Zachary Simmons

Electrocardiographic Abnormalities and Sudden Death in Myotonic Dystrophy Type 1

BACKGROUND Sudden death can occur as a consequence of cardiac-conduction abnormalities in the neuromuscular disease myotonic dystrophy type 1. The determinants of the risk of sudden death remain imprecise. METHODS We assessed whether the electrocardiogram (ECG) was useful in predicting sudden death in 406 adult patients with genetically confirmed myotonic dystrophy type 1. A patient was characterized as having a severe abnormality if the ECG had at least one of the following features: rhythm other than sinus, PR interval of 240 msec or more, QRS duration of 120 msec or more, or second-degree or third-degree atrioventricular block. RESULTS Patients with severe abnormalities according to the entry ECG were older than patients without severe abnormalities, had more severe skeletal-muscle impairment, and were more likely to have heart failure, left ventricular systolic dysfunction, or atrial tachyarrhythmia. Such patients were more likely to receive a pacemaker or an implantable cardioverter-defibrillator during the follow-up period. During a mean follow-up period of 5.7 years, 81 patients died; there were 27 sudden deaths, 32 deaths from progressive neuromuscular respiratory failure, 5 nonsudden deaths from cardiac causes, and 17 deaths from other causes. Among the 17 patients who died suddenly in whom postcollapse rhythm was evaluated, a ventricular tachyarrhythmia was observed in 9. A severe ECG abnormality (relative risk, 3.30; 95% confidence interval [CI], 1.24 to 8.78) and a clinical diagnosis of atrial tachyarrhythmia (relative risk, 5.18; 95% CI, 2.28 to 11.77) were independent risk factors for sudden death. CONCLUSIONS Patients with adult myotonic dystrophy type 1 are at high risk for arrhythmias and sudden death. A severe abnormality on the ECG and a diagnosis of an atrial tachyarrhythmia predict sudden death. (ClinicalTrials.gov number, NCT00622453.)

Quality of life in ALS is maintained as physical function declines

Article abstract—Objectives: To study patients with ALS to determine how physical function, quality of life (QOL), and spirituality or religiousness change over time, and what relationship these changes have to one another. Methods: Sixty patients with ALS were studied prospectively. They were assessed at baseline, 3 months, and 6 months, using questionnaires designed to measure general quality of life (McGill Quality of Life questionnaire), religiosity (Idler Index of Religiosity), ALS-specific health-related quality of life (SIP/ALS-19), and ALS-specific function (ALS functional rating scale). Results: A two-way repeated measures multivariate analysis of variance revealed that both the passage of time and the specific QOL scales used were factors in predicting patient quality of life (F[1, 59]5 9.87, p , 0.003 and F[3, 177]5 16.90, p , 0.001) Despite a progressive decline in physical function as measured by the ALS-specific function score, the general QOL and religiosity scores changed little. In contrast, the ALS-specific health-related QOL score declined in parallel with the ALS-specific function score. Conclusions: QOL in patients with ALS appears to be independent of physical function, which agrees with a previous cross-sectional study. The ALS-specific health-related QOL score is primarily a measure of physical function. QOL instruments that assess spiritual, religious, and psychological factors produce different results than those obtained using measures of physical function alone.

Genetic risk factors associated with lipid-lowering drug-induced myopathies.

Lipid‐lowering drugs produce myopathic side effects in up to 7% of treated patients, with severe rhabdomyolysis occurring in as many as 0.5%. Underlying metabolic muscle diseases have not been evaluated extensively. In a cross‐sectional study of 136 patients with drug‐induced myopathies, we report a higher prevalence of underlying metabolic muscle diseases than expected in the general population. Control groups included 116 patients on therapy with no myopathic symptoms, 100 asymptomatic individuals from the general population never exposed to statins, and 106 patients with non–statin‐induced myopathies. Of 110 patients who underwent mutation testing, 10% were heterozygous or homozygous for mutations causing three metabolic myopathies, compared to 3% testing positive among asymptomatic patients on therapy (P = 0.04). The actual number of mutant alleles found in the test group patients was increased fourfold over the control group (P < 0.0001) due to an increased presence of mutation homozygotes. The number of carriers for carnitine palmitoyltransferase II deficiency and for McArdle disease was increased 13‐ and 20‐fold, respectively, over expected general population frequencies. Homozygotes for myoadenylate deaminase deficiency were increased 3.25‐fold with no increase in carrier status. In 52% of muscle biopsies from patients, significant biochemical abnormalities were found in mitochondrial or fatty acid metabolism, with 31% having multiple defects. Variable persistent symptoms occurred in 68% of patients despite cessation of therapy. The effect of statins on energy metabolism combined with a genetic susceptibility to triggering of muscle symptoms may account for myopathic outcomes in certain high‐risk groups. Muscle Nerve, 2006

Women's estradiol predicts preference for facial cues of men's testosterone

A growing body of research has shown that women express stronger attraction to more masculine traits when they are tested near ovulation than when tested during other times in the menstrual cycle. Although these effects have been interpreted as increased preferences for markers of elevated testosterone during times in the cycle when conception is most likely, no previous studies have directly demonstrated that women express stronger attraction to higher testosterone men at different times in the cycle. In addition, little research has addressed which hormonal or other physiological mechanisms may regulate temporal shifts in womens attractiveness judgments. In this research, we demonstrate that women with higher estradiol concentrations exhibit stronger preferences for the faces of men with higher testosterone concentrations, and that womens testosterone preference and estradiol curves track one another across days of the cycle. The findings are the first direct demonstration in humans that hormone concentrations in one sex are associated with attraction to cues of hormonal status in the opposite sex. The results support a functional role for estradiol in calibrating womens mating psychology to indices of their current fertility, analogous to similar processes that have been documented in nonhuman species. A strong correlation between estradiol and testosterone preference specifically during the luteal phase further suggests that womens mate preferences may track their fertility between different cycles in addition to being calibrated to the timing of ovulation within individual cycles.

A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complicated pathogenesis that poses challenges with respect to diagnosis and monitoring of disease progression. Objectives: To identify a biomarker panel that elucidates ALS disease pathogenesis, distinguishes patients with ALS from neurologic disease controls, and correlates with ALS disease characteristics, and to determine the effect of HFE gene variants, a potential risk factor for sporadic ALS, on the biomarker profile. Methods: We obtained CSF samples by lumbar puncture from 41 patients with ALS and 33 neurologic disease controls. All patients were genotyped for HFE polymorphisms. We performed a multiplex cytokine and growth factor analysis and immunoassays for iron-related analytes. Classification statistics were generated using a support vector machine algorithm. Results: The groups of patients with ALS and neurologic disease controls were each associated with distinct profiles of biomarkers. Fourteen biomarkers differed between patients with ALS and the control group. The five proteins with the lowest p values differentiated patients with ALS from controls with 89.2% accuracy, 87.5% sensitivity, and 91.2% specificity. Expression of IL-8 was higher in those patients with lower levels of physical function. Expression of β2-microglobulin was higher in subjects carrying an H63D HFE allele, while expression of several markers was higher in subjects carrying a C282Y HFE allele. Conclusions: A CSF inflammatory profile associated with amyotrophic lateral sclerosis (ALS) pathogenesis may distinguish patients with ALS from neurologic disease controls, and may serve as a biomarker panel to aid in the diagnosis of ALS pending further validation. Some of these biomarkers differ by HFE genotype.

Presentation and initial clinical course in patients with chronic inflammatory demyelinating polyradiculoneuropathy Comparison of patients without and with monoclonal gammopathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may occur in association with a monoclonal gammopathy of undetermined significance (MGUS) or a variety of other systemic illnesses. It is not known if the clinical features of CIDP are altered by the presence of an MGUS. We compared demographic features, clinical presentation, improvement and outcome after initial treatment, and electrodiagnostic features of a group of 77 patients with idiopathic CIDP (CIDP-I, no associated systemic illness) with 26 patients with CIDP in whom an MGUS was found during evaluation of the neuropathy (CIDP-MGUS). Patients with CIDP-MGUS had, on average, a more indolent course and less severe weakness than patients with CIDP-I, despite similar motor conduction studies. CIDP-MGUS patients also demonstrated less functional impairment, more frequent sensory loss, and more abnormal sensory conduction studies than patients with CIDP-I. Because of the greater improvement of CIDP-I patients with treatment, both groups had similar outcomes from their initial episodes of weakness. Subgroup analysis of CIDP-MGUS patients did not demonstrate differences between groups with IgM and IgG or IgA gammopathies.

Management strategies for patients with amyotrophic lateral sclerosis from diagnosis through death.

Background:Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is inevitably fatal. There are no effective treatments to stop or reverse the natural course of the disease. The role of the physician is to provide comfort and optimize quality of life. Review Summary:Management of patients with ALS is a process extending over months to years. It begins with breaking the news of the diagnosis and extends through the terminal phase. Medication may extend lifespan by a small amount. However, most efforts are centered around symptom management. Areas of importance include respiration, nutrition, secretions, communication, pseudobulbar affect, therapy and exercise, spasticity and cramps, pain, depression and suicide, spirituality and religion, cognitive changes, the development of advance directives, and care at the end of life. Multidisciplinary ALS clinics provide much-needed support for patients with ALS and their caregivers. Conclusion:Although physicians cannot cure ALS or even halt progression, there is much that can be done to manage the physical and emotional symptoms, thereby maintaining or enhancing quality of life.

Update on diabetic neuropathy

Purpose of reviewThis review will focus on recent advances in the field of diabetic neuropathy, with an emphasis on distal symmetric sensory and sensorimotor polyneuropathy. Some new information in the areas of diabetic amyotrophy and diabetic autonomic neuropathy will also be reviewed. Recent findingsThe pathogenesis of diabetic neuropathy is multifactorial. There is increasing evidence to link abnormalities in the polyol pathway to the pathogenesis of diabetic neuropathy. In addition, there appear to be abnormalities of nerve regeneration and of sodium and calcium channels. Aldose reductase inhibitors have shown promise in animal models for reversing neuropathy if started early and used for a sufficient time, but those used to date in human trials are probably not of sufficient potency. Neurotrophic factors and vascular endothelial growth factor both also show promise. Specific recommendations and pathways for diabetic foot care have been devised. Lamotrigine and bupropion represent new treatments for neuropathic pain. The role of impaired glucose tolerance is being explored as it relates to polyneuropathy. SummaryAn increasing understanding of the pathogenetic mechanisms holds out promise for the effective treatment of diabetic neuropathy. The early detection of abnormal glucose metabolism is particularly important, as treatments will probably be most effective if administered early in the course of the neuropathy, when abnormalities of peripheral nerves are more likely to be reversible.

A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.

Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences

The etiology of amyotrophic lateral sclerosis (ALS) is unknown. The presence of mutations in the superoxide dismutase gene (SOD1) has led to theories regarding a role for oxidative stress in the pathogenesis of this disease. A primary cause of oxidative stress is perturbations in cellular iron homeostasis. Cellular iron mismanagement and oxidative stress are associated with a number of neurodegenerative diseases. One mechanism by which cells fail to properly regulate their iron status is through a mutation in the Hfe gene. Mutations in the Hfe gene are associated with the iron overload disease, hemochromatosis. In the current study, 31% of patients with sporadic ALS carried a mutation in the Hfe gene, compared to only 14% of patients without identifiable neuromuscular disease, or with neuromuscular diseases other than ALS (p<0.005). To determine the cellular consequences of carrying an Hfe mutation, a human neuronal cell line was transfected with genes carrying the Hfe mutation. The presence of the Hfe mutation disrupted expression of tubulin and actin at the protein levels potentially consistent with the disruption of axonal transport seen in ALS and was also associated with a decrease in CuZnSOD1 expression. These data provide compelling evidence for a role for the Hfe mutation in etiopathogenesis of ALS and warrant further investigation.