The empowerment of translational research: lessons from laminopathies.

The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy.

Phenotypic overlap in familial and sporadic primary adult-onset extracranial dystonia.

We recently demonstrated that familial and sporadic blepharospasms share several phenotypic features (including age of dystonia onset, sex, and tendency to spread) believed to reflect the etiology of a blepharospasm. To investigate whether familial and sporadic forms of primary adult-onset dystonia other than the blepharospasm also share phenotypic features, we studied the families of 98 probands with primary adult-onset dystonia other than blepharospasms using a validated two-step procedure (questionnaire and clinical examination) that yields 95 % sensitivity and 100 % specificity when used to identify dystonia among relatives. The 98 probands provided a population of 402 living first-degree relatives aged 20 years or more, 336 of whom (83 %, 111 parents, 152 siblings, and 73 children) were screened for dystonia.

Eye symptoms in relatives of patients with primary adult-onset dystonia.

Methods: Using a validated questionnaire, we screened eye symptoms (burning sensation, grittiness, dry eye) in 333 first-degree relatives of 140 probands with different forms of primary adult-onset dystonia, 208 healthy subjects, and 293 patients with primary blepharospasm.

Results: The rate of eye symptoms was similar in the relatives of focal dystonia patients and in healthy subjects (adjusted HR, 1.1; 95% CI, 0.

Impact of medical audit on electrodiagnostic medicine in polyneuropathy.

Objective: The aim of the study was to investigate whether experienced physicians' electrodiagnostic practice and criteria can be influenced by international collaboration involving peer review medical audit.

Methods: Data was obtained from the ESTEEM project, an ongoing collaboration since 1991 among European neurophysiologists concerned with quality improvement in electrodiagnostic medicine. Three sets of the physicians' polyneuropathy examinations performed with intervals of 2-4 years were analysed.

Microneurographic evaluation of sympathetic activity in small fiber neuropathy.

Objective: Small fiber neuropathy (SFN) may involve somatic and autonomic fibers. Assessment of somatic epidermal nerve fiber density (ENFs) is considered the gold standard test in the diagnosis of SFN. By contrast, autonomic involvement in SFN is more difficult to ascertain.

A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16.

Dominant optic atrophy (DOA) is genetically heterogeneous and pathogenic mutations have been identified in the OPA1 and OPA3 genes, both encoding for mitochondrial proteins. We characterized clinical and laboratory features in a large OPA1-negative family with complicated DOA. Search for mitochondrial dysfunction was performed by studying muscle biopsies, fibroblasts, platelets and magnetic resonance (MR) spectroscopy.

Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study.

Bortezomib is a new chemotherapeutic agent approved for the treatment of relapsed/refractory and newly diagnosed multiple myeloma. One of the major side effects of bortezomib is a peripheral length-dependent sensory axonal neuropathy and, less frequently, a small fiber neuropathy. Autonomic symptoms like postural dizziness, syncope, diarrhoea, ileus, impotence and urinary disturbances have been reported, nevertheless, autonomic neuropathy has never been characterized.

Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations.

Objective: To assess whether impaired energy metabolism in skeletal muscle is a hallmark feature of patients with dominant optic atrophy due to several different mutations in the OPA1 gene.

Design: We used phosphorus 31 magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in subjects with molecularly defined dominant optic atrophy carrying different mutations in the OPA1 gene. In a subset of patients, we also evaluated serum lactate levels after exercise and muscle biopsy results for histology and mitochondrial DNA analysis.

Isolated noradrenergic failure in adult-onset autosomal dominant leukodystrophy.

We evaluated the autonomic control of the cardiovascular system and the skin innervation of a patient from a new Italian family with a genetically proven diagnosis of adult-onset autosomal dominant leukodystrophy (ADLD) due to lamin B1 gene duplication. Cardiovascular reflexes and pharmacological assessment indicated a selective sympathetic failure, sparing cardiovagal function. Microneurography revealed absent sympathetic activity.

Variation in the neurophysiological examination of amyotrophic lateral sclerosis in Europe.

Our objective was to analyse how patients with amyotrophic lateral sclerosis (ALS) are examined neurophysiologically at different European centres in order to identify possible areas with variation or disagreement in the neurophysiological examination of ALS. Ninety-three prospectively collected examinations from six out of seven neurophysiologists in the European ESTEEM project were analysed. All examinations were peer reviewed with an electromyographic consensus diagnosis of motor neuron disease and the diagnosis of ALS confirmed by clinical follow-up.

Autonomic disturbances in narcolepsy.

Narcolepsy is a clinical condition characterized mainly by excessive sleepiness and cataplexy. Hypnagogic hallucinations and sleep paralysis complete the narcoleptic tetrad; disrupted night sleep, automatic behaviors and weight gain are also usual complaints. Different studies focus on autonomic changes or dysfunctions among narcoleptic patients, such as pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache and extremities dysthermia.

Small fiber neuropathy in female patients with fabry disease.

Recent studies suggest that heterozygous female Fabry disease (FD) patients develop peripheral neuropathy. We used skin biopsy to define somatic and autonomic peripheral nerve characteristics in 21 females with FD who were mainly asymptomatic and had normal renal function. Somatic epidermal and dermal autonomic nerve fiber reductions were found, prevalently in the leg, and no differences were found between symptomatic and asymptomatic individuals.

A defective SERCA1 protein is responsible for congenital pseudomyotonia in Chianina cattle.

Recently, a muscular disorder defined as "congenital pseudomyotonia" was described in Chianina cattle, one of the most important Italian cattle breeds for quality meat and leather. The clinical phenotype of this disease is characterized by an exercise-induced muscle contracture that prevents animals from performing muscular activities. On the basis of clinical symptoms, Chianina pseudomyotonia appeared related to human Brody's disease, a rare inherited disorder of skeletal muscle function that results from a sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1) deficiency caused by a defect in the ATP2A1 gene that encodes SERCA1.

Sympathetic and cardiovascular activity during cataplexy in narcolepsy.

Autonomic nervous system activity changes have been described during cataplexy as playing a role in triggering it. To confirm these previous findings, we investigated the time course of sympathetic and cardiovascular activities during cataplexy. We made for the first time microneurographic recordings of 10 cataplectic episodes in three patients with hypocretin-deficient narcolepsy.

Idiopathic central sleep apnoea syndrome treated with zolpidem.

We report the case of a 47-year-old man with idiopathic central sleep apnoeas recurring during wake-sleep transitions at night or at diurnal naps. Symptoms associated with central apnoeas were sudden awakening with shortness of breath, sleep fragmentation and daytime tiredness. Following the failure of CPAP and BiPAP, we treated the patient with zolpidem which reduced central apnoea events, improved sleep and eliminated the patient's nocturnal disturbing symptoms.

Visual system involvement in patients with Friedreich's ataxia.

Optic neuropathy is common in mitochondrial disorders, but poorly characterized in Friedreich's ataxia (FRDA), a recessive condition caused by lack of the mitochondrial protein frataxin. We investigated 26 molecularly confirmed FRDA patients by studying both anterior and posterior sections of the visual pathway using a new, integrated approach. This included visual field testing and optical coherence tomography (OCT), pattern visual evoked potentials (P-VEPs) and diffusion-weighted imaging.

Axial myoclonus in paraproteinemic polyneuropathy.

We describe a patient with a paraproteinemic anti-myelin-associated glycoprotein (anti-MAG) antibody polyneuropathy and concomitant axial myoclonic jerks. Neurophysiological investigation revealed that axial jerks were asymmetrical and exaggerated by lying in bed. They disappeared during mental arousal and sleep.

Anhidrosis in multiple system atrophy: a preganglionic sudomotor dysfunction?

Anhidrosis occurs in the majority of multiple system atrophy (MSA) patients but the underlying site of lesion is not well established. We describe three patients with long-standing MSA and anhidrosis diagnosed on the basis of a thermoregulatory sweating test. In biopsies of anhidrotic skin, immunofluorescence analysis disclosed a well preserved postganglionic sudomotor innervation in all three patients supporting the hypothesis of a preganglionic nerve fiber lesion underlying their anhidrosis.

A prospective multicentre study on sural nerve action potentials in ALS.

Objective: To evaluate sensory nerve conduction studies in ALS in a prospective multicentre study involving 7 neurophysiologists from 6 European countries.

Methods: Bilateral sural potentials were obtained in 35 ALS patients and 35 age-matched controls according to a standardised examination protocol using antidromic surface technique. The recordings from the right sural nerve of the controls were used for reference values.

OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.

Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability.