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1.  Parkin regulates kainate receptors by interacting with the GluK2 subunit 
Nature Communications  2014;5:5182.
Although loss-of-function mutations in the PARK2 gene, the gene that encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, the responsible molecular mechanisms remain unclear. Evidence suggests that a loss of parkin dysregulates excitatory synapses. Here we show that parkin interacts with the kainate receptor (KAR) GluK2 subunit and regulates KAR function. Loss of parkin function in primary cultured neurons causes GluK2 protein to accumulate in the plasma membrane, potentiates KAR currents and increases KAR-dependent excitotoxicity. Expression in the mouse brain of a parkin mutant causing autosomal recessive juvenile parkinsonism results in GluK2 protein accumulation and excitotoxicity. These findings show that parkin regulates KAR function in vitro and in vivo, and suggest that KAR upregulation may have a pathogenetic role in parkin-related autosomal recessive juvenile parkinsonism.
Loss-of-function mutations in the PARK2 gene are implicated in autosomal recessive juvenile parkinsonism, but the mechanisms are unclear. Here, the authors show that these mutations cause accumulation of the kainate receptor subunit GluK2 in the plasma membrane of neurons, which facilitates neuronal death.
PMCID: PMC4218952  PMID: 25316086
2.  Oligoclonal bands in the cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated mutations 
Journal of neurology  2012;260(1):85-92.
In amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) analysis is usually performed to exclude inflammatory processes of the central nervous system. Although in a small subset of patients an intrathecal synthesis of IgG is detectable, usually there is no clear explanation for this evidence. This study investigates the occurrence of oligoclonal bands (OCBs) in the CSF of a large series of ALS patients, attempting a correlation with genotype data. CSF was collected from 259 ALS patients. CSF parameters were measured according to standard procedures, and detection of OCBs performed by isoelectric focusing. The patients were screened for mutations in SOD1, FUS, TARDBP, ANG, OPTN, and C9ORF72. We observed the presence of OCBs in the CSF of 9/259 ALS patients (3.5 %), and of disease-associated mutations in 12 cases. OCBs were significantly more frequent in mutation carriers compared to the remaining cohort (3/12 vs 6/247; p < 0.01). Among patients with OCBs, two patients had the TARDBP p.A382T mutation (one of which in homozygous state), and one the ANG p.P-4S variant. Both patients carrying the p.A382T mutation had an atypical phenotype, one of them manifesting signs suggestive of a cerebellar involvement, and the other presenting neuroradiological findings suggestive of an inflammatory disorder of the central nervous system. Our results suggest that ALS patients with OCBs may harbor mutations in disease-causing genes. We speculate that mutations in both TARDBP and ANG genes may disrupt the blood–brain barrier (BBB), promoting local immune responses and neuroinflammation. The role of mutant TARDBP and ANG genes on BBB integrity of ALS patients warrants further investigation.
PMCID: PMC4196642  PMID: 22752089
ALS; Genetics; Neuroimmunology; CSF; Motor neuron disease
3.  Screening of the PFN1 gene in sporadic ALS and in FTD 
Neurobiology of aging  2012;34(5):1517.e9-1517.e10.
Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth through its binding to monomeric G-actin, have been recently identified in familial amyotrophic lateral sclerosis (ALS). Functional studies performed on ALS-associated PFN1 mutants demonstrated aggregation propensity, alterations in growth cone and cytoskeletal dynamics. Previous screening of PFN1 gene in sporadic ALS (SALS) cases led to the identification of the p.E117G mutation, which is likely to represent a less pathogenic variant according to both frequency data in controls/cases and functional experiments. To determine the effective contribution of PFN1 mutations in SALS, we analyzed a large cohort of 1168 Italian SALS patients and also included 203 FTD (Frontotemporal Dementia) cases given the great overlap between these two neurodegenerative diseases. We detected the p.E117G variant in 1 SALS and the novel synonymous change p.G15G in another patient, but none in a panel of 1512 controls. Our results suggest that PFN1 mutations in sporadic ALS and in FTD are rare, at least in the Italian population.
PMCID: PMC3548975  PMID: 23063648
amyotrophic lateral sclerosis; frontotemporal dementia; profilin 1; mutation analysis
4.  The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder 
A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/−FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/−FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/−FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10−8). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
PMCID: PMC3522204  PMID: 22692064
ALS; common founder; C9ORF72
5.  Extramotor Damage Is Associated with Cognition in Primary Lateral Sclerosis Patients 
PLoS ONE  2013;8(12):e82017.
This is a cross-sectional study aimed at investigating cognitive performances in patients with primary lateral sclerosis (PLS) and using diffusion tensor (DT) magnetic resonance imaging (MRI) to determine the topographical distribution of microstructural white matter (WM) damage in patients with or without cognitive deficits.
DT MRI scans were obtained from 21 PLS patients and 35 age- and sex-matched healthy controls. All PLS patients underwent a comprehensive neuropsychological battery. Tract-based-spatial-statistics (TBSS) was used to perform a whole-brain voxel-wise analysis of fractional anisotropy (FA), axial, radial (radD) and mean diffusivity (MD).
Ten PLS patients had abnormal scores in at least one neuropsychological test (PLS with cognitive deficits, PLS-cd). Compared with healthy controls and cognitively unimpaired PLS patients (PLS-cu), PLS-cd cases showed decreased FA and increased MD and radD in the corticospinal tract (CST), corpus callosum, brainstem, anterior limb of internal capsule, superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes, bilaterally. Compared with healthy controls, PLS-cd patients showed further decreased FA and increased radD in the cerebellar WM, bilaterally. Compared with controls, PLS-cu patients showed decreased FA in the mid-body of corpus callosum. In PLS, executive and language test scores correlated with WM damage.
This is the first study evaluating the relationship between cognitive performance and WM tract damage in PLS patients. PLS can be associated with a multi-domain cognitive impairment. WM damage to interhemispheric, limbic and major associative WM tracts seem to be the structural correlate of cognitive abnormalities in these patients.
PMCID: PMC3857796  PMID: 24349172
6.  Molecular Signatures of Amyotrophic Lateral Sclerosis Disease Progression in Hind and Forelimb Muscles of an SOD1G93A Mouse Model 
Antioxidants & Redox Signaling  2012;17(10):1333-1350.
Aims: This study utilized proteomics, biochemical and enzymatic assays, and bioinformatics tools that characterize protein alterations in hindlimb (gastrocnemius) and forelimb (triceps) muscles in an amyotrophic lateral sclerosis (ALS) (SOD1G93A) mouse model. The aim of this study was to identify the key molecular signatures involved in disease progression. Results: Both muscle types have in common an early down-regulation of complex I. In the hindlimb, early increases in oxidative metabolism are associated with uncoupling of the respiratory chain, an imbalance of NADH/NAD+, and an increase in reactive oxygen species (ROS) production. The NADH overflow due to complex I inactivation induces TCA flux perturbations, leading to citrate production, triggering fatty acid synthase (FAS), and lipid peroxidation. These early metabolic changes in the hindlimb followed by sustained and comparatively higher metabolic and cytoskeletal derangements over time precede and may catalyze the progressive muscle wasting in this muscle at the late stage. By contrast, in the forelimb, there is an early down-regulation of complexes I and II that is associated with the reduction of oxidative metabolism, which promotes metabolic homeostasis that is accompanied by a greater cytoskeletal stabilization response. However, these early compensatory systems diminish by a later time point. Innovation: The identification of potential early- and late-stage disease molecular signatures in an ALS model: muscle albumin, complex I, complex II, citrate synthase, FAS, and phosphoinositide 3-kinase functions as diagnostic markers and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers. Conclusion: The differing pattern of cellular metabolism and cytoskeletal derangements in the hind and forelimb identifies the potential dysmetabolism/hypermetabolism molecular signatures associated with disease progression, which may serve as diagnostic/disease progression markers in ALS patients. Antioxid. Redox Signal. 17, 1333–1350.
PMCID: PMC3437050  PMID: 22563797
7.  Dose Dependent Side Effect of Superparamagnetic Iron Oxide Nanoparticle Labeling on Cell Motility in Two Fetal Stem Cell Populations 
PLoS ONE  2013;8(11):e78435.
Multipotent stem cells (SCs) could substitute damaged cells and also rescue degeneration through the secretion of trophic factors able to activate the endogenous SC compartment. Therefore, fetal SCs, characterized by high proliferation rate and devoid of ethical concern, appear promising candidate, particularly for the treatment of neurodegenerative diseases. Super Paramagnetic Iron Oxide nanoparticles (SPIOn), routinely used for pre-clinical cell imaging and already approved for clinical practice, allow tracking of transplanted SCs and characterization of their fate within the host tissue, when combined with Magnetic Resonance Imaging (MRI). In this work we investigated how SPIOn could influence cell migration after internalization in two fetal SC populations: human amniotic fluid and chorial villi SCs were labeled with SPIOn and their motility was evaluated. We found that SPIOn loading significantly reduced SC movements without increasing production of Reactive Oxygen Species (ROS). Moreover, motility impairment was directly proportional to the amount of loaded SPIOn while a chemoattractant-induced recovery was obtained by increasing serum levels. Interestingly, the migration rate of SPIOn labeled cells was also significantly influenced by a degenerative surrounding. In conclusion, this work highlights how SPIOn labeling affects SC motility in vitro in a dose-dependent manner, shedding the light on an important parameter for the creation of clinical protocols. Establishment of an optimal SPIOn dose that enables both a good visualization of grafted cells by MRI and the physiological migration rate is a main step in order to maximize the effects of SC therapy in both animal models of neurodegeneration and clinical studies.
PMCID: PMC3820601  PMID: 24244310
8.  Weight loss, dysphagia and supplement intake in patients with amyotrophic lateral sclerosis (ALS): impact on quality of life and therapeutic options 
BMC Neurology  2013;13:84.
Weight loss is a frequent feature in the motor neuron disease Amyotrophic lateral sclerosis (ALS). In this study we investigated possible causes of weight loss in ALS, its impact on mood/quality of life (QOL) and the benefit of high calorie nutritional/other dietary supplements and percutaneous endoscopic gastrostomy (PEG).
121 ALS patients were interviewed and answered standardized questionnaires (Beck depression inventory - II, SF36 Health Survey questionnaire, revised ALS functional rating scale). Two years after the initial survey we performed a follow-up interview.
In our ALS-cohort, 56.3% of the patients suffered from weight loss. Weight loss had a negative impact on QOL and was associated with a shorter survival. Patients who took high calorie nutritional supplements respectively had a PEG stated a great benefit regarding weight stabilization and/or QOL.
38.2% of our patients had significant weight loss without suffering from dysphagia. To clarify the reasons for weight loss in these patients, we compared them with patients without weight loss. The two groups did not differ regarding severity of disease, depression, frontotemporal dementia or fasciculations, but patients with weight loss declared more often increased respiratory work.
Weight loss is a serious issue in ALS and cannot always be attributed to dysphagia. Symptomatic treatment of weight loss (high calorie nutritional supplements and/ or PEG) should be offered more frequently.
PMCID: PMC3717067  PMID: 23848967
Amyotrophic lateral sclerosis; Nutrition; Dietary supplements; Weight loss; Dysphagia; High calorie supplements
9.  Mutations in the Profilin 1 Gene Cause Familial Amyotrophic Lateral Sclerosis 
Nature  2012;488(7412):499-503.
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years1-9, nearly 50% of FALS cases have unknown genetic etiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is critical for monomeric (G)-actin conversion to filamentous (F)-actin. Exome sequencing of two large ALS families revealed different mutations within the PFN1 gene. Additional sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F-/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.
PMCID: PMC3575525  PMID: 22801503
10.  Mutational Analysis of TARDBP in Neurodegenerative Diseases 
Neurobiology of aging  2009;32(11):2096-2099.
Neurodegenerative diseases are often characterized by the presence of aggregates of misfolded proteins. TDP-43 is a major component of these aggregates in Amyotrophic Lateral Sclerosis (ALS), but has also been observed in Alzheimer's (AD) and Parkinson's Diseases (PD). In addition, mutations in the TARDBP gene, encoding TDP-43, have been found to be a significant cause of familial ALS (FALS). All mutations, except for one, have been found in exon 6. To confirm this observation in ALS and to investigate whether TARDBP may play a role in the pathogenesis of AD and PD, we screened for mutations in exon 6 of the TARDBP gene in three cohorts composed of 376 AD, 463 PD (18% familial PD) and 376 ALS patients (50% FALS). We found mutations in ∼7% of FALS and ∼0.5% of sporadic ALS (SALS) patients, including two novel mutations, p.N352T and p.G384R. In contrast, we did not find TARDBP mutations in our cohort of AD and PD patients. These results suggest that mutations in TARDBP are not a significant cause of AD and PD.
PMCID: PMC2889148  PMID: 20031275
11.  The use of P300-based BCIs in amyotrophic lateral sclerosis: from augmentative and alternative communication to cognitive assessment 
Brain and Behavior  2012;2(4):479-498.
The use of augmentative and alternative communication (AAC) tools in patients with amyotrophic lateral sclerosis (ALS), as effective means to compensate for the progressive loss of verbal and gestural communication, has been deeply investigated in the recent literature. The development of advanced AAC systems, such as eye-tracking (ET) and brain-computer interface (BCI) devices, allowed to bypass the important motor difficulties present in ALS patients. In particular, BCIs could be used in moderate to severe stages of the disease, since they do not require preserved ocular-motor ability, which is necessary for ET applications. Furthermore, some studies have proved the reliability of BCIs, regardless of the severity of the disease and the level of physical decline. However, the use of BCI in ALS patients still shows some limitations, related to both technical and neuropsychological issues. In particular, a range of cognitive deficits in most ALS patients have been observed. At the moment, no effective verbal-motor free measures are available for the evaluation of ALS patients’ cognitive integrity; BCIs could offer a new possibility to administer cognitive tasks without the need of verbal or motor responses, as highlighted by preliminary studies in this field. In this review, we outline the essential features of BCIs systems, considering advantages and challenges of these tools with regard to ALS patients and the main applications developed in this field. We then outline the main findings with regard to cognitive deficits observed in ALS and some preliminary attempts to evaluate them by means of BCIs. The definition of specific cognitive profiles could help to draw flexible approaches tailored on patients’ needs. It could improve BCIs efficacy and reduce patients’ efforts. Finally, we handle the open question, represented by the use of BCIs with totally locked in patients, who seem unable to reliably learn to use such tool.
PMCID: PMC3432970  PMID: 22950051
Amyotrophic lateral sclerosis; augmentative and alternative communication; brain-computer interface; cognitive assessment; P300
12.  Longitudinal Tracking of Human Fetal Cells Labeled with Super Paramagnetic Iron Oxide Nanoparticles in the Brain of Mice with Motor Neuron Disease 
PLoS ONE  2012;7(2):e32326.
Stem Cell (SC) therapy is one of the most promising approaches for the treatment of Amyotrophic Lateral Sclerosis (ALS). Here we employed Super Paramagnetic Iron Oxide nanoparticles (SPIOn) and Hoechst 33258 to track human Amniotic Fluid Cells (hAFCs) after transplantation in the lateral ventricles of wobbler (a murine model of ALS) and healthy mice. By in vitro, in vivo and ex vivo approaches we found that: 1) the main physical parameters of SPIOn were maintained over time; 2) hAFCs efficiently internalized SPIOn into the cytoplasm while Hoechst 33258 labeled nuclei; 3) SPIOn internalization did not alter survival, cell cycle, proliferation, metabolism and phenotype of hAFCs; 4) after transplantation hAFCs rapidly spread to the whole ventricular system, but did not migrate into the brain parenchyma; 5) hAFCs survived for a long time in the ventricles of both wobbler and healthy mice; 6) the transplantation of double-labeled hAFCs did not influence mice survival.
PMCID: PMC3288077  PMID: 22384217
13.  The Survival of Motor Neuron (SMN) Protein Interacts with the mRNA-Binding Protein HuD and Regulates Localization of Poly(A) mRNA in Primary Motor Neuron Axons 
Spinal muscular atrophy (SMA) results from reduced levels of the survival of motor neuron (SMN) protein, which has a well-characterized function in spliceosomal small nuclear ribonucleoprotein assembly. Currently, it is not understood how deficiency of a housekeeping protein leads to the selective degeneration of spinal cord motor neurons. Numerous studies have shown that SMN is present in neuronal processes and has many interaction partners, including mRNA binding proteins, suggesting a potential non-canonical role in axonal mRNA metabolism. In this study, we have established a novel technological approach using bimolecular fluorescence complementation (BiFC) and quantitative image analysis to characterize SMN-protein interactions in primary motor neurons. Consistent with biochemical studies on the SMN complex, BiFC analysis revealed that SMN dimerizes and interacts with Gemin2 in nuclear gems and axonal granules. In addition, using pull down assays, immunofluorescence, cell transfection, and BiFC, we characterized a novel interaction between SMN and the neuronal mRNA-binding protein HuD, which was dependent on the Tudor domain of SMN. A missense mutation in the SMN Tudor domain, which is known to cause SMA, impaired the interaction with HuD, but did not affect Smn axonal localization or self-association. Furthermore, time-lapse microscopy revealed SMN co-transport with HuD in live motor neurons. Importantly, SMN knockdown in primary motor neurons resulted in a specific reduction of both HuD protein and poly(A) mRNA levels in the axonal compartment. These findings reveal a non-canonical role for SMN whereby its interaction with mRNA binding proteins may facilitate the localization of associated poly(A) mRNAs into axons.
PMCID: PMC3070748  PMID: 21389246
14.  Paraoxonase Gene Mutations in Amyotrophic Lateral Sclerosis 
Annals of neurology  2010;68(1):102-107.
Three clustered, homologous paraoxonase genes (PON1, PON2 and PON3) have roles in preventing lipid oxidation and detoxifying organophosphates. Recent reports describe a genetic association between the PON genes and sporadic amyotrophic lateral sclerosis (ALS). We now report that in genomic DNA from individuals with familial and sporadic ALS we have identified at least seven PON gene mutations that are predicted to alter PON function.
PMCID: PMC2945725  PMID: 20582942
15.  Amyotrophic lateral sclerosis: applications of stem cells – an update 
Neurodegenerative diseases are a growing public health challenge, and amyotrophic lateral sclerosis (ALS) remains a fatal incurable disease. The advent of stem cell therapy has opened new horizons for both researchers and ALS patients, desperately looking for a treatment. ALS must be considered a systemic disease affecting many cell phenotypes besides motor neurons, even outside the central nervous system. Cell replacement therapy needs to address the specific neurobiological issues of ALS to safely and efficiently reach clinical settings. Moreover, the enormous potential of induced pluripotent cells directly derived from patients for modeling and understanding the pathological mechanisms, in correlation with the discoveries of new genes and animal models, provides new opportunities that need to be integrated with previously described transplantation strategies. Finally, a careful evaluation of preclinical data in conjunction with wary patient choice in clinical trials needs to be established in order to generate meaningful results.
PMCID: PMC3781739  PMID: 24198520
amyotrophic lateral sclerosis; regenerative medicine; stem cell therapy; clinical trials
16.  Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study 
Lancet Neurology  2010;9(10):986-994.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS–frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries.
We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10−7
After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10−6; odds ratio [OR] 1·39, 95% CI 1·21–1·59) and rs2814707 (p=3·32×10−6; 1·38, 1·20–1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10−10; OR 1·22, 95% CI 1·15–1·30) and rs2814707 (p=4·72×10−10; 1·22, 1·15–1·30) were associated with ALS.
We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS–frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS–frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene.
ALS Therapy Alliance, the Angel Fund, the Medical Research Council, the Motor Neurone Disease Association of Great Britain and Northern Ireland, the Wellcome Trust, and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network (DeNDRoN).
PMCID: PMC3257853  PMID: 20801717
17.  Aripiprazole in the treatment of Huntington’s disease: a case series 
The aim of the study was to describe the effects of aripiprazole, a new atypical antipsychotic drug that acts as a partial dopamine agonist on motor, behavioral and cognitive functions in patients with genetically confirmed Huntington’s disease (HD).
Methods and results:
Three HD patients were evaluated for Unified Huntington Disease Rating Scale part I and II and Beck Depression Inventory at baseline, after two months and one-year treatment. Aripiprazole effectively controlled involuntary movements and psychiatric symptoms, with effects on cognitive functions.
Our case reports suggest that aripiprazole is well tolerated, remarkably improving some of the motor and behavioral symptoms in patients affected by HD. Randomized, controlled, long-term studies are warranted.
PMCID: PMC2695210  PMID: 19557093
Huntington’s disease; aripiprazole; treatment; chorea
20.  Low Anaerobic Threshold and Increased Skeletal Muscle Lactate Production in Subjects with Huntington's Disease 
Movement Disorders  2010;26(1):130-137.
Mitochondrial defects that affect cellular energy metabolism have long been implicated in the etiology of Huntington's disease (HD). Indeed, several studies have found defects in the mitochondrial functions of the central nervous system and peripheral tissues of HD patients. In this study, we investigated the in vivo oxidative metabolism of exercising muscle in HD patients. Ventilatory and cardiometabolic parameters and plasma lactate concentrations were monitored during incremental cardiopulmonary exercise in twenty-five HD subjects and twenty-five healthy subjects. The total exercise capacity was normal in HD subjects but notably the HD patients and presymptomatic mutation carriers had a lower anaerobic threshold than the control subjects. The low anaerobic threshold of HD patients was associated with an increase in the concentration of plasma lactate. We also analyzed in vitro muscular cell cultures and found that HD cells produce more lactate than the cells of healthy subjects. Finally, we analyzed skeletal muscle samples by electron microscopy and we observed striking mitochondrial structural abnormalities in two out of seven HD subjects. Our findings confirm mitochondrial abnormalities in HD patients' skeletal muscle and suggest that the mitochondrial dysfunction is reflected functionally in a low anaerobic threshold and an increased lactate synthesis during intense physical exercise. © 2010 Movement Disorder Society
PMCID: PMC3081141  PMID: 20931633
Huntington's disease; skeletal muscle; anaerobic threshold; mitochondria
21.  Impaired Expression of Insulin-Like Growth Factor-1 System in Skeletal Muscle of Amyotrophic Lateral Sclerosis Patients 
Muscle & Nerve  2012;45(2):200-208.
Adult muscle fibers are a source of growth factors, including insulin-like growth factor-1 (IGF-1). These factors influence neuronal survival, axonal growth, and maintenance of synaptic connections.
We investigated the components of the IGF system in skeletal muscle samples obtained from 17 sporadic amyotrophic lateral sclerosis patients (sALS) and 29 control subjects (17 with normal muscle and 12 with denervated muscle unrelated to ALS).
The muscle expression of IGF-1 and IGF-binding proteins 3, 4, and 5 (IGF-BP3, -4, and -5, respectively), assessed by immunohistochemistry, was differently decreased in sALS compared with both control groups; conversely, IGF-1 receptor β subunit (IGF-1Rβ) was significantly increased. Western blot analysis confirmed the severe reduction of IGF-1, IGF-BP3, and -BP5 with the increment of IGF-1Rβ in sALS.
In this study we describe the abnormal expression of the IGF-1 system in skeletal muscle of sALS patients that could participate in motor neuron degeneration and should be taken into account when developing treatments with IGF-1. Muscle Nerve, 2012
PMCID: PMC3306791  PMID: 22246875
amyotrophic lateral sclerosis; IGF-1; IGF-BPs; IGF-1 receptor; skeletal muscle
22.  A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories 
Journal of Medical Genetics  2014;51(6):419-424.
The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories.
The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference.
Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9–100%), and the mean specificity was 98.0% (87.5–100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories.
Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.
PMCID: PMC4033024  PMID: 24706941
Motor neurone disease; Molecular genetics; Neurology

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