ataxias.

Gait disorders in elderly individuals are a major cause of falls and their attendant morbidities. Ataxia is one of the neurologic components of fall risk, as are inattention or confusion, visual impairment, vestibular impairment, subcortical white matter disease, parkinsonism, weakness, sensory loss, orthostasis or arrhythmia with alterations in blood pressure, pain, medication use, and environmental hazards. Ataxia in the geriatric population has many causes. Correctly identifying them can improve clinicians' ability to offer treatment and management strategies to patients and their families. The goals should be safe mobility and preserved activities of daily living.

Aged↗
PubMed2005

Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging findings, and review of the literature.

BACKGROUND: Friedreich ataxia (FA), the most common hereditary ataxia, is caused by pathological expansion of GAA repeats in the first intron of the X25 gene on chromosome 9. Since the discovery of the gene, atypical features are increasingly recognized in individuals with FA, and up to 25% of patients with recessive or sporadic ataxia do not fulfill the Harding or Quebec Cooperative Study on Friedreich's Ataxia criteria for FA. Late-onset FA (LOFA) is defined as onset after age 25 years. OBJECTIVES: To describe and further delineate the clinical and magnetic resonance imaging findings in patients with LOFA and to review the literature. DESIGN: Clinical evaluation and comparison of clinical data and investigations. SETTING: Ataxia clinics at UCLA and Cedars-Sinai Medical Center. PATIENTS: Thirteen patients with LOFA with 13 sex-matched and Inherited Ataxia Progression Scale-matched patients with typical FA. RESULTS: Gait and limb ataxias were seen in all the participants. Dysarthria, loss of vibration sense, and abnormal eye movements were also common in both groups. Patients with LOFA more often had lower limb spasticity (40% vs 0%; chi2 = 4.0; P = .04) and retained reflexes (46.1% vs 7.7%; chi2 = 3.46; P = .05). They had no complaint of sphincter disturbances, and there was no evidence of cardiomyopathy on echocardiograms (chi2 = 4.0; P = .04). Five of 9 patients with LOFA had cerebellar atrophy on neuroimaging. CONCLUSIONS: Patients with gait and limb ataxias, dysarthria, loss of vibration sense, and fixational instability after age 25 years should be considered for molecular testing for GAA expansion in the FA gene. In contrast to previous studies, cerebellar vermian atrophy is not an uncommon finding.

Adult↗
PubMed2004

Symptomatic and disease-modifying therapy for the progressive ataxias.

BACKGROUND: The progressive ataxias are a diverse group of neurologic diseases that share features of degeneration of the cerebellum and its inflow/outflow pathways but differ in etiology, course, and associated noncerebellar system involvement. Some will have treatable causes, but for most, the pathophysiology is incompletely known. REVIEW SUMMARY: Treatment strategies will include (1) definitive therapy when available, (2) symptomatic treatment and prevention of complications, and (3) rehabilitation and support resources. The physician will have to decide whether to introduce or approve the use of therapies based on as yet-unproven mechanisms or the use of complementary medicine approaches. CONCLUSIONS: There are as yet no drugs that have been approved by the Food and Drug Administration for the treatment of the progressive ataxias and relatively few disease-modifying therapies, but symptomatic and rehabilitation interventions can greatly improve the quality of life of individuals with these disabling neurodegenerative disorders.

Ataxia↗
PubMed2003

Spinocerebellar degeneration.

The spinocerebellar degenerations/ataxias (SCAs) are a diverse group of rare, slowly progressive, neurological diseases, often inherited but of incompletely understood pathophysiology, which affect the cerebellum and its related pathways. They have few animal models and share no reliable biomarkers. They have, as yet, no universally validated rating scale for use in clinical trials. In the past 25 years, there have been, at most, 18 controlled (Class 1) trials for ataxia, which have focused on neurotransmitter mechanisms. There is currently only one National Institute of Neurological Disorders and Stroke-sponsored drug trial for ataxia (Phase I study of idebenone in Friedreich's ataxia). There are, as yet, no FDA-approved drugs for SCA. Current treatment practices encompass rehabilitation interventions and off-label use of symptomatic medications [1,2].

Animals↗
PubMed2002

Spinocerebellar degenerations: an update.

Over the past decade, the spinocerebellar degenerations have gone from a diverse group of loosely defined phenotypes to a family of diseases with many identifiable genotypes and the promise of gene-specific treatments. The evaluation of the spinocerebellar ataxias has been simplified, and the counseling of patients and families has been enhanced by the growing number of molecular diagnostic tests now available. Management strategies remain symptomatic and focused on rehabilitation, with empirical use of antioxidants based on research in other neurogenetic diseases.

Animals↗