Late-onset glycogen storage disease type 2.

Glycogenosis II (GSDII) is an autosomal recessive lysosomal storage disorder resulting from acid alpha-glucosidase (GAA) deficiency, subsequent lysosomal accumulation of glycogen in muscles, impairment of autophagic processes and progressive cardiac, motor and respiratory failure. The infantile form usually appears in the first month of life, progresses rapidly and presents with severe cardiac involvement and complete deficiency of alpha-glucosidase activity (< 1% of normal controls). The late-onset form is characterized by great variability of the phenotypical spectrum. Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent. Residual GAA enzyme activity may correlate with severity of phenotype but many adult patients sharing the same mutations present with a wide variability in residual enzyme activity, age of onset and rate of disease progression, thus supporting a role for other factors, i.e., post-translational modifications and modifier genes, in modulating disease presentation. Enzyme replacement therapy (ERT) with alglucosidase alfa stabilizes the disease or improves muscle and/or respiratory function. However, efficacy of ERT may be influenced by several factors including age when ERT begins, extent of muscle damage, degree of defective autophagy, diversity in muscle fiber composition, difficulties in delivery of the therapeutic agent and antibody production. Further studies should be warranted to investigate factors determining the differences in clinical expression and therapeutic response in order to achieve better clinical and therapeutic management of these patients

Non-muscle involvement in late-onset Glycogenosis II

Glycogenosis II (GSD II) is an autosomal recessive lysosomal storage disorder resulting from acid alpha-glucosidase deficiency, subsequent accumulation of glycogen in tissues, impairment of autophagic processes and progressive cardiac, motor and respiratory failure. The late-onset form is characterized by wide variability in residual enzyme activity, age of onset, rate of disease progression and phenotypical spectrum. Although the pathological process mainly affects the skeletal muscle, several other tissues may be involved in the course of the disease; therefore GSD II should be regarded as a multisystem disorder in which glycogen accumulation is present in skeletal and smooth muscle, heart, brain, liver, spleen, salivary glands, kidney and blood vessels. In this review, we briefly summarize the main non-muscle targets of the pathological process in late-onset GSD II. Further studies aimed at evaluating the extra-muscle involvement in this group of patients will help to better define clinical features and prognostic factors and to delineate the natural history of the disease

The role of mitochondria in neurodegenerative diseases.

Mitochondria are implicated in several metabolic pathways including cell respiratory processes, apoptosis, and free radical production. Mitochondrial abnormalities have been documented in neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Several studies have demonstrated that mitochondrial impairment plays an important role in the pathogenesis of this group of disorders. In this review, we discuss the role of mitochondria in the main neurodegenerative diseases and review the updated knowledge in this field

Current options in the treatment of mitochondrial diseases.

Mitochondrial diseases (MD) are disorders caused by an impairment of the mitochondrial respiratory chain function. They are usually progressive, isolated or multi-system diseases and have variable times of onset. Because mitochondria have their own DNA (mtDNA), MD can be caused by mutations in both mtDNA and nuclear DNA (nDNA). The complexity of genetic control of mitochondrial function is in part responsible for the intra- and inter-familiar clinical heterogeneity of this class of diseases. Despite the remarkable progress in understanding of the molecular bases of these disorders, therapy of MD is quite inadequate. Present options of treatment mainly include physical, pharmacological and gene therapy approaches. Aerobic exercise and physical therapy is useful to prevent or correct deconditioning and may improve exercise tolerance. Pharmacological approach is based on removing noxious metabolites, using reactive oxygen species scavengers and administrating vitamins and cofactors which is especially important in case of primary deficiencies of specific compounds such as Coenzyme Q10. Gene therapy is fascinating but it is difficult to apply because of polyplasmy and heteroplasmy. Experimental methods include gene shifting, allotopic expression, mitochondrial transfection or correcting mtDNA mutations with specific restriction endonucleases. Here, we discussed some recent patents. Progresses in each of these fields may open interesting perspectives for the future

Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a treatment for patients with MNGIE and a standardized approach to HSCT in this condition has recently been developed. We report on the transplant course, management and short-term follow-up in two MNGIE patients who underwent HSCT. The source of stem cells was bone marrow taken from an HLA 9/10 allele-matched unrelated donor in the first patient and from an HLA 10/10 allele-matched sibling donor in the second. Both patients achieved full donor chimerism, and we observed restoration of buffy coat TP activity and lowered urine nucleoside concentrations in both of them. The post-transplant clinical follow-up showed improvement in gastrointestinal dysmotility, abdominal cramps and diarrhea. Neurological assessment remained unchanged. However, the first patient died 15 months after HSCT due to gastrointestinal obstruction and shock; the second patient died 8 months after the procedure due to respiratory distress following septic shock. Although HSCT corrects biochemical abnormalities and improves gastrointestinal symptoms, the procedure can be risky in subjects already in poor medical condition as are many MNGIE patients. Since transplant-related morbidity and mortality increases with progression of the disease and number of comorbidities, MNGIE patients should be submitted to HSCT when they are still relatively healthy, in order to minimize the complications of the procedure. Anyway, there is still incomplete knowledge on the natural history of the disease in many affected patients and it is not yet clear when the best time to do a transplant is. Further clues to the therapeutic potential of HSCT could result from a prolonged observation in a greater number of non-transplanted and transplanted patients, which would allow us to answer the questions of if, how and when MNGIE patients require HSCT treatment

The Italian Dystonia Registry: rationale, design and preliminary findings

The Italian Dystonia Registry is a multicenter data collection system that will prospectively assess the phenomenology and natural history of adult-onset dystonia and will serve as a basis for future etiological, pathophysiological and therapeutic studies. In the first 6 months of activity, 20 movement disorders Italian centres have adhered to the registry and 664 patients have been recruited. Baseline historical information from this cohort provides the first general overview of adult-onset dystonia in Italy. The cohort was characterized by a lower education level than the Italian population, and most patients were employed as artisans, builders, farmers, or unskilled workers. The clinical features of our sample confirmed the peculiar characteristics of adult-onset dystonia, i.e. gender preference, peak age at onset in the sixth decade, predominance of cervical dystonia and blepharospasm over the other focal dystonias, and a tendency to spread to adjacent body parts, The sample also confirmed the association between eye symptoms and blepharospasm, whereas no clear association emerged between extracranial injury and dystonia in a body site. Adult-onset dystonia patients and the Italian population shared similar burden of arterial hypertension, type 2 diabetes, coronary heart disease, dyslipidemia, and hypothyroidism, while hyperthyroidism was more frequent in the dystonia population. Geographic stratification of the study population yielded no major difference in the most clinical and phenomenological features of dystonia. Analysis of baseline information from recruited patients indicates that the Italian Dystonia Registry may be a useful tool to capture the real world clinical practice of physicians that visit dystonia patients

Is firstly diagnosed ALS really ALS? Results of a population-based study with long-term follow-up

OBJECTIVE: To revise the first diagnosis of amyotrophic lateral sclerosis (ALS) in patients from a well-defined population. METHODS: Patients diagnosed with ALS in the years 1998-2002 and resident of Lombardy Region, Northern Italy were followed until death or April 30 2016 to assess long-term survival. During follow-up, the caring neurologists were asked to confirm the first diagnosis. Revised diagnoses were classified as confirmed and unconfirmed motor neuron disease (MND) with further specification where available. The two groups were compared for age, sex, disease duration at diagnosis, site of onset, and El Escorial category. Survival with predictors were also compared. RESULTS: Included were 280 men and 203 women aged 18-93 years. During follow-up, 25 cases (5.2%) received a diagnosis different from MND. Diseases of spinal roots and peripheral nerves and vascular encephalopathy predominated. Patients with definite (OR 0.15; 95%CI 0.04-0.52) and probable (OR 0.15; 95%CI 0.04-0.62) ALS were least likely to have an unconfirmed MND diagnosis. At end of follow-up, 2.2% of patients with confirmed MND and 44.0% of patients with unconfirmed MND were reported alive (HR 0.14; 95%CI 0.08-0.25). CONCLUSIONS: At the time of a first diagnosis of ALS, the possibility still exists that another, less severe clinical condition, is present

Long-term survival in amyotrophic lateral sclerosis: A population-based study

Objective To determine the long-term survival in amyotrophic lateral sclerosis (ALS) and identify predictors of prolonged survival in a population-based cohort of newly diagnosed patients. Methods An incident cohort from a population-based registry during the years 1998 through 2002 in Lombardy, Italy was followed until death or to February 28, 2013. Age, sex, date of onset of symptoms, site of onset, date of diagnosis, and El Escorial diagnostic category were collected. Survival was assessed using Kaplan-Meier curves. Cox proportional hazards function was used to identify independent prognostic predictors. Standardized mortality ratios (SMRs) were used to assess the 5-year and 10-year excess mortality of ALS patients. Results Included were 280 men and 203 women aged 18 to 93 years. Spinal onset ALS was present in 312 cases (64.6%). Definite ALS was diagnosed in 213 cases (44.1%), probable ALS in 130 (26.9%), possible ALS in 93 (19.3%), and suspected ALS in 47 (9.7%). The cumulative time-dependent survival at 1, 5, and 10 years from diagnosis was 76.2%, 23.4%, and 11.8%, respectively. Independent predictors included younger age, the diagnosis of possible/suspected ALS, spinal onset, and symptoms having started >12 months previously at diagnosis. SMR was 9.4 at 5 years and 5.4 at 10 years. SMR at 10 years was higher until age 75 year, predominating in women, and became nonsignificant for males thereafter. Interpretation The outcome in ALS varies with phenotype. Longer survival is predicted by younger age, spinal onset, male gender, and suspected ALS. After age 75 years, 10-year survival in men with ALS is similar to the general population