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1.  Valproate Treatment in an ALS Patient Carrying a c.194G>A Spastin Mutation and SMN2 Homozygous Deletion 
Here we report the case of an ALS patient found to carry both a novel heterozygous change (c.194G>A) within the spastin gene and a homozygous deletion of the SMN2 gene. The patient was started on valproic acid (VPA, 600 mg/die per os) considering the capacity of this drug of increasing survival motor neuron through an epigenetic mechanism. Patient clinical course and molecular effects of VPA on skin fibroblasts obtained from the proband are described. This c.194G>A spastin mutation might expand the previously known borders of type 4 spastic paraplegia (SPG4) and we suggest the intriguing possibility that the absence of SMN2 might have acted as a contributory risk factor for starting lower motor neuron damage. Exploring the relationship genocopy-phenocopy in selected ALS patients might represent an interesting strategy for understanding its clinical variability.
doi:10.1155/2014/216094
PMCID: PMC4124810  PMID: 25143843
2.  C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population 
Neurobiology of Aging  2012;33(8):1848.e15-1848.e20.
It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (familial ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1,757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1,523 from mainland Italy. Sixty (3.7%) of 1,624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally-matched control samples (1,238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived one year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucloetide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the commonest mutation in Italy and the second more common in Sardinia.
doi:10.1016/j.neurobiolaging.2012.02.011
PMCID: PMC3372681  PMID: 22418734
Amyotrophic lateral sclerosis; C9ORF72; frontotemporal dementia; survival
3.  Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72 
Brain  2012;135(3):784-793.
A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ∼40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis–frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis–frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6–7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7–2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ∼60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.
doi:10.1093/brain/awr366
PMCID: PMC3286333  PMID: 22366794
amyotrophic lateral sclerosis; familial ALS, C9ORF72 gene; phenotype–genotype correlation
4.  Respiratory function of people with amyotrophic lateral sclerosis and caregiver distress level: a correlational study 
Background
Amyotrophic Lateral Sclerosis (ALS) is a rare, fatal neurodegenerative disorder with no curative treatment characterized by degeneration of motor neurons involving a progressive impairment of motor and respiratory functions. Most patients die of ventilator respiratory failure. Caregivers have a great influence on the patient”s quality of life as well as on the quality of care. Home influence of the caregiver on patient care is notable. To date, no study has investigated how psychological issues of caregivers would influence respiratory variables of ALS patients. The study aimed at finding out if there is a relationship between the respiratory function of ALS patients and the level of distress of their caregivers.
Methods
A cross-sectional study was conducted to investigate respiratory issues (PCF and FVC) and the perception of social support of ALS patients. Caregivers filled questionnaires about trait anxiety, depression, and burden of care. Forty ALS patients and their caregivers were recruited.
Results
FVC and PCF were positively related to patient perception of social support and negatively related to caregiver anxiety, depression, and burden.
Discussion
The distress of ALS caregivers is related to patient respiratory issues. The first and more intuitive explanation emphasizes the impact that the patient’s clinical condition has with respect to the caregiver. However, it is possible to hypothesize that if caregivers feel psychologically better, their patient’s quality of life improves and that a condition of greater well-being and relaxation could also increase ventilatory capacity. Furthermore, care management could be carried out more easily by caregivers who pay more attention to the patient's respiratory needs.
Conclusion
Patient perception of social support and caregiver distress are related to respiratory issues in ALS.
doi:10.1186/1751-0759-6-14
PMCID: PMC3472192  PMID: 22721255
Quality of life; Bio-psycho-social interaction; Amyotrophic lateral sclerosis; Non-invasive ventilation; Health care; Caregivers
5.  Amyotrophic Lateral Sclerosis Multiprotein Biomarkers in Peripheral Blood Mononuclear Cells 
PLoS ONE  2011;6(10):e25545.
Background
Amyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.
Methodology/Principal Findings
We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%), and from patients with neurological disorders that may resemble ALS (91%), between two levels of disease severity (90%), and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.
Conclusions/Significance
Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms.
doi:10.1371/journal.pone.0025545
PMCID: PMC3187793  PMID: 21998667
6.  Clinical Psychology and Amyotrophic Lateral Sclerosis 
Amyotrophic lateral sclerosis is a fatal and progressive disease, characterized by progressive muscles weakness, with consequent loss of physical capacities. Psychologists can play an important role in ALS care, by providing clinical activities in every step of the disease, including support and counseling activities directed to patients, their caregivers and to physicians.
doi:10.3389/fpsyg.2010.00033
PMCID: PMC3153752  PMID: 21833203
amyotrophic lateral sclerosis; clinical psychology; neurological illness; psychological support; burnout
7.  Impaired Expression of Insulin-Like Growth Factor-1 System in Skeletal Muscle of Amyotrophic Lateral Sclerosis Patients 
Muscle & Nerve  2012;45(2):200-208.
Introduction
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.
Methods
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).
Results
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.
Conclusion
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
doi:10.1002/mus.22288
PMCID: PMC3306791  PMID: 22246875
amyotrophic lateral sclerosis; IGF-1; IGF-BPs; IGF-1 receptor; skeletal muscle

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