Free carnitine and branched chain amino acids are not good biomarkers in Huntington’s disease

ABSTRACT Background: Huntington’s disease (HD), caused by an expanded CAG repeat at HTT, has no treatment, and biomarkers are needed for future clinical trials. Objective: The objective of this study was to verify if free carnitine and branched chain amino acids levels behave as potential biomarkers in HD. Methods: Symptomatic and asymptomatic HD carriers and controls were recruited. Age, sex, body mass index (BMI), age of onset, disease duration, UHDRS scores, and expanded CAG tract were obtained; valine, leucine, isoleucine, and free carnitine were measured. Baseline and longitudinal analysis were performed. Results: Seventy-four symptomatic carriers, 20 asymptomatic carriers, and 22 non-carriers were included. At baseline, valine levels were reduced in symptomatic and asymptomatic HD carriers when compared to non-carriers. No difference in free carnitine or isoleucine+leucine levels were observed between groups. BMI of symptomatic individuals was lower than those of non-carriers. Valine levels correlated with BMI. Follow-up evaluation was performed in 43 symptomatic individuals. UHDRS total motor score increased 4.8 points/year on average. No significant reductions in BMI or valine were observed, whereas free carnitine and isoleucine+leucine levels increased. Conclusions: Although valine levels were lower in HD carriers and were related to BMI losses observed in pre-symptomatic individuals, none of these metabolites seem to be biomarkers for HD.

Download Full-text

High Plasma Branched-Chain Amino Acids Are Associated with Higher Risk of Post-Transplant Diabetes Mellitus in Renal Transplant Recipients

Journal of Clinical Medicine ◽

10.3390/jcm9020511 ◽

2020 ◽

Vol 9 (2) ◽

pp. 511 ◽

Cited By ~ 2

Author(s):

Maryse C. J. Osté ◽

Jose L. Flores-Guerrero ◽

Eke G. Gruppen ◽

Lyanne M. Kieneker ◽

Margery A. Connelly ◽

...

Keyword(s):

Diabetes Mellitus ◽

Amino Acids ◽

Renal Transplant ◽

Branched Chain Amino Acids ◽

Resonance Spectroscopy ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Post Transplant ◽

Branched Chain

Post-transplant diabetes mellitus (PTDM) is a serious complication in renal transplant recipients. Branched-chain amino acids (BCAAs) are involved in the pathogenesis of insulin resistance. We determined the association of plasma BCAAs with PTDM and included adult renal transplant recipients (≥18 y) with a functioning graft for ≥1 year in this cross-sectional cohort study with prospective follow-up. Plasma BCAAs were measured in 518 subjects using nuclear magnetic resonance spectroscopy. We excluded subjects with a history of diabetes, leaving 368 non-diabetic renal transplant recipients eligible for analyses. Cox proportional hazards analyses were used to assess the association of BCAAs with the development of PTDM. Mean age was 51.1 ± 13.6 y (53.6% men) and plasma BCAA was 377.6 ± 82.5 µM. During median follow-up of 5.3 (IQR, 4.2–6.0) y, 38 (9.8%) patients developed PTDM. BCAAs were associated with a higher risk of developing PTDM (HR: 1.43, 95% CI 1.08–1.89) per SD change (p = 0.01), independent of age and sex. Adjustment for other potential confounders did not significantly change this association, although adjustment for HbA1c eliminated it. The association was mediated to a considerable extent (53%) by HbA1c. The association was also modified by HbA1c; BCAAs were only associated with renal transplant recipients without prediabetes (HbA1c < 5.7%). In conclusion, high concentrations of plasma BCAAs are associated with developing PTDM in renal transplant recipients. Alterations in BCAAs may represent an early predictive biomarker for PTDM.

Download Full-text

The Association between CAG Repeat Length and Age of Onset of Juvenile-Onset Huntington’s Disease

Brain Sciences ◽

10.3390/brainsci10090575 ◽

2020 ◽

Vol 10 (9) ◽

pp. 575 ◽

Cited By ~ 1

Author(s):

Jordan L. Schultz ◽

Amelia D. Moser ◽

Peg C. Nopoulos

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Age Of Onset ◽

Repeat Length ◽

Cag Repeat ◽

Linear Regression Models ◽

Juvenile Onset ◽

Additional Information ◽

Using Data ◽

The Relationship

There is a known negative association between cytosine–adenine–guanine (CAG) repeat length and the age of motor onset (AMO) in adult-onset Huntington’s Disease (AOHD). This relationship is less clear in patients with juvenile-onset Huntington’s disease (JOHD), however, given the rarity of this patient population. The aim of this study was to investigate this relationship amongst a relatively large group of patients with JOHD using data from the Kids-JOHD study. Additionally, we analyzed data from the Enroll-HD platform and the Predict-HD study to compare the relationship between CAG repeat length and AMO amongst patients with AOHD to that amongst patients with JOHD using linear regression models. In line with previous reports, the variance in AMO that was predicted by CAG repeat length was 59% (p < 0.0001) in the Predict-HD study and 57% from the Enroll-HD platform (p < 0.0001). However, CAG repeat length predicted 84% of the variance in AMO amongst participants from the Kids-JOHD study (p < 0.0001). These results indicate that there may be a stronger relationship between CAG repeat length and AMO in patients with JOHD as compared to patients with AOHD. These results provide additional information that may help to model disease progression of JOHD, which is beneficial for the planning and implementation of future clinical trials.

Download Full-text

Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington’s disease

Experimental Biology and Medicine ◽

10.1177/1535370219856620 ◽

2019 ◽

Vol 244 (17) ◽

pp. 1584-1595 ◽

Cited By ~ 3

Author(s):

Irina Matlahov ◽

Patrick CA van der Wel

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Structural Biology ◽

Age Of Onset ◽

Repeat Expansion ◽

Cag Repeat ◽

Mutant Huntingtin ◽

Cag Repeat Expansion ◽

Recent Developments ◽

Mutant Huntingtin Protein

Huntington’s disease, like other neurodegenerative diseases, continues to lack an effective cure. Current treatments that address early symptoms ultimately fail Huntington’s disease patients and their families, with the disease typically being fatal within 10–15 years from onset. Huntington’s disease is an inherited disorder with motor and mental impairment, and is associated with the genetic expansion of a CAG codon repeat encoding a polyglutamine-segment-containing protein called huntingtin. These Huntington’s disease mutations cause misfolding and aggregation of fragments of the mutant huntingtin protein, thereby likely contributing to disease toxicity through a combination of gain-of-toxic-function for the misfolded aggregates and a loss of function from sequestration of huntingtin and other proteins. As with other amyloid diseases, the mutant protein forms non-native fibrillar structures, which in Huntington’s disease are found within patients’ neurons. The intracellular deposits are associated with dysregulation of vital processes, and inter-neuronal transport of aggregates may contribute to disease progression. However, a molecular understanding of these aggregates and their detrimental effects has been frustrated by insufficient structural data on the misfolded protein state. In this review, we examine recent developments in the structural biology of polyglutamine-expanded huntingtin fragments, and especially the contributions enabled by advances in solid-state nuclear magnetic resonance spectroscopy. We summarize and discuss our current structural understanding of the huntingtin deposits and how this information furthers our understanding of the misfolding mechanism and disease toxicity mechanisms. Impact statement Many incurable neurodegenerative disorders are associated with, and potentially caused by, the amyloidogenic misfolding and aggregation of proteins. Usually, complex genetic and behavioral factors dictate disease risk and age of onset. Due to its principally mono-genic origin, which strongly predicts the age-of-onset by the extent of CAG repeat expansion, Huntington’s disease (HD) presents a unique opportunity to dissect the underlying disease-causing processes in molecular detail. Yet, until recently, the mutant huntingtin protein with its expanded polyglutamine domain has resisted structural study at the atomic level. We present here a review of recent developments in HD structural biology, facilitated by breakthrough data from solid-state NMR spectroscopy, electron microscopy, and complementary methods. The misfolded structures of the fibrillar proteins inform our mechanistic understanding of the disease-causing molecular processes in HD, other CAG repeat expansion disorders, and, more generally, protein deposition disease.

Download Full-text

Huntington’s Disease in a Patient Misdiagnosed as Conversion Disorder

Case Reports in Psychiatry ◽

10.1155/2018/3915657 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4

Author(s):

João Machado Nogueira ◽

Ana Margarida Franco ◽

Susana Mendes ◽

Anabela Valadas ◽

Cristina Semedo ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Psychiatric Symptoms ◽

Age Of Onset ◽

Late Onset ◽

Psychiatric Patients ◽

Conversion Disorder ◽

Cag Repeat ◽

Clinical Assessments ◽

Clinical Presentations

Huntington’s disease (HD) is an inherited, progressive, and neurodegenerative neuropsychiatric disorder caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide in Interested Transcript (IT) 15 gene on chromosome 4. This pathology typically presents in individuals aged between 30 and 50 years and the age of onset is inversely correlated with the length of the CAG repeat expansion. It is characterized by chorea, cognitive deficits, and psychiatric symptoms. Usually the psychiatric disorders precede motor and cognitive impairment, Major Depressive Disorder and anxiety disorders being the most common presentations. We present a clinical case of a 65-year-old woman admitted to our Psychiatric Acute Unit. During the 6 years preceding the admission, the patient had clinical assessments made several times by different specialties that focused only on isolated symptoms, disregarding the syndrome as a whole. In the course of her last admission, the patient was referred to our Neuropsychiatric Team, which made the provisional diagnosis of late-onset Huntington’s disease, later confirmed by genetic testing. This clinical vignette highlights the importance of a multidisciplinary approach to atypical clinical presentations and raises awareness for the relevance of investigating carefully motor symptoms in psychiatric patients.

Download Full-text

Age of onset in Huntington’s disease is influenced by CAG repeat variations in other polyglutamine disease-associated genes

Brain ◽

10.1093/brain/awx122 ◽

2017 ◽

Vol 140 (7) ◽

pp. e42-e42 ◽

Cited By ~ 4

Author(s):

Geerte Stuitje ◽

Martine J. van Belzen ◽

Sarah L. Gardiner ◽

Willeke M. C. van Roon-Mom ◽

Merel W. Boogaard ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Age Of Onset ◽

Cag Repeat ◽

Polyglutamine Disease ◽

Disease Associated Genes

Download Full-text

Bootstrapped neural network models for analyzing the responses of broiler chicks to dietary protein and branched chain amino acids

Canadian Journal of Animal Science ◽

10.4141/cjas2013-078 ◽

2014 ◽

Vol 94 (1) ◽

pp. 79-85 ◽

Cited By ~ 5

Author(s):

A. Faridi ◽

A. Golian ◽

A. Heravi Mousavi ◽

J. France

Keyword(s):

Neural Network ◽

Amino Acids ◽

Dietary Protein ◽

Average Daily Gain ◽

Network Models ◽

Branched Chain Amino Acids ◽

Broiler Chicks ◽

Neural Network Models ◽

Isoleucine Leucine ◽

Branched Chain

Faridi, A., Golian, A., Heravi Mousavi, A. and France, J. 2014. Bootstrapped neural network models for analyzing the responses of broiler chicks to dietary protein and branched chain amino acids. Can. J. Anim. Sci. 94: 79–85. Reliable prediction of avian responses to dietary nutrients is essential for planning, management, and optimization activities in poultry nutrition. In this study, two bootstrapped neural network (BNN) models, each containing 100 separated neural networks (SNN), were developed for predicting average daily gain (ADG) and feed efficiency (FE) of broiler chicks in response to intake of protein and branched chain amino acids (BCAA) in the starter period. Using a re-sampling method, 100 different batches of data were generated for both the ADG and FE sets. Starting with 270 data lines extracted from eight studies in the literature, SNN models were trained, tested, and validated with 136, 67, and 67 data lines, respectively. All 200 SNN models developed, along with their respective BNN ones, were subjected to optimization (to find the optimum dietary protein and BCAA levels that maximize ADG and FE). Statistical analysis indicated that based on R 2, the BNN models were more accurate in 76 and 56 cases (out of 100) compared with the SNN models developed for ADG and FE, respectively. Optimization of the BNN models showed protein, isoleucine, leucine, and valine requirements for maximum ADG were 231.80, 9.05, 14.03 and 10.90 g kg−1 of diet, respectively. Also, maximum FE was obtained when the diet contained 232.30, 9.07, 14.50, and 11.04 g kg−1 of protein, isoleucine, leucine, and valine, respectively. The results of this study suggest that in meta-analytic modelling, bootstrap re-sampling algorithms should be used to better analyze available data and thereby take full advantage of them. This issue is of importance in the animal sciences as producing reliable data is both expensive and time-consuming.

Download Full-text

Abstract 048: Circulating Branched-Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of US Women

Circulation ◽

10.1161/circ.137.suppl_1.048 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Deirdre K Tobias ◽

Patrick R Lawler ◽

Paulo H Harada ◽

Olga V Demler ◽

Paul M Ridker ◽

...

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Amino Acids ◽

Prospective Cohort ◽

Branched Chain Amino Acids ◽

Health Study ◽

Blood Collection ◽

Cvd Risk ◽

Isoleucine Leucine ◽

Branched Chain

Introduction: Recent metabolomics studies have identified circulating levels of branched-chain amino acids (BCAAs; isoleucine, leucine, valine) as strong predictors of type 2 diabetes (T2D). Whether BCAAs are implicated in cardiovascular disease (CVD) risk has not been established. Hypothesis: We hypothesized that higher baseline levels of plasma BCAAs are associated with an elevated risk of incident CVD events, and evaluated whether this relationship was dependent on an intermediate diagnosis of T2D. Methods: Participants enrolled in the Women’s Health Study prospective cohort were eligible if they did not report CVD or cancer prior to baseline blood collection (N=27,172, mean baseline age=54.7 years). Plasma BCAA metabolites were measured via proton NMR spectroscopy, ln-transformed, and standardized for analysis. We used multivariable Cox proportional regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) per standard deviation (SD) of total and individual BCAAs with incident CVD (myocardial infarction [MI], stroke, coronary revascularization). Results: 1,917 confirmed CVD events occurred over follow-up (mean 18.6 years). In models adjusted for age, body mass index, smoking status, diet quality, physical activity, and other established CVD risk factors, total BCAAs were positively associated with CVD (per SD, HR=1.13, CI=1.08 to 1.19), comparable in magnitude to the association of LDL cholesterol with CVD (per SD, HR=1.15, CI=1.09 to 1.21). In particular, BCAAs were associated with coronary events (MI: HR=1.21, CI=1.10 to 1.33; revascularization: HR=1.15, CI=1.07 to 1.23), but not with stroke (HR=1.07, CI=0.98 to 1.15). The BCAA-CVD relationship was notably greater (p-interaction=0.008) among participants who developed T2D prior to a CVD event (HR=1.25, CI=1.13 to 1.39), vs. women without T2D (HR=1.07, CI=1.01 to 1.13). Isoleucine, leucine, and valine were each associated with CVD (p<0.05). Further adjusting for biomarkers of potential intermediates, HbA1c, lipids, and a lipoprotein-based insulin resistance score entirely eliminated the associations of BCAAs with CVD. Conclusions: Circulating plasma BCAAs were positively associated with long-term incident CVD in a cohort of US women, in particular among women who developed T2D prior to a CVD event. Impaired BCAA metabolism may represent a shared pathway of insulin resistance that links the risks of T2D and CVD.

Download Full-text