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Background and purpose: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. Methods: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. Results: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ‐aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. Conclusions: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug‐related adverse events in individuals living with PMD‐related epilepsy. [ABSTRACT FROM AUTHOR]

Background and purpose: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. Methods: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. Results: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. Conclusions: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities. [ABSTRACT FROM AUTHOR]

The article discusses the importance of studying rare neurological diseases (RNDs) and the advancements in genetic research that have allowed for a better understanding of these conditions. It highlights the role of Italian neurology centers in the study of RNDs and their participation in international rare disease organizations. The article emphasizes the need for early and accurate diagnosis, collaboration among researchers, patient-centered approaches, and raising awareness about RNDs. The Italian Society of Neurology is committed to addressing these challenges and driving positive transformation in healthcare and research. [Extracted from the article]

Background and purpose: Seven thousand rare diseases have been identified; most of them are of genetic origin. The diagnosis of a neurogenetic disease is difficult, and management and training programs are not well defined through Europe. To capture and assess care needs, the Neurogenetics Panel of the European Academy of Neurology (EAN) has performed an explorative survey. Methods: The survey covering multiple topics of neurogenetics was sent to all neurologists and neuropediatricians affiliated with the EAN practicing in Europe. Results: We collected answers from 239 members based in 40 European member states. Even though most of the responders were aware of neurogenetic diseases, when we came to amenability of carrying out a complete genetic diagnosis, almost one‐third of the responders declared they were not happy with the current way of ordering genetic analyses in their countries. Furthermore, although single‐gene analysis is diffusely present in Europe, whole exome and genome sequencing are not easily accessible, with considerable variabilities among countries. Almost 10% of the responders did not know if presymptomatic and prenatal diagnosis was available in their countries, and 47.3% were not aware of which newborn screening programs were available. Finally, 96.3% of responders declared that there is a need for education and training in neurogenetics. Conclusions: We believe that this survey may be of importance for all European stakeholders in neurogenetics in identifying key priorities, targeting areas to encourage education/travel fellowships, and educational seminars in the future, because this area will only accelerate, and diagnostic requirements will expand. [ABSTRACT FROM AUTHOR]

Objective: We describe a severe case of vaccine-induced immune thrombotic thrombocytopenia (VITT) after the first dose of the ChAdOx1 nCoV-19 vaccine leading to massive ischemic stroke.Methods: A 42-year-old woman developed acute left hemiparesis (NIHSS 12) 9 days after the first vaccine dose.Results: The blood tests revealed low platelets (70 103/μL) and severe increment of D-dimer (70,745 ng/mL FEU). Brain non-contrast computed tomography and multiphasic CT angiography demonstrated a right middle cerebral artery occlusion. The patient was treated with primary thrombectomy, steroids, immunoglobulin, and fondaparinux. Despite the treatment, the neurological status deteriorated and underwent decompressive hemicraniectomy. She was transferred to the rehab's unit 52 days after the onset.Discussion: Healthcare providers should be aware of the possibility of ischemic stroke as a manifestation of VITT. Awareness on this very rare and possibly fatal complication should be reinforced on both the vaccine recipients and general practitioners. [ABSTRACT FROM AUTHOR]

Therefore, it is now time to accelerate on the field; we suggest the following key priorities to be achieved in the next 3 years: Key Priority 1: Ensure European patients get the right diagnosis faster wherever they live, including prenatal diagnosis and newborn screening for the treatable RNDs. Neurogenetics, rare diseases, rare neurological diseases, awareness Keywords: awareness; neurogenetics; rare diseases; rare neurological diseases EN awareness neurogenetics rare diseases rare neurological diseases 1553 1554 2 05/09/23 20230601 NES 230601 On 28 February, we observed Worldwide Rare Diseases Day, a full day dedicated to raising awareness and generating concrete changes for the 300 million people worldwide living with a rare disease, their families, and carers. [Extracted from the article]

Rare neurological diseases (RNDs) are a heterogeneous group of disorders mainly affecting the central and peripheral nervous systems, representing almost 50% of all rare diseases; this explains why neurologists are very often involved in their diagnosis, treatment and research. The purpose of this study was to quantitatively describe the awareness of RNDs among the neurological community of the Italian Society of Neurology (SIN). A survey of the Italian Neurogenetics and Rare diseases group of the SIN, similar to what was submitted to the members of the EAN Task Force on Rare Neurologic Diseases and to EAN Panels Scientific Committee Management Groups, was launched in January 2019 in order to verify the specific Italian situations and possibly the regional differences. Answers were collected online. We observed that Italian Members of the SIN Neurogenetics and Rare Neurologic Diseases Scientific Group are well aware of the burden posed by RNDs but at the national and regional level, the relative awareness is sketchy and disparate. Although many national initiatives have been undertaken to facilitate the diagnosis and management in Italy, our survey reveals that much works has to be done in supporting RNDs patients, including a deeper collaboration between politics, universities and all stakeholders in the field. [ABSTRACT FROM AUTHOR]

• Patients with mitochondrial diseases (MDs) are considered potentially at-risk for a severe COVID-19. • From March 1st to January 30th, 2020, we have identified 27 Italian MDs patients with COVID-19. • Most of the patients were pauci or asymptomatic and treated at home. • The most common signs of COVID-19 were fever, fatigue and myalgia. • MDs infected individuals seemed to be similarly affected by SARS-CoV-2 compared with general population. Patients with mitochondrial diseases, who usually manifest a multisystem disease, are considered potentially at-risk for a severe coronavirus disease 2019 (COVID-19). The objective of this study is to analyze the clinical features, prognosis and outcomes of COVID-19 in patients with primary mitochondrial diseases in a cohort of patients followed in Italy. We searched for patients with primary mitochondrial diseases and COVID-19 followed by the Italian Collaborative Network of Mitochondrial Diseases. In a total of 1843 patients followed by the National Network, we have identified from March 1st to January 30th, 2021, 27 SARS-CoV-2 infection. Most of the patients were pauci or asymptomatic (85%) and treated at home. The most common signs of COVID-19 were fever (78,9%), fatigue (47,4%), myalgia (42,1%), cough and headache (36,8%), and dyspnea (31,6%). Those who required COVID-19 therapy were treated with low-molecular-weight heparin, glucocorticoids, and antibiotics (mainly azithromycin) without serious side effects related to the therapy. Five patients (18,5%) clinically deteriorated during the infection, and one of them died for pneumonia. Primary mitochondrial diseases infected individuals seemed to be similarly affected by SARS-CoV-2 compared with the general Italian population in terms of clinical presentation and outcome. [ABSTRACT FROM AUTHOR]

Abstract Objectives To summarise and discuss recent findings and future perspectives concerning mitochondrial disorders (MIDs) affecting the retinal ganglion cells and the optic nerve (mitochondrial optic neuropathy. MON). Method Literature review. Results MON in MIDs is more frequent than usually anticipated. MON may occur in specific as well as non-specific MIDs. In specific and non-specific MIDs, MON may be a prominent or non-prominent phenotypic feature and due to mutations in genes located either in the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). Clinically, MON manifests with painless, bilateral or unilateral, slowly or rapidly progressive visual impairment and visual field defects. In some cases, visual impairment may spontaneously recover. The most frequent MIDs with MON include LHON due to mutations in mtDNA-located genes and autosomal dominant optic atrophy (ADOA) or autosomal recessive optic atrophy (AROA) due to mutations in nuclear genes. Instrumental investigations for diagnosing MON include fundoscopy, measurement of visual acuity, visual fields, and color vision, visually-evoked potentials, optical coherence tomography, fluorescein angiography, electroretinography, and MRI of the orbita and cerebrum. In non-prominent MON, work-up of the muscle biopsy with transmission electron microscopy may indicate mitochondrial destruction. Treatment is mostly supportive but idebenone has been approved for LHON and experimental approaches are promising. Conclusions MON needs to be appreciated, requires extensive diagnostic work-up, and supportive treatment should be applied although loss of vision, as the most severe outcome, can often not be prevented. Highlights • MON in MIDs is more frequent than usually anticipated • In specific and non-specific MIDs, MON may be a prominent or non-prominent phenotypic feature • MON manifests clinically with painless, bilateral or unilateral, slowly or rapidly progressive visual impairment [ABSTRACT FROM AUTHOR]

Involvement of the peripheral nervous system in mitochondrial disorders has been previously reported. However, the prevalence of peripheral neuropathy in mitochondrial disorders is still unclear. Based on the large database of the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”, we reviewed the clinical data of 1200 patients, with special regard to peripheral neuropathy (mean age at onset 24.3 ± 20.1 years; age at last evaluation 39.8 ± 22.3 years; females 52.7%; childhood onset [before age 16 years] 43.1%). Peripheral neuropathy was present in 143/1156 patients (12.4%), being one of the ten most common signs and symptoms. POLG mutations cause a potentially painful, axonal/mixed, mainly sensory polyneuropathy; TYMP mutations lead to a demyelinating sensory-motor polyneuropathy; SURF1 mutations are associated with a demyelinating/mixed sensory-motor polyneuropathy. The only mtDNA mutation consistently associated with peripheral neuropathy (although less severely than in the above-considered nuclear genes) was the m.8993T > G (or the rarer T > C) changes, which lead to an axonal, mainly sensory polyneuropathy. In conclusion, peripheral neuropathy is one of the most common features of a mitochondrial disorder, and may negatively impact on the quality of life of these patients. Furthermore, the presence or absence of peripheral neuropathy, as well as its specific forms and the association with neuropathic pain (indicative of a POLG-associated disease) can guide the molecular analysis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ABSTRACT 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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: We describe a case of an adult male patient with progressive external ophthalmoplegia and upper limb weakness, who presented with an episode of sudden respiratory failure. Muscle biopsy showed ragged-red and COX-negative fibers associated with discrete inflammatory infiltrates and necrotizing features. Apart from artificial ventilator support, he was treated with intravenous immunoglobulins and carnitine, with excellent clinical outcome. Mitochondrial DNA analysis revealed the 3251A>G mutation, previously reported in association with rapidly progressive mitochondrial myopathy and respiratory failure. Our case expands the spectrum of this mutation and suggests a therapeutic attempt with immunoglobulins in mitochondrial patients with acute respiratory failure, at least when this mutation and/or muscle inflammation is present. Moreover, this case supports the idea of a pathologic inflammatory response induced by mitochondrial disease; such an abnormal response may be a contributory factor in disease progression or acute exacerbation typical of some mitochondrial diseases, but further studies are needed. [Copyright &y& Elsevier]

Mitochondrial disorders are caused by impairment of the respiratory chain. Psychiatric features often represent part of their clinical spectrum. However, the real incidence of psychiatric disorders in these diseases is unknown. The aim of this study was to evaluate psychiatric involvement in a group of patients with mitochondrial disorders and without already diagnosed mental illness. Twenty-four patients with mitochondrial disorder and without already diagnosed mental diseases have been studied by means of the mini-international neuropsychiatric interview (MINI) and the newcastle mitochondrial diseases adult scale (NMDAS). In patients with mitochondrial disease, psychiatric conditions were far more common than in general Italian population (about 60 vs. 20-25%), and included major depression, agoraphobia and/or panic disorder, generalized anxiety disorder, social anxiety disorder, psychotic syndromes. Psychiatric involvement did not seem to depend on disease progression. Large, multicenter studies are strongly needed to better characterize the natural history of mitochondrial disorders and of their psychiatric involvement. Moreover, the possibility of mitochondrial diseases should be considered in patients with psychiatric diseases. Finally, we encourage psychiatric evaluation as a routinary approach to mitochondrial patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: The pathogenic role of oxidative stress in obstructive sleep apnea syndrome (OSAS) is still a matter of debate, with different studies obtaining contrasting results. Methods: The aim of the present study was to evaluate three well-known markers of oxidative stress (advanced oxidation protein products [AOPP], ferric reducing antioxidant power [FRAP], and total glutathione [GSH]) in a cohort of 41 untreated patients with a new diagnosis of OSAS. Results: We observed that OSAS patients showed increased protein oxidative damage and impaired antioxidant defenses. Patients with more severe OSAS had a lower total antioxidant capability. Preliminary data on a subgroup of patients (n =7) treated with CPAP show a significant increment of the FRAP values (P <0.005). Conclusions: Our findings indicate that such oxidative stress markers may be useful to detect and monitor redox imbalance in OSAS. Moreover, FRAP might be a new useful biomarker to monitor in vivo the oxidative response to CPAP therapy. [Copyright &y& Elsevier]

Involvement of the peripheral nervous system in mitochondrial disorders (MD) has been previously reported. However, the exact prevalence of peripheral neuropathy and/or myopathy in MD is still unclear. In order to evaluate the prevalence of neuropathy and myopathy in MD, we performed sensory and motor nerve conduction studies (NCS) and concentric needle electromyography (EMG) in 44 unselected MD patients. NCS were abnormal in 36.4% of cases, and were consistent with a sensori-motor axonal multineuropathy (multifocal neuropathy), mainly affecting the lower limbs. EMG evidence of myopathy was present in 54.5% of patients, again mainly affecting the lower limbs. Nerve and muscle involvement was frequently subclinical. Peripheral nerve and muscle involvement is common in MD patients. Our study supports the variability of the clinical expression of MD. Further studies are needed to better understand the molecular basis underlying the phenotypic variability among MD patients. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is a common neurological disease of unknown etiopathogenesis, possibly neurodegenerative, characterized by kinetic tremor at the arms. Here we reported the case of an HCV-positive patient with inflammatory myopathy, who did not develop typical neuromuscular signs or symptoms during at least 7 years of hyperCKemia, in whom kinetic tremor of the arms was the prominent clinical feature, suggesting a possible diagnosis of ET. After 3 months of treatment with corticosteroids/methotrexate, creatine kinase (CK) levels were nearly normal and the tremor was remarkably improved. To our knowledge, similar cases have not been previously reported. Postural tremor can be present in muscular diseases, but only very rarely tremor has been reported as a major clinical feature. Because inflammatory myopathies are potentially treatable conditions it is very important to consider this diagnosis. Our case suggests that in patients with isolated postural and kinetic tremor routine laboratory assays should include CK blood screening. [ABSTRACT FROM AUTHOR]

possible relationship between human circadian rhythmicity and polymorphisms in clock genes have been documented. However, these data are controversial, and studies both corroborating and denying them have been reported. T3111C Clock polymorphism had been associated with the human evening preference, however, this association has not been confirmed. Moreover, C111G Per2 polymorphism has been associated with the 'morning larks' chronotype in one study, not yet replicated. We have, therefore, performed this study to evaluate whether Per2 C111G and Clock T3111C polymorphisms might influence sleep circadian rhythmicity in a sample of 219 Italian volunteers. A possible interaction between these polymorphisms was also investigated. No differences in Per2 C111G and Clock T3111C allele and genotype frequencies were found, and none of the combined Clock T3111C-Per2 C11G genotypes resulted more frequent in one group compared to the others. Present results do not support a role of these polymorphisms in the circadian phenotypes. [ABSTRACT FROM AUTHOR]

Mitochondrial diseases are due to impairment of the mitochondrial respiratory chain. A plausible pathogenic mechanism leading to cellular dysfunction and phenotypic expression is oxidative stress, but there are surprisingly few clinical studies on this subject. Glutathione (GSH) deficiency has been reported in mitochondrial diseases, and the biosynthesis of glutathione depends on cysteine availability. We have examined oxidative stress biomarkers [advanced oxidation protein products (AOPP) and ferric reducing antioxidant power (FRAP)] in blood samples from 27 patients and 42 controls. AOPP levels were greater in patients than in controls ( P value <0.00001). Therefore, we performed a double-blind cross-over study to evaluate if 30-day supplementation with a whey-based cysteine donor could modify these markers, reduce lactate concentration during aerobic exercise, or enhance muscular strength and quality of life. Treatment did not modify lactate concentration, clinical scale (MRC) or quality of life (SF-36), but significantly reduced oxidative stress levels. Our findings reinforce the notions that in mitochondrial diseases oxidative stress is important and can be reduced by administration of a cysteine donor. Oxidative stress biomarkers may be useful to detect redox imbalance in mitochondrial diseases and to provide non-invasive tools to monitor disease status. [ABSTRACT FROM AUTHOR]

Creutzfeldt–Jakob disease (CJD) is typically characterized by rapidly progressive dementia and myoclonus, and it is caused by a conformational change of the prion protein. The heritable forms are associated with mutation in the gene encoding the prion protein ( PRNP). We report a 63-year-old Italian woman harboring the E200K PRNP mutation. Electroencephalogram, cerebrospinal fluid analysis, PRNP gene sequencing, histopathologic examination, immunohistochemical studies, and Western blotting analysis confirmed the diagnosis of CJD. Pyramidal involvement was the first sign and the prominent clinical feature. Later on, she developed also myoclonus, ataxia, spastic tetraplegia, and at last dementia with akinetic mutism. Usually, signs of degeneration of the pyramidal tracts occur in a small number of patients as the disease advances. Our report supports the variability of the clinical expression of the E200K genetic CJD. Further studies are needed to understand the molecular basis underlying the phenotypic variability among patients carrying this mutation. [ABSTRACT FROM AUTHOR]

Abstract: Various lines of evidence demonstrate the involvement of mitochondrial dysfunction in the pathogenesis of Huntington''s disease (HD). However, the precise role of mitochondria in the neurodegenerative cascade leading to HD is still unclear. Mitochondrial DNA (mtDNA) haplogroups-specific polymorphisms were previously related to several neurodegenerative diseases. The length of CAG repeat seems to be related to the clinical features of HD, such as age of onset and progression of motor impairment. The basis for the impaired cognitive functions and for the mood changes is less clear. Aim of this study was to determine whether mtDNA polymorphism(s) play the role of “modifier gene(s)” in this disease. In this work we have genotyped predefined European mtDNA haplogroups in 51 patients with HD and 181 matched controls. The frequency of the haplogroups and haplogroup clusters did not differ between the two groups, and no correlation with gender, age of onset and disease status was observed. No significant difference was observed between different haplogroups and haplogroup clusters in the cognitive or motor progression of the disease. Our study does not support any association between mtDNA haplogroups and HD. [Copyright &y& Elsevier]

Headache is the most common symptom in patients with cervical artery dissection. This symptom, however, rarely occurs in isolation, and more commonly is associated with other neurological symptoms and signs. Visual symptoms associated with vertebral artery dissection (VD) have also been observed, but do not typically mimic the migraine aura. Here, we report a young patient who presented VD, embolic ischemic lesions, and visual symptoms with the features of aura, followed by migraine headache. The suggestion of VD dissection should be kept in mind in those cases complaining of the first attack of headache that mimics migraine with aura. In these cases, an extensive neuroimaging study is advisable. [ABSTRACT FROM AUTHOR]

Abstract: Background: Psychiatric problems, including bipolar affective disorder (BD) and schizophrenia, are common in mitochondrial diseases (MD) and frequently precede the diagnosis of mitochondrial dysfunction. However, they are rarely the only persistent manifestation of a MD and they are usually associated with other neurological or non-neurological features. Case report: Here, we describe an Italian family with multiple deletions of mtDNA in muscle, in which BD, schizophrenia, and depression recurred over several generations in the absence of other major signs of mitochondrial dysfunction. Conclusion: In patients with positive family history of psychiatric problems, the possibility of MD should be kept in mind, even in absence of other canonical features of mitochondrial encephalomyopathies. [Copyright &y& Elsevier]

Abstract: Amyotropic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease causing the loss of motoneurons of the brain and the spinal cord. The etiology of ALS is still uncertain, but males are at increased risk for the disease than females. Several studies have suggested that motoneurons in ALS might be subjected to the double insult of increased DNA oxidative damage and deficiencies in DNA repair systems. Particularly, increased levels of 8-oxoguanine and impairments of the DNA base excision repair system have been observed in neurons of ALS patients. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. To evaluate the role of the hOGG1 Ser326Cys polymorphism in sporadic ALS (sALS), we screened 136 patients and 129 matched controls. In the total population, we observed association between both the Cys326 allele (p =0.02) and the combined Ser326Cys+Cys326Cys genotype (OR=1.65, 95% CI=1.06–2.88) and increased risk of disease. After stratification by gender, the Cys326 allele (p =0.01), both the Ser326Cys genotype (OR=2.14, 95% CI=1.09–4.19) and the combined Ser326Cys+Cys326Cys genotype (OR=2.15, 95% CI=1.16–4.01) were associated with sALS risk only in males. No significant association between the Ser326Cys polymorphism and disease phenotype, including age and site of onset and disease progression, was observed. Present results suggest a possible involvement of the hOGG1 Ser326Cys polymorphism in sALS pathogenesis. [Copyright &y& Elsevier]

Abstract: Oxidative damage accumulates in the DNA of the human brain over time, and is supposed to play a critical role in the pathogenesis of Alzheimer''s disease (AD). It has been suggested that the brain in AD might be subjected to the double insult of increased oxidative stress, as well as deficiencies in repair mechanisms responsible for the removal of oxidized bases. The type of damage that is most likely to occur in neuronal cells is oxidative DNA damage which is primarily removed by the base excision repair (BER) pathway, and a decrease in BER activity was observed in post-mortem brain regions of AD individuals, especially in the activity of 8-oxoguanine DNA glycosylase. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. However, although a deficient BER was proposed in the etiology of AD by several authors, polymorphisms of BER genes have not been studied in AD yet. We performed a case-control study including 178 patients with sporadic AD (sAD) and 146 matched controls to evaluate the role of the Ser326Cys polymorphism as a risk factor for sAD. In the present study we failed to find any association between allele (χ 2 =0.03, p =0.86) or genotype (χ 2 =0.25, p =0.882) frequencies of hOGG1 Ser326Cys and the risk of sAD. Present results suggest that the Ser326Cys polymorphism of the hOGG1 gene is not an independent risk factor for sAD. [Copyright &y& Elsevier]

Mitochondria play a critical role in several metabolic processes and apoptotic pathways, regulating life cycle from the cradle to the grave. Despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question "is mitochondrial dysfunction a necessary step in neurodegeneration?" is still unanswered. Moreover, a growing body of evidence seems to indicate that oxidative stress, which is increased in damaged mitochondria, is an earlier event associated with neurodegeneration. Here we examine the current evidences in this field, which indicate a key role of mitochondria and oxidative stress in contributing to the neurodegenerative processes. [ABSTRACT FROM AUTHOR]

There is substantial evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with Alzheimer's disease (AD). However, the precise role of mitochondria in the neurodegenerative cascade leading to AD is still unclear, leaving the answer to the question "what's first: the chicken or the egg?" pending. Here we focus our attention on the progress made in this field in the past few years, which indicates a key role of this fossil organelle and of its specific DNA in contributing to the disease. [ABSTRACT FROM AUTHOR]

Summary: Education is the most important part of medical-science training. Assessment of training programmes and examination of trainees'' skills are necessary to guarantee that trainees develop competence. Training programmes vary between and within countries. The impending integration of the medical-job market among European countries highlights the need for people training to be specialists to achieve a certain standard. Here, we review the neurological training programmes in Europe, principally those in Italy, and discuss the standardisation of the training of residents in Italy and the quality control of current residency training, or its absence, in Europe. [Copyright &y& Elsevier]

Abstract: Three patients with different clinical phenotypes harbored the same point mutation at nucleotide 14709 (T14709C) in the tRNAGlu gene of mitochondrial DNA (mtDNA). The first patient was a 21-month-old child with severe congenital myopathy, respiratory distress and mild mental retardation. Muscle biopsy showed about 12% cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs), and markedly decreased activities of mitochondrial respiratory chain complexes I, III and IV. The other two patients were 51- and 55-year-old siblings with slowly progressive myopathy and diabetes mellitus. Muscle biopsy showed focal COX-negative RRFs and decreased activities of complexes I, III and IV. In all three patients, the T14709C mutation was abundant in muscle but present at lower levels in accessible tissues. Previously described patients with the same mutation also showed congenital or late-onset myopathy. Diabetes is frequently associated with both phenotypes and is a clinical clue to the molecular diagnosis. [Copyright &y& Elsevier]

Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls. Individuals classified as haplogroup I demonstrated a significant decrease in risk of ALS versus individuals carrying the most common haplogroup, H (odds ratio 0.08, 95% confidence interval 0.04–0.4, p < 0.01). Further stratification of the dataset by sex, age and site of onset of disease and survival failed to reach significance for association.Our study provides evidence of the contribution of mitochondrial variation to the risk of ALS development in Caucasians. Further it may help elucidate the mechanism of the mitochondrial dysfunction detectable in ALS, and may be of relevance in development of strategies for the treatment of this disease. [Copyright &y& Elsevier]

Focal spongy degeneration of the white matter and Purkinje cell loss were the neuropathological hallmarks in an infant with hepato-cerebral syndrome and a 4-bp GATT duplication (nucleotides 763–766) in exon 6 of the dGK gene. Liver disease became manifest in the first months of life and was followed by progressive cirrhosis and death at 31 months. Neurological symptoms appeared later and were mild, in agreement with the limited brain pathology. Molecular analysis of the dGK gene should be performed in infants with cirrhosis even in the absence of CNS involvement. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that mitochondrial dysfunction occurs in the central nervous system as well as in the peripheral tissues from Alzheimer’s disease (AD) patients. We have recently shown that mitochondrial cytochrome c oxidase (COX) activity is significantly reduced in brain and platelets from AD patients compared to controls. In the present study we investigated whether impaired COX activity could have functional consequences on energy metabolism. Blood lactate concentration was monitored at rest and during incremental exercise in 22 AD patients in whom COX activity in platelets was decreased compared to controls (35.7 ± 11.4 vs 48.4 ± 1.4 nmol/min/mg, P < 0.01). In both resting and exercising conditions, blood lactate was significantly higher in AD patients than in controls. Although the magnitude of exercise-related lactate accumulation was not different between the two groups, an anticipated anaerobic lactate threshold during the incremental forearm exercise was found in AD patients (50% of maximal voluntary contraction MVC compared to 60% in controls). COX activity was inversely related to lactate at a significant level for resting condition (r = −0.65) and borderline for anaerobic threshold exercise level. These results support the hypothesis of a systemic impairment of the mitochondrial function in AD and indicate that decreased COX activity could have functional consequences on metabolism. [Copyright &y& Elsevier]

The Aspartate-90-Alanine (D90A) mutation on SOD-1 gene, the only known change causing recessive familial amyotrophic lateral sclerosis (FALS), is associated with a uniform phenotype characterized by slowly ascending paresis and long survival. Originally reported in Scandinavian cases, it has also been detected in patients from other countries. A common haplotype, probably of Scandinavian origin, has been demonstrated in D90A recessive pedigrees. In this study we screened the SOD-1 gene for the D90A mutation in 56 Italian patients from north-west Tuscany with sporadic ALS in order to evaluate the occurrence of this mutation and its genotype-phenotype correlation in Italy. We found the homozygous D90A mutation in one patient (1.8%), harboring the classical phenotype related to this mutation. No other mutations were detected in any of the five SOD-1 exons in our group. Our results confirm that recessive D90A mutation is present in Italy and it is associated with the phenotype already described A screening for that mutation, easily made by RFLP, should be made in sporadic ALS patients, especially where clinical investigation indicates its presence. [ABSTRACT FROM AUTHOR]

We conclude that the EAN consensus recommendation provides a sensitive model for clinicians involved in the diagnosis of monogenic cSVD, as confirmed in this additional real-world study. We were interested to read the letter from Carvalho et al., who applied the European Academy of Neurology (EAN) consensus recommendation on cerebral monogenic small-vessel diseases (cSVDs)[1] to their cohort of patients with suspected genetic cSVD, to determine in which patients they should have studied the I Notch3 i gene according to the EAN recommendations. Response to Carvalho et al.: Diagnosis of monogenic small-vessel disease - "real- world" application of the consensus recommendation of the European Academy of Neurology. [Extracted from the article]

Background Methods Results Conclusion Primary mitochondrial diseases (PMDs) are the most common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. They can result from mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). These disorders are multisystemic and mainly affect high energy‐demanding tissues, such as muscle and the central nervous system (CNS). Among many clinical features of CNS involvement, parkinsonism is one of the most common movement disorders in PMDs.This review provides a pragmatic educational overview of the most recent advances in the field of mitochondrial parkinsonism, from pathophysiology and genetic etiologies to phenotype and diagnosis.mtDNA maintenance and mitochondrial dynamics alterations represent the principal mechanisms underlying mitochondrial parkinsonism. It can be present in isolation, alongside other movement disorders or, more commonly, as part of a multisystemic phenotype. Mutations in several nuclear‐encoded genes (ie, POLG, TWNK, SPG7, and OPA1) and, more rarely, mtDNA mutations, are responsible for mitochondrial parkinsonism. Progressive external opthalmoplegia and optic atrophy may guide genetic etiology identification.A comprehensive deep‐phenotyping approach is needed to reach a diagnosis of mitochondrial parkinsonism, which lacks distinctive clinical features and exemplifies the intricate genotype‐phenotype interplay of PMDs. [ABSTRACT FROM AUTHOR]

Abstract: We report a patient with myoclonic epilepsy who underwent muscle biopsy for suspected mitochondrial disease (myoclonic epilepsy with ragged-red fibers, MERRF). In spite of normal histochemical studies and of the absence of a severe COX deficiency, the molecular analysis showed the common MERRF mutation (A8344G) in the tRNALys gene on mitochondrial DNA. The case serves to illustrate the importance of pursuing the proposed mitochondrial genetic abnormality, even in patients with normal biopsy findings. [Copyright &y& Elsevier]

Abstract: The treatment of progressive myoclonic epilepsy (PME) is largely empirical, even though valproic acid (VPA) is usually considered the drug of first choice. However, VPA should be used with caution in PME due to mitochondrial dysfunction, i.e. in MERRF (myoclonic epilepsy with ragged red fibers) syndrome, because of its interaction with mitochondrial respiration and metabolism. Levetiracetam (LEV) treatment was started in combination with VPA in a patient with typical clinical, histological, and biochemical features of MERRF due to a mutation on the tRNA of Phenilalanine gene. The average myoclonus score improved dramatically, as well as the quality of life and no side effects were observed, even after having withdrawn VPA. LEV may benefit myoclonus in PME of mitochondrial origin without altering mitochondrial function, and it could be considered the drug of first choice for the treatment of myoclonus in MERRF. [Copyright &y& Elsevier]

A 19-year-old woman complained of life-long exercise intolerance and had chronic lactic acidosis. Neurological examination was normal, but muscle biopsy showed cytochrome c oxidase-positive fibers and marked complex III deficiency.Sequence analysis showed a novel stop-codon mutation (G15761A) in the mitochondrial DNA (mtDNA)-encoded cytochrome b gene, resulting in loss of the last 41 amino acids of the protein.By PCR/restriction fragment-length polymorphism (RFLP) analysis, the G15761A mutation was very abundant (73%) in the patient''s muscle, barely detectable (less than 1%) in her urine, and absent in her blood; it was also absent in muscle, urine and blood from the patient''s mother. This mutation fulfills all accepted criteria for pathogenicity. [Copyright &y& Elsevier]

Cerebellar ataxia is a neurological syndrome characterized by the imbalance (e.g., truncal ataxia, gait ataxia) and incoordination of limbs while executing a task (dysmetria), caused by the dysfunction of the cerebellum or its connections. It is frequently associated with other signs of cerebellar dysfunction, including abnormal eye movements, dysmetria, kinetic tremor, dysarthria, and/or dysphagia. Among the so-termed mitochondrial ataxias, variants in genes encoding steps of the coenzyme Q10 biosynthetic pathway represent a common cause of autosomal recessive primary coenzyme Q10 deficiencies (PCoQD)s. PCoQD is a potentially treatable condition; therefore, a correct and timely diagnosis is essential. After a brief presentation of the illustrative case of an Italian woman with this condition (due to a novel homozygous nonsense mutation in COQ8A), this article will review ataxias due to PCoQD. [ABSTRACT FROM AUTHOR]

Background: The EURO-NMD Registry collects data from all neuromuscular patients seen at EURO-NMD's expert centres. In-kind contributions from three patient organisations have ensured that the registry is patient-centred, meaningful, and impactful. The consenting process covers other uses, such as research, cohort finding and trial readiness. Results: The registry has three-layered datasets, with European Commission-mandated data elements (EU-CDEs), a set of cross-neuromuscular data elements (NMD-CDEs) and a dataset of disease-specific data elements that function modularly (DS-DEs). The registry captures clinical, neuromuscular imaging, neuromuscular histopathology, biological and genetic data and patient-reported outcomes in a computer-interpretable format using selected ontologies and classifications. The EURO-NMD registry is connected to the EURO-NMD Registry Hub through an interoperability layer. The Hub provides an entry point to other neuromuscular registries that follow the FAIR data stewardship principles and enable GDPR-compliant information exchange. Four national or disease-specific patient registries are interoperable with the EURO-NMD Registry, allowing for federated analysis across these different resources. Conclusions: Collectively, the Registry Hub brings together data that are currently siloed and fragmented to improve healthcare and advance research for neuromuscular diseases. [ABSTRACT FROM AUTHOR]

Metabolic myopathies are a group of genetic disorders that affect the normal functioning of muscles due to abnormalities in metabolic pathways. These conditions result in impaired energy production and utilization within muscle cells, leading to limitations in muscle function with concomitant occurrence of related signs and symptoms, among which fatigue is one of the most frequently reported. Understanding the underlying molecular mechanisms of muscle fatigue in these conditions is challenging for the development of an effective diagnostic and prognostic approach to test targeted therapeutic interventions. This paper outlines the key biomolecules involved in muscle fatigue in metabolic myopathies, including energy substrates, enzymes, ion channels, and signaling molecules. Potential future research directions in this field are also discussed. [ABSTRACT FROM AUTHOR]

Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment of the mitochondrial oxidative phosphorylation (OXPHOS). The unique features of mitochondrial genetics and the pivotal role of mitochondria in cell biology explain the phenotypical heterogeneity of primary mitochondrial diseases and the resulting diagnostic challenges that follow. Some peculiar features ("red flags") may indicate a primary mitochondrial disease, helping the physician to orient in this diagnostic maze. In this narrative review, we aimed to outline the features of the most common mitochondrial red flags offering a general overview on the topic that could help physicians to untangle mitochondrial medicine complexity. [ABSTRACT FROM AUTHOR]

A correction to the article "Redefining Phenotypes Associated With Mitochondrial DNA Single Deletion" in a 2015 issue of the "Journal of Neurology" is presented.

A letter to the editor is presented in relation to a case study concerning Ramsay-Hunt syndrome complicated by unilateral multiple cranial nerve palsies.