[Mitochondrial diseases in adults: An update]. / Les maladies mitochondriales de l'adulte : mise au point.

Mitochondrial diseases, characterized by a respiratory chain deficiency, are considered as rare genetic diseases but are the most frequent among inherited metabolic disorders. The complexity of their diagnosis is due to the dual control by the mitochondrial (mtDNA) and the nuclear DNA (nDNA), and to the heterogeneous clinical presentations; illegitimate association of symptoms should prompt the clinician to evoke a mitochondrial disorder. The goals of this review are to provide clinicians a better understanding of mitochondrial diseases in adults. After a brief overview on the mitochondrial origin and functions, especially their role in the energy metabolism, we will describe the genetic bases for mitochondrial diseases, then we will describe the various clinical presentations with the different affected tissues as well as the main symptoms encountered. Even if the new sequencing approaches have profoundly changed the diagnostic process, the brain imaging, the biological, the biochemical, and the histological explorations are still important highlighting the need for a multidisciplinary approach. While for most of the patients with a mitochondrial disease, only supportive and symptomatic therapies are available, recent advances in the understanding of the pathophysiological mechanisms have been made and new therapies are being developed and are evaluated in human clinical trials.

Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families.

BACKGROUND AND PURPOSE: The aim was to determine the genetic background of unknown muscular dystrophy in five French families. METHODS: Twelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro. RESULTS: Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation. CONCLUSIONS: The mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.

Combination of acid phosphatase positivity and rimmed vacuoles as useful markers in the diagnosis of adult-onset Pompe disease lacking specific clinical and pathological features.

INTRODUCTION: The clinical and histological presentations of the adult form of Pompe disease may be atypical. In such cases, identifying histological signs that point to the diagnosis would be crucial to avoid a delay in care. The aim of our study was to investigate the presence of rimmed vacuoles and acid phosphatase positivity in muscle biopsies of patients with late-onset Pompe disease. MATERIAL AND METHODS: We retrospectively studied muscle biopsies of all cases of the adult form of Pompe disease diagnosed at the University Hospital of Caen. Three of these four cases showed atypical clinical signs, and diagnosis was established tardily based on family history or systematic analysis of acid maltase activity. RESULTS: All biopsies showed some rimmed vacuoles. The acid phosphatase reaction showed positive inclusions and labelled vacuoles in biopsies of all patients. CONCLUSIONS: The presence of rimmed vacuoles and acid phosphatase positivity in muscle biopsy should suggest the diagnosis of the adult form of Pompe disease, this is decisive since effective therapy is available.

Restless legs syndrome associated with exercise intolerance: Data from a retrospective observational clinical neuromuscular center study.

INTRODUCTION: Exercise intolerance (EI) is a frequent motive for seeking neuromuscular consultation and may be a sign of metabolic disease or, rarely, muscular dystrophy. The diagnosis is not established in many patients with a typical clinical presentation. Nevertheless, some of them complain of sleep disorders and more especially of restless legs syndrome (RLS). OBJECTIVE: The objective of our study was to estimate the frequency of RLS in patients presenting with EI. METHODS: Our retrospective observational study included all patients seen in the center from 2005 to 2011, who were subsequently investigated for EI in the neuromuscular department of the Caen University hospital. Data were collected on clinical RLS and muscular investigations (creatine kinase [CK], EMG, maximal exercise tests magnetic resonance imaging [MRI] and muscle biopsy obtained along with muscle exploration). RESULTS: Of the 318 patient records analyzed, 84 showed patients accurately complaining of EI. RLS was diagnosed in 25 of these patients (29.7%). This percentage was significantly higher (P<0.001) than found in the general population. Improvement was seen in 91.3% of the patients receiving specific treatment. CONCLUSION: RLS can sometimes present with pain, potentially worsening with exercise, inappropriately leading to a hypothesis of EI. Clinicians should thus explore the possible diagnosis of RLS when a muscular disease is not found in patients presenting with such symptoms.

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease.

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France. This report describes the main clinical and molecular features, at the time of inclusion in the French registry, of 126 patients followed up in 21 hospital-based neuromuscular or metabolic centres. Sixty-five men and 61 women have been included in the registry. Median age at inclusion was 49 years, and the median age at onset of progressive limb weakness was 35 years. Fifty-five percent of the patients were walking without assistance, 24% were using a stick or a walking frame, and 21% were using a wheelchair. Forty-six percent of the patients needed ventilatory assistance, which was non-invasive in 35% of the cases. When performed, muscle biopsies showed specific features of Pompe disease in less than two-thirds of the cases, confirming the importance of acid alpha-glucosidase enzymatic assessment to establish the diagnosis. Molecular analysis detected the common c.-32-13T>G mutation, in at least one allele, in 90% of patients. The French Pompe registry is so far the largest country-based prospective study of patients with Pompe disease, and further analysis will be performed to study the impact of enzyme replacement therapy on the progression of the disease.

CCM3 Mutations Are Associated with Early-Onset Cerebral Hemorrhage and Multiple Meningiomas.

Mutations of CCM3/PDCD10 cause 10-15% of hereditary cerebral cavernous malformations. The phenotypic characterization of CCM3-mutated patients has been hampered by the limited number of patients harboring a mutation in this gene. This is the first report on molecular and clinical features of a large cohort of CCM3 patients. Molecular screening for point mutations and deletions was used to identify 54 CCM3-mutated index patients. Age at referral and clinical onset, type of inaugural events and presence of extra-axial lesions were investigated in these 54 index patients and 22 of their mutated relatives. Mean age at clinical onset was 23.0 ± 16 years. Clinical onset occurred before 10 years in 26% of the patients, and cerebral hemorrhage was the initial presentation in 72% of these patients. Multiple extra-axial, dural-based lesions were detected in 7 unrelated patients. These lesions proved to be meningiomas in 3 patients who underwent neurosurgery and pathological examination. This 'multiple meningiomas' phenotype is not associated with a specific CCM3 mutation. Hence, CCM3 mutations are associated with a high risk of early-onset cerebral hemorrhage and with the presence of multiple meningiomas.

Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study.

AIMS: Pineal parenchymal tumours (PPTs) are rare neoplasms that are divided into pineocytoma (PC), pineoblastoma (PB) and PPT of intermediate differentiation (PPTID). Factors affecting the survival of patients with PPTs are morphological subtype and histological grading according to mitotic index and neurofilament immunostaining. Grading criteria to distinguish PPTIDs are difficult to define, particularly when using small specimens. The Ki67 labelling index (LI) might be helpful in distinguishing between grade II and III PPTIDs. Our study was performed to assess the predictive value of the Ki67 LI in a large cooperative series of PPTs and to evaluate whether inclusion of this data would improve and refine the World Health Organization classification. METHODS: A retrospective analysis of 33 PPTs was performed. The histological features of the tumours were reviewed and Ki67 LI scoring was evaluated by immunohistochemistry. Data were correlated with the patients' survival. RESULTS: The mean Ki67 LI was significantly different for tumour grades (0 in PC, 5.2 ± 0.4 in PPTID grade II, 11.2 ± 2.0 in PPTID grade III, 36.4 ± 6.2 in PB; P < 0.0001). However, there was no statistically significant difference in either overall or disease-free survival evaluated by the Kaplan-Meier method for patients with different grade tumours or Ki67 LI, possibly due to the different clinical management of patients in different centres. CONCLUSIONS: The Ki67 LI may be a useful additional tool for grading PPTs, more particularly in small tumour samples.

[Subarachnoid hemorrhages form ruptured aneurysms as the presenting feature of lupus cerebral vasculitis]. / Hémorragies cérébro-méningées sur ruptures d'anévrismes inaugurales d'une vascularite cérébrale lupique.

Cerebral aneurysms secondary to cerebral vasculitis related to systemic lupus erythematosus are rare. We report a 31-year-old woman who presented with a lupus flare associated with inaugural generalized seizures. Computed tomography angiography showed subarachnoid hemorrhage by rupture of a cerebellar artery fusiform aneurysm. Later, despite the initiation of corticosteroids and cyclophosphamide, she presented a second cerebral hemorrhage due to the rupture of a new aneurysm in lenticulostriates arteries. The outcome was fatal. We discuss the frequency and management of this severe complication of systemic lupus erythematosus.

Is brain maturation comparable in fetuses and premature neonates at term equivalent age?

BACKGROUND AND PURPOSE: Improved knowledge of brain maturation in fetuses and premature neonates is crucial for the early detection of pathologies and would help determine whether MR data from the premature brain might be used to evaluate fetal maturation. Using diffusion-weighted MR imaging and (1)H-MR spectroscopy, we compared cerebral microstructure and metabolism in normal in utero fetuses imaged near term and premature neonates imaged at term equivalent. MATERIALS AND METHODS: Forty-eight subjects were investigated: 24 in utero fetuses (mean gestational age, 37 ± 1 weeks) and 24 premature neonates (mean postconceptional age, 37 ± 1 weeks). ADC values were measured in cerebellum, pons, white matter, brain stem, basal ganglia, and thalamus. MR spectroscopy was performed in deep white matter. RESULTS: Mean ADC values from fetuses and premature neonates were comparable except for the pons and the parietal white matter. ADC values were lower in the pons of premature neonates, whereas greater values were found in their parietal white matter compared with fetuses. Proton MR spectroscopy showed higher levels of NAA/H(2)O, Glx/H(2)O, tCr/H(2)O, and mIns/H(2)O in premature neonates compared with fetuses. CONCLUSIONS: Our study provides evidence of subtle anomalies in the parietal white matter of healthy premature neonates. In addition, the reduced ADC values in the pons together with the increased levels of NAA/H(2)O, tCr/H(2)O, and Glx/H(2)O in the centrum semiovale suggest a more advanced maturation in some white matter regions. Our results indicate that MR data from the premature brain are not appropriate for the assessment of the fetal brain maturation.

Five-Year Longitudinal MRI Follow-up and (1)H Single Voxel MRS in 14 patients with Gliomatosis Treated with Temodal, Radiotherapy and Antiangiogenic Therapy.

Gliomatosis cerebri (GC) is a challenging tumor, considered to have a poor prognosis and poor response to treatments. The purpose of this study is to better understand glial tumor metabolism and post chemotherapy, radiotherapy and antiangiogenic variations in a longitudinal study to determine cerebral variation in MRS area, amplitude, and ratios of metabolites and spectral profiles during a five year longitudinal follow-up in 14 patients with gliomatosis without initial hyperperfusion and treated with chemotherapy (Temozolomide (Temodal(®))), radiotherapy and subsequent antiangiogenic therapy. The study also aimed to detect changes in infiltration, proliferation, lipids or glycolytic metabolism, as these changes could be monitored longitudinally in humans with glial brain tumors (low and high grade) after therapy, using conventional magnetic resonance imaging (MRI), spectroscopy (MRS) and MR perfusion. Most patients had first initial clinical and MRS improvement and stable MRI. After 12 to 24 chemotherapy treatment cycles MRS usually showed an increase in the Cho/Cr ratio (proliferation) and sometimes contrast enhancements. Later, the patients showed clinical deterioration and radiotherapy was started. There was an improvement with radiotherapy that lasted nine to 18 months. This was followed by a worsening that led to try antiangiogenic therapy. Later in the evolution for three patients with hyperperfusion this symptom disappeared, but proliferation, infiltration and glycolytic metabolism remained at a high level. Spectroscopic and metabolic changes often occur well before clinical deterioration and sometimes before improvement. Therefore, MRS could be more sensitive and could detect changes earlier than MRI and is sometimes predictive. Despite the difficulty, the variability and unknown factors, these repeated measurements give us a better insight into the nature of the different processes, tumor progression and could lead to better understanding of therapeutic response.

Mechanisms underlying Andersen's syndrome pathology in skeletal muscle are revealed in human myotubes.

Andersen's syndrome is a rare disorder that has been defined with a triad: periodic paralysis, cardiac arrhythmia, and development anomalies. Muscle weakness has been reported in two-thirds of the patients. KCNJ2 remains the only gene linked to Andersen's syndrome; this gene encodes for the alpha-subunit of the strong inward-rectifier K+ channel Kir2.1. Several studies have shown that Andersen's syndrome mutations lead to a loss of function of the K+ channel activity in vitro. However, ex vivo studies on isolated patient muscle tissue have not been reported. We have performed muscle biopsies of controls and patients presenting with clinically and genetically defined Andersen's syndrome disorder. Myoblasts were cultured and characterized morphologically and functionally using the whole cell patch-clamp technique. No morphological difference was observed between Andersen's syndrome and control myoblasts at each passage of the cell culture. Cellular proliferation and viability were quantified in parallel with direct cell counts and showed no difference between control and Andersen's syndrome patients. Moreover, our data show no significant difference in myoblast fusion index among Andersen's syndrome and control patients. Current recordings carried out on myotubes revealed the absence of an inwardly rectifying Ba2+-sensitive current in affected patient cells. One consequence of the Ik1 current loss in Andersen's syndrome myotubes is a shift of the resting membrane potential toward depolarizing potentials. Our data describe for the first time the functional consequences of Andersen's syndrome mutations ex vivo and provide clues to the K+ channel pathophysiology in skeletal muscle.

Wernicke encephalopathy and Creutzfeldt-Jakob disease.

We assessed the prevalence of Wernicke encephalopathy (WE) in all 657 cases suspected of Creutzfeldt-Jakob (CJD) referred from 2001 to 2006 to the French Neuropathology Network of CJD. Clinical, biological and imaging data were reviewed when the diagnosis of WE was made at autopsy. No CJD was found in five cases suspected of sporadic CJD. In these five cases, myoclonus had been observed in four, CSF 14-3-3 protein in two. In 14 other cases, WE was combined with CJD, 13 of which were sporadic. These belonged mainly to the molecular variants of sporadic CJD associated with a long duration of disease. This stresses the necessity of remaining alert to the diagnosis of WE when CJD is suspected.

[Imaging of brain tumors in children]. / Imagerie des tumeurs cérébrales de l'enfant.

Few studies exist in the literature on pediatric brain tumors examined with advances MRI techniques. The aim of this review is to try to find out some specific tissular characteristics of the main cerebral tumors encountered in children, especially through diffusion imaging, perfusion imaging and proton magnetic resonance spectroscopy (MRS). However, hemispheric cerebral tumors are not as common as in the adult population.

[Frontal giant cell glioblastoma: radio-induced tumor? Case report and literature review]. / Glioblastome frontal à cellules géantes : tumeur radio-induite ? A propos d'un cas, avec revue de la littérature.

The current WHO classification recognizes two distinct variants of glioblastoma multiforme (GBMs): giant cell glioblastoma (GCG) and gliosarcoma, based on histological heterogeneity. Unlike conventional GBMs, GCGs preferentially occur in younger individuals and are associated with a better prognosis, a few reports documenting prolonged survival up to 17 years after diagnosis. However, transformation to gliosarcoma is possible and has been already reported. Radio-induced glioblastoma, which meets Cahan's criteria for radio-induced tumor, is very rare; the first case was published by Kleriga et al. We report a rare case observed in a 46-year-old man with a past history of right nose leiomyosarcoma treated 40 years earlier by surgery and interstitial and external beam radiation. At admission, the patient presented left hemiparesis revealing a right frontal GCG confirmed by pathology after cranial surgery. We describe this case firstly because of its rare histological variety and discuss its clinical, radiological, histopathological, therapeutic and prognostic characteristics with literature data. Secondly, because of its occurrence 40 years after external radiotherapy, which could suggest the hypothesis of radio-induced glioblastoma.