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Movement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.

Z-band alternatively spliced PDZ-motif protein (ZASP) is a sarcomeric component expressed both in cardiac and skeletal muscles. Mutations in the LDB3/ZASP gene cause cardiomyopathy and myofibrillar myopathy. We describe a c.76C>T / p.[Pro26Ser] mutation in the PDZ motif of LDB3/ZASP in two siblings exhibiting late-onset myopathy with axial, proximal and distal muscles involvement and marked variability in clinical severity in the absence of a significant family history for neuromuscular disorders. Notably, we identified involvement of the psoas muscle on MRI and muscle CT, a feature not previously documented. Proband's muscle biopsy showed an increase of ZASP expression by western blotting. Muscle fibres morphological features included peculiar sarcolemmal invaginations, pathological aggregates positive to ZASP, ubiquitin, p62 and LC3 antibodies, and the accumulation of autophagic vacuoles, suggesting that protein aggregate formation and autophagy are involved in this additional case of zaspopathy.

Many aspects of epilepsy in mitochondrial disorders (MDs) need to be further clarified. To this aim, we explored retrospectively a cohort of individuals with MDs querying the “Nationwide Italian Collaborative Network of Mitochondrial Diseases” (NICNMD) database (1467 patients included since 2010 to December 2016). We collected information on age at epilepsy onset, seizure type and frequency, genetic findings, and antiepileptic drugs (AEDs). At the time of our survey, 147/1467 (10%) patients in the NICNMD database had epilepsy. Complete information was available only for 98 patients, 52 males and 46 females, aged 5–92years (mean age 40.4 ± 18.4; 14/98 children/teenagers and 84 adults). Epilepsy was the presenting feature of MD in 46/98 (47%) individuals, with onset at a median age of 19years (range, 0.2–68; < 3years in 14/97 (14%), 3–19years in 36/97 (37%), > 19years in 47/97 (49%)). Moreover, 91/98 patients (93%) displayed multiple seizures, with daily or weekly frequency in 25/91 (28%). Interictal EEG was abnormal in 70/78 (90%) patients, displaying abnormal background (47/70; 67%) and/or interictal paroxysms (53/70; 76%). Eighty of 90 patients (89%) displayed a 50–100% reduction of seizures on AEDs; levetiracetam was the most commonly used. Forty-one patients (42%) carried the m.3243A>G mutation, 16 (16%) the m.8344A>G, and 9 (9%) nuclear DNA (nDNA) mutations. Individuals with early-onset seizures mainly carried nDNA mutations and had a more severe epilepsy phenotype, higher seizure frequency, and disorganized background EEG activity. A better definition of epilepsy in MDs may foster the diagnostic workup, management, and treatment of affected patients, and allow more homogeneous patient stratification.

Introduction. Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the “lockdown”. The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic. Methods. We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials. Results. 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine. Conclusions. Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.

Muscle pain may be part of many neuromuscular disorders including myopathies, peripheral neuropathies and lower motor neuron diseases. Although it has been reported also in mitochondrial diseases (MD), no extensive studies in this group of diseases have been performed so far. We reviewed clinical data from 1398 patients affected with mitochondrial diseases listed in the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", to assess muscle pain and its features. Muscle pain was present in 164 patients (11.7%). It was commonly observed in subjects with chronic progressive external ophthalmoplegia (cPEO) and with primary myopathy without cPEO, but also-although less frequently-in multisystem phenotypes such as MELAS, MERFF, Kearns Sayre syndrome, NARP, MNGIE and Leigh syndrome. Patients mainly complain of diffuse exercise-related muscle pain, but focal/multifocal and at rest myalgia were often also reported. Muscle pain was more commonly detected in patients with mitochondrial DNA mutations (67.8%) than with nuclear DNA changes (32.2%). Only 34% of the patients showed a good response to drug therapy. Interestingly, patients with nuclear DNA mutations tend to have a better therapeutic response than patients with mtDNA mutations. Muscle pain is present in a significant number of patients with MD, being one of the most common symptoms. Although patients with a myopathic phenotype are more prone to develop muscle pain, this is also observed in patients with a multi system involvement, representing an important and disabling symptom having poor response to current therapy.

Progressive external ophthalmoplegia (PEO), Kearns–Sayre syndrome (KSS) and Pearson syndrome are the three sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA (mtDNA). PEO plus is a term frequently utilized in the clinical setting to identify patients with PEO and some degree of multisystem involvement, but a precise definition is not available. The purpose of the present study is to better define the clinical phenotypes associated with a single mtDNA deletion, by a retrospective study on a large cohort of 228 patients from the database of the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”. In our database, single deletions account for about a third of all patients with mtDNA-related disease, more than previously recognized. We elaborated new criteria for the definition of PEO and “KSS spectrum” (a category of which classic KSS represents the most severe extreme). The criteria for “KSS spectrum” include the resulting multisystem clinical features associated with the KSS features, and which therefore can predict their presence or subsequent development. With the new criteria, we were able to classify nearly all our single-deletion patients: 64.5% PEO, 31.6% KSS spectrum (including classic KSS 6.6%) and 2.6% Pearson syndrome. The deletion length was greater in KSS spectrum than in PEO, whereas heteroplasmy was inversely related with age at onset. We believe that the new phenotype definitions implemented here may contribute to a more homogeneous patient categorization, which will be useful in future cohort studies of natural history and clinical trials. © 2015, Springer-Verlag Berlin Heidelberg.

Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases," we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as "the MERRF mutation"). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term "myoclonic epilepsy" seems inadequate and potentially misleading. © 2014 International Parkinson and Movement Disorder Society.

The m.3243A>G "MELAS" (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) mutation is one of the most common point mutations of the mitochondrial DNA, but its phenotypic variability is incompletely understood. The aim of this study was to revise the phenotypic spectrum associated with the mitochondrial m.3243A>G mutation in 126 Italian carriers of the mutation, by a retrospective, database-based study ("Nation-wide Italian Collaborative Network of Mitochondrial Diseases"). Our results confirmed the high clinical heterogeneity of the m.3243A>G mutation. Hearing loss and diabetes were the most frequent clinical features, followed by stroke-like episodes. "MIDD" (maternally-inherited diabetes and deafness) and "PEO" (progressive external ophthalmoplegia) are nosographic terms without any real prognostic value, because these patients may be even more prone to the development of multisystem complications such as stroke-like episodes and heart involvement. The "MELAS" acronym is convincing and useful to denote patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Of note, we observed for the first time that male gender could represent a risk factor for the development of stroke-like episodes in Italian m.3243A>G carriers. Gender effect is not a new concept in mitochondrial medicine, but it has never been observed in MELAS. A better elucidation of the complex network linking mitochondrial dysfunction, apoptosis, estrogen effects and stroke-like episodes may hold therapeutic promises. © 2013 Springer-Verlag Berlin Heidelberg.