Combination of anti-CGRP/CGRP-R mAbs with onabotulinumtoxin A as a novel therapeutic approach for refractory chronic migraine: a retrospective study of real-world clinical evidence and a protocol for a double-blind, randomized clinical trial to establish the efficacy and safety.

Chronic migraine is a disabling neurovascular disorder that ranks amongst the top causes of years lived with disability worldwide. The duration and the frequency of migraine affect cognitive and affective domains, inducing worsening of memory, executive functions, orientation and causing anxiety. Population-based studies report a worrying level of resistance to treatments. Therefore, this study aims: 1) to assess efficacy of monoclonal antibodies (mAbs) directed towards the calcitonin gene-related peptide (CGRP) or its receptor (CGRP-R) for chronic migraine resistant to current preventatives; 2) to design a clinical trial protocol to evaluate the efficacy and safety of combination therapy utilizing anti-CGRP/CGRP-R together with onabotulinumtoxin A in patients suffering from resistant chronic migraine; 3) to provide a molecular rationale for combination therapy. A controlled trial is warranted as pooled analysis of real-world data from our group highlighted that combined treatment provides ≥50% reduction vs. baseline (onabotulinumtoxin A) of monthly headache days (MHDs) in up to 58.8% of patients, but there has been only sparse application of this combined therapy to date. The mAbs chosen are: erenumab, because its combination effect with onabotulinumtoxin A improved symptoms in 65% of patients; eptinezumab, due to its faster action. The results highlight that early diagnosis of migraine improves therapeutic outcomes with mAbs alone, confirming their effectiveness and the need for an adequately powered clinical trial evaluating the safety and potential superior effectiveness of eptinezumab/erenumab and onabotulinumtoxin A together.

NAbiximols Clinical Translation To the treatment of Pain and Agitation In Severe Dementia (NACTOPAISD): Clinical trial protocol.

Up to 80 % nursing home residents with dementia experiences chronic pain. Contextually, 97 % presents fluctuant neuropsychiatric symptoms (NPS). Among the most challenging is agitation, connected with undertreated pain and managed through neuroleptics doubling death risk. Evidence is accumulating in favor of the involvement of the endocannabinoid system in nociception and NPS. This double-blind, placebo-controlled, randomized trial (NAbiximols Clinical Translation To the treatment of Pain and Agitation In Severe Dementia [NACTOPAISD]) aims at investigating efficacy and safety of oral spray nabiximols, containing Δ9-tetrahydrocannabinol and cannabidiol (Sativex®), for pain and agitation treatment in severe dementia patients (Mini-Mental State Examination ≤ 12) over 65. The coprimary endpoints are efficacy on pain and agitation, assessed through the recently validated Italian Mobilization-Observation-Behavior-Intensity-Dementia and the Cohen-Mansfield Agitation Inventory. The secondary endpoint is the evaluation of efficacy duration after wash-out and the assessment of quality of life through the DEMQOL. Any adverse events will be reported. The results undergo statistical analysis plan. NACTOPAISD might provide rationale for a translational safer pain and agitation treatment in severe dementia. It is approved by Calabria Region Ethics Committee and follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and the Consolidated Standards of Reporting Trials (CONSORT) statements.

Primary mitochondrial myopathy: 12-month follow-up results of an Italian cohort.

OBJECTIVES: To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM). METHODS: Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test-retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation. RESULTS: At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS. CONCLUSIONS: PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.

Pain and agitation treatment in severe dementia patients: The need for Italian Mobilization-Observation-Behavior-Intensity-Dementia (I-MOBID2) pain scale translation, adaptation and validation with psychometric testing.

The 97% of dementia patients develops fluctuant neuropsychiatric symptoms often related to under-diagnosed and unrelieved pain. Up to 80% severe demented nursing home residents experiences chronic pain due to age-related comorbidities. Patients lacking self-report skills risk not to be appropriately treated for pain. Mobilization-Observation-Behavior-Intensity-Dementia (MOBID2) is the sole pain scale to consider the frequent co-occurrence of musculoskeletal and visceral pain and to unravel concealed pain through active guided movements. Accordingly, the Italian real-world setting can benefit from its translation and validation. This clinical study provides a translated, adapted and validated version of the MOBID2, the Italian I-MOBID2. The translation, adaptation and validation of the scale for non-verbal, severe demented patients was conducted according to current guidelines in a cohort of 11 patients over 65 with mini-mental state examination ≤ 12. The I-MOBID2 proves: good face and scale content validity index (0.89); reliable internal consistency (Cronbach's α = 0.751); good to excellent inter-rater (Intraclass correlation coefficient, and test-retest (ICC = 0.902) reliability. The construct validity is high (Rho = 0.748 p < 0.05 for 11 patients, Spearman rank order correlation of the overall pain intensity score with the maximum item score of I-MOBID2 Part 1; rho=0.895 p < 0.01 for 11 patients, for the overall pain intensity score with the maximum item score of I-MOBID2 Part 2) and a good rate of inter-rater and test-retest agreement was demonstrated by Cohen's K = 0.744. The average execution time is of 5.8 min, thus making I-MOBID2 a useful tool suitable also for future development in community setting with administration by caregivers.

Adult-onset mitochondrial movement disorders: a national picture from the Italian Network.

INTRODUCTION: Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown. METHODS: Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical, genetic, neuroimaging and neurophysiological data of adult patients with primary mitochondrial diseases (n = 764) where ataxia, myoclonus or other movement disorders were part of the clinical phenotype. RESULTS: Ataxia, myoclonus and movement disorders were present in 105/764 adults (13.7%), with the onset coinciding or preceding the diagnosis of the mitochondrial disease in 49/105 (46.7%). Ataxia and parkinsonism were the most represented, with an overall prevalence at last follow-up of 59.1% and 30.5%, respectively. Hyperkinetic movement disorders were reported in 15.3% at last follow-up, being the less common reported movement disorders. The pathogenic m.8344A > G and POLG variants were always associated with a movement disorder, while LHON variants and mtDNA single deletions were more commonly found in the subjects who did not present a movement disorder. The most common neuroimaging features were cortical and/or cerebellar atrophy, white matter hyperintensities, basal ganglia abnormalities and nigro-striatal degeneration. Almost 70% of patients with parkinsonism responded to dopaminergic therapy, mainly levodopa, and 50% with myoclonus were successfully treated with levetiracetam. CONCLUSION: Movement disorders, mainly ataxia and parkinsonism, are important findings in adult primary mitochondrial diseases. This study underlies the importance of looking for a mitochondrial etiology in the diagnostic flowchart of a movement disorder and may help direct genetic screening in daily practice.

Is there a rational basis for cannabinoids research and development in ocular pain therapy? A systematic review of preclinical evidence.

BACKGROUND: Purpose of the present systematic review is to investigate preclinical evidence in favor of the working hypothesis of efficacy of cannabinoids in ocular pain treatment. METHODS: Literature search includes the most relevant repositories for medical scientific literature from inception until November, 24 2021. Data collection and selection of retrieved records adhere to PRISMA criteria. RESULTS: In agreement with a priori established protocol the search retrieved 2471 records leaving 479 results after duplicates removal. Eleven records result from title and abstract screening to meet the inclusion criteria; only 4 results are eligible for inclusion in the qualitative synthesis impeding meta-analysis. The qualitative analysis highlights the antinociceptive and anti-inflammatory efficacy of Δ8-tetrahydrocannabinol, cannabidiol and its derivative HU-308 and of new racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229. Moreover, CB2R agonists RO6871304 and RO6871085 and CB2R ligand HU910 provide evidence of anti-inflammatory efficacy. CB2 agonist HU308 reduces of 241% uveitis-induced leukocyte adhesion and changes lipidome profile. Methodological and design issues raise concern of risk of bias and the amount of studies is too small for generalization. Furthermore, the ocular pain model used can resemble only inflammatory but not neuropathic pain. CONCLUSIONS: The role of the endocannabinoid system in ocular pain is underinvestigated, since only two studies assessing the effects of cannabinoid receptors modulators on pain behavior and other two on pain-related inflammatory processes are found. Preclinical studies investigating the efficacy of cannabinoids in ocular inflammatory and neuropathic pain models are needed to pave the way for clinical translation.

Addressing Pain for a Proper Rehabilitation Process in Patients With Severe Disorders of Consciousness.

Consciousness constitutes a fundamental prerequisite in the individual appraisal and experience of pain. In the same way, a person needs to be able to report on pain perception. Patients who suffered a severe brain injury with disorders of consciousness (DOC) represent a spectrum of pathologies affecting patients' capacity to interact with the external world. In these patients, the most relevant aspects in response to pain are physiologic and behavioral. The treatments and management of pain are challenging issues in these patients, arising serious ethical concerns and bringing emotional load among medical staff, caregivers, and relatives. In this review, we report the importance of having a correct pain management in DOC patients, to individuate the best pharmacological treatment that can make the difference in detecting a behavioral response, indicative of a change in the level of consciousness, and in planning a more effective rehabilitative approach.

Diagnosis, genetic characterization and clinical follow up of mitochondrial fatty acid oxidation disorders in the new era of expanded newborn screening: A single centre experience.

INTRODUCTION: Mitochondrial fatty acid oxidation disorders (FAODs) are a heterogeneous group of hereditary autosomal recessive diseases included in newborn screening (NBS) program in Italy. The aim of this study was to analyse FAODs cases, identified either clinically or by NBS,for clinical and genetic characterization and to evaluate a five years' experience of NBS, in the attempt to figure out the complexity of genotype-phenotype correlation and to confirm the clinical impact of NBS in our centre experience. MATERIALS AND METHODS: We analysed FAODs patients diagnosed either by NBS or clinically, followed since February 2014 to April 2019 at the Regional Screening Centre and Inherited Metabolic Diseases Unit of Verona. Diagnosis was confirmed by plasma acylcarnitines, urinary organic acids, enzymatic and genetic testing. For not clear genotypes due to the presence of variants of uncertain significance, in silico predictive tools have been used as well as enzymatic activity assays. Patients underwent clinical, nutritional and biochemical follow up. RESULTS: We diagnosed 30 patients with FAODs. 20 by NBS: 3 CUD, 6 SCADD, 5 MCADD, 4 VLCADD, 2 MADD. Overall incidence of FAODs diagnosed by NBS was 1:4316 newborns. No one reported complications during the follow up period. 10 patients were diagnosed clinically: 2 CUD, 2 CPT2D, 1 VLCADD, 5 MADD. Mean age at diagnosis was 29.3 years. Within this group, complications or symptoms were reported at diagnosis, but not during follow-up. 12 mutations not previously reported in literature were found, all predicted as pathogenic or likely pathogenic. DISCUSSION AND CONCLUSIONS: Our study highlighted the great phenotypic variability and molecular heterogeneity of FAODs and confirmed the importance of a tailored follow up and treatment. Despite the short duration of follow up, early identification by NBS prevented diseases related complications and resulted in normal growth and psycho-motor development as well.

Eptinezumab for the treatment of migraine.

Eptinezumab (ALD-403) is a genetically engineered humanized IgG1kappa directed towards calcitonin gene-related peptide (CGRP), currently in late-stage clinical development. Eptinezumab targets the pathway of CGRP, importantly implicated in migraine pathophysiology, and may represent the first-to-market infusion therapy for migraine prevention. The background for its approval consists in preclinical data and clinical trials. Here, we provide a comprehensive review of molecular pharmacology, pharmacokinetics, metabolism, efficacy and safety investigated in the preclinical and clinical studies, with insight on possible future directions.

Influence of neurorehabilitation on stroke-induced modifications of the quadriceps muscle in elderly subacute stroke patients with paresis.

The influence of intensive multifunctional neurorehabilitation on post-stroke changes at the level of the paretic leg quadriceps muscle was examined in elderly subacute stroke patients. We assessed paretic leg muscle mass thickness and muscle fatty infiltration thickness, as well as clinical outcome measures (National Institutes of Health Stroke Scale, modified Ranking Scale, and Barthel Index) both before and after neurorehabilitation. Improved outcome measures (p ≤ 0.01) and increased muscle mass thickness (p = 0.005) with decreased muscle fatty infiltration thickness (p = 0.005) were observed after neurorehabilitation. No correlations were found between clinical outcome measures and muscle parameters either before or after neurorehabilitation. The findings of this study suggest that neurorehabilitation has a positive influence on global functional recovery and on remodelling of the quadriceps muscle, even in elderly stroke patients, but they do not support the hypothesis that post-stroke muscle changes might have prognostic significance in terms of the severity of neurological deficit and disability, nor do they suggest that these changes can be regarded as a determinant of stroke severity.

What impact can hospitalization environment produce on the ANS functioning in patients with Unresponsive Wakefulness Syndrome? - 24-hour monitoring.

Objectives: Studies showed that the recovery of patients with Unresponsive Wakefulness Syndrome (UWS) is also correlated to the recovery of circadian rhythms. In this study, we observed the correlations between patients with UWS biometrical and ambient parameters. Methods: A dedicated monitoring system was realized to record and correlate the level of noise and luminosity with biometric Heart Rate (HR), Heart Rate Variability (HRV) and Breath Rate (BR) parameters. Eleven patients with UWS were recruited and monitored for 13 ± 7 days. Correlation of ambient and biometric parameters was analyzed by Spearman's test. Wilcoxon's test was used to compare the biometric parameters in two different moments of daily activity in the rehabilitation unit (night and day). Patients showed a moderate negative or positive correlation between biometric and ambient parameters. Results: Significant differences between night and morning (0.0001 < p ≤ 0.001) were found for HR, HRV and BR in seven, five and four patients, respectively, at Wilcoxon's test. HR and BR were higher during the night while HRV was lower. Conclusion: In patients with UWS, lower HRV and higher HR and BR during the night might be indicative of interference in sleep/wake cycles. The modifications of the environment surrounding the patient due to the unit procedures of the staff and/or some interaction modalities of the relatives may have an effect on residual endogenous mechanisms of self-regulation. However, differences between night and day in the biometrical parameters are not necessarily linked to the changes in the environment care unit.

Effectiveness of intensive neurorehabilitation in obese subacute stroke patients.

The relationship between abdominal subcutaneous adipose tissue thickness (aSAT), body fat percentage (BFP), waist-to-hip ratio (WHR) and body mass index (BMI) and outcome measures of neurological deficit and functional recovery was evaluated in obese subacute stroke patients before and after neurorehabilitation. Decreased National Institutes of Health Stroke Scale (p = 0.0001) and modified Rankin Scale (mRS) (p= 0.002) scores, as well as increased Barthel Index (p= 0.0001) scores were detected after neurorehabilitation. Decreased BMI, aSAT, BFP and WHR observed after neurorehabilitation did not penalize the overall functional recovery as shown by correlations between the clinical measure scores and fat mass indices. The correlation observed after neurorehabilitation between BMI and mRS (rho = 0.4526, p < 0.05) suggests that a high BMI may compromise functional recovery. Monitoring of body fat mass indices may provide information aimed at improving the disability of obese stroke patients.

Effects of short-to-long term enzyme replacement therapy (ERT) on skeletal muscle tissue in late onset Pompe disease (LOPD).

AIMS: Pompe disease is an autosomal recessive lysosomal storage disorder resulting from deficiency of acid α-glucosidase (GAA) enzyme. Histopathological hallmarks in skeletal muscle tissue are fibre vacuolization and autophagy. Since 2006, enzyme replacement therapy (ERT) is the only approved treatment with human recombinant GAA alglucosidase alfa. We designed a study to examine ERT-related skeletal muscle changes in 18 modestly to moderately affected late onset Pompe disease (LOPD) patients along with the relationship between morphological/biochemical changes and clinical outcomes. Treatment duration was short-to-long term. METHODS: We examined muscle biopsies from 18 LOPD patients at both histopathological and biochemical level. All patients underwent two muscle biopsies, before and after ERT administration respectively. The study is partially retrospective because the first biopsies were taken before the study was designed, whereas the second biopsy was always performed after at least 6 months of ERT administration. RESULTS: After ERT, 15 out of 18 patients showed improved 6-min walking test (6MWT; P = 0.0007) and most of them achieved respiratory stabilization. Pretreatment muscle biopsies disclosed marked histopathological variability, ranging from an almost normal pattern to a severe vacuolar myopathy. After treatment, we detected morphological improvement in 15 patients and worsening in three patients. Post-ERT GAA enzymatic activity was mildly increased compared with pretreatment levels in all patients. Protein levels of the mature enzyme increased in 14 of the 18 patients (mean increase = +35%; P < 0.05). Additional studies demonstrated an improved autophagic flux after ERT in some patients. CONCLUSIONS: ERT positively modified skeletal muscle pathology as well as motor and respiratory outcomes in the majority of LOPD patients.

Revisiting mitochondrial ocular myopathies: a study from the Italian Network.

Ocular myopathy, typically manifesting as progressive external ophthalmoplegia (PEO), is among the most common mitochondrial phenotypes. The purpose of this study is to better define the clinical phenotypes associated with ocular myopathy. This is a retrospective study on a large cohort from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". We distinguished patients with ocular myopathy as part of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy), and then PEO with isolated ocular myopathy from PEO-plus when PEO was associated with additional features of multisystemic involvement. Ocular myopathy was the most common feature in our cohort of mitochondrial patients. Among the 722 patients with a definite genetic diagnosis, ocular myopathy was observed in 399 subjects (55.3%) and was positively associated with mtDNA single deletions and POLG mutations. Ocular myopathy as manifestation of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy, n = 131) was linked to the m.3243A>G mutation, whereas the other "PEO" patients (n = 268) were associated with mtDNA single deletion and Twinkle mutations. Increased lactate was associated with central neurological involvement. We then defined, among the PEO group, as "pure PEO" the patients with isolated ocular myopathy and "PEO-plus" those with ocular myopathy and other features of neuromuscular and multisystem involvement, excluding central nervous system. The male proportion was significantly lower in pure PEO than PEO-plus. This study reinforces the need for research on the role of gender in mitochondrial diseases. The phenotype definitions here revisited may contribute to a more homogeneous patient categorization, useful in future studies and clinical trials.

European core curriculum in neurorehabilitation.

To date, medical education lacks Europe-wide standards on neurorehabilitation. To address this, the European Federation of NeuroRehabilitation Societies (EFNR) here proposes a postgraduate neurorehabilitation training scheme. In particular, the European medical core curriculum in neurorehabilitation should include a two-year residency in a neurorehabilitation setting where trainees can gain practical experience. Furthermore, it should comprise six modules of classroom training organized as weekend seminars or summer/winter schools. In conclusion, after defining the European medical core curriculum in neurorehabilitation, the next activities of the EFNR will be to try and reach the largest possible consensus on its content among all national societies across Europe in order to further validate it and try to extend it to the other, non-medical, professionals on the neurorehabilitation team in line with their core curricula defined by each professional association.

LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population.

OBJECTIVE: A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. DESIGN/METHODS: 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age ≥5 years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid α-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. RESULTS: In a 14-month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5 years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. CONCLUSIONS: LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression.

Comparison of the cough reflex test and water swallowing test in healthy participants and neurological patients.

Comparison of the cough reflex test and water swallowing test in healthy participants and neurological patients. BACKGROUND: Silent aspiration is poorly identified by traditional clinical swallowing evaluations. Recently, sevral studies have proposed the use of a cough reflex test (CRT) for screening patients at risk of aspirations. The first aithis study is to investigate the CRT thresholds of citric acid concentration for identifying cough responses in healthy participants and neurological patients. The second aim is to compare the results of the CRT with the water swallowing test (WST), a standard screening test for identifying cough responses in neurological patients. METHODS: The CRT and then the WST were administered to 100 neurological patients and 100 healthy participants. For the CRT, we administered incremental solutions of citric acid interspersed with placebo doses. We used the results of the CRT in healthy participants to define a citric acid concentration cut-off, which could be used with neurological patients as a screening for aspirations. RESULTS: As all controls coughed at a concentration of 0.1 mol/L, this was used as a cut-off in patients to identify coughing as a screening for aspiration risk. Patients showed cough reflexes at concentrations significantly higher than controls (p=0 .001). The WST was not administered to 17 patients, due to cognitive deficits and severe clinical conditions. Thirty six patients had a cough response above the screening cut-off (> 0.1 mol/L), 25 of which (30.1%) also had a positive cough response during the WST. CONCLUSION: The CRT correlated significantly with the WST. Unlike the WST, the CRT could be easily administered to severely impaired patients. Our results indicate the use of the CRT as a screening test for silent aspirators.

[A case of acute renal failure secondary to late-onset McArdle's disease]. / Un caso di insufficienza renale acuta secondaria a malattia di McArdle ad esordio tardivo.

INTRODUCTION: Mc Ardles disease, also known as Type V glycogen storage disease, is a rare deficiency of the enzyme glycogen phosphorylase in muscle cells, inherited as an autosomal recessive trait. In the absence of this enzyme, muscles cannot break down glycogen during exercise, so in patients affected by McArdles disease even moderate physical activity produces cramps, pain and fatigue. Anaerobic activity leads to severe fixed contractures and rhabdomyolisis with myoglobinuria and raised serum creatine-kinase, which, in turn, can lead to acute renal failure. Disease onset is usually in early childhood, although diagnosis is often not made until the second or third decade. CASE REPORT: We present the case of a 68-year-old man who presented to the Emergency Room with fatigue, vertigo, diarrhea and oliguria. The patient underwent five daily hemodialysis sessions, diuresis reappeared and there was progressive recovery of renal function. The patient described episodes of fatigue and muscular pain occurring since childhood: the positive personal history, together with persistently raised CPK levels in the absence of any infective or toxic cause of myositis, led us to suspect the presence of this rare metabolic disease, which was subsequently confirmed by muscle biopsy. CONCLUSION: To date, there is no specific treatment for type V glycogenosis, although a diet rich in protein and saccarose, vitamin B6 supplementation and creatine administration are generally recommended. Moderate physical activity can help manage symptoms by improving exercise tolerance and blood supply to the muscles, ensuring provision of glucose and free fatty acids for the muscle fibers.

Fatigue and exercise intolerance in mitochondrial diseases. Literature revision and experience of the Italian Network of mitochondrial diseases.

Fatigue and exercise intolerance are common symptoms of mitochondrial diseases, but difficult to be clinically assessed. New methods to quantify these rather common complaints are strongly needed in the clinical practice. Coenzyme Q10 administration and aerobic exercise may improve exercise intolerance, but more definite studies are still pending. Herein, we have revised "how to measure" and "how to treat" these symptoms of mitochondrial patients. Subsequently, we reviewed the clinical data of the 1164 confirmed mitochondrial patients present in the Italian nation-wide database of mitochondrial disease, with special regard to exercise intolerance. We observed that more of 20% of mitochondrial patients complain of exercise intolerance. This symptom seems to be frequently associated with specific patient groups and/or genotypes. Ragged red fibers and COX-negative fibers are more often present in subjects with exercise intolerance, whereas lactate levels could not predict this symptom. Multicenter efforts are strongly needed for rare disorders such as mitochondrial diseases, and may represent the basis for more rigorous longitudinal studies.

Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families.

BACKGROUND: Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer. We studied ovarian and breast cancer families having at least one woman affected by ovarian carcinoma, to assess the importance of RAD51D mutations in such families. METHODS: The coding region of the RAD51D gene was analysed in 175 BRCA1/2-negative families with family histories of both ovarian and breast cancer ascertained from two Canadian and two Belgian institutions. RESULTS: We identified one previously reported deleterious mutation, p.Arg186(*) (c.556C>T), and two novel variants; missense substitution p.Cys119Arg and an intronic variant c.83-26A>G. p.Arg186(*) segregated with the disease in the family and two ovarian carcinomas available for analysis showed loss of the wild-type allele, but the novel variants are likely neutral. CONCLUSION: RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. We show that mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer, and we feel testing should be preferentially offered to affected women from such families.