Claudia Sobreira

Mitochondrial encephalomyopathy with coenzyme Q10 deficiency

Coenzyme Q10 (CoQ10) transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex 111. There is one published report of human CoQ10 deficiency describing two sisters with encephalopathy, proximal weakness, myoglobinuria, and lactic acidosis. We report a patient who had delayed motor milestones, proximal weakness, premature exertional fatigue, and episodes of exercise-induced pigmenturia. She also developed partial-complex seizures. Serum creatine kinase was approximately four times the upper limit of normal and venous lactate was mildly elevated. Skeletal muscle biopsy revealed many ragged-red fibers, cytochrome c oxidase-deficient fibers, and excess lipid. In isolated muscle mitochondria, impaired oxygen consumption was corrected by the addition of decylubiquinone. During standardized exercise, ventilatory and circulatory responses were compatible with a defect of oxidation-phosphorylation, which was confirmed by near-infrared spectroscopy analysis. Biochemical analysis of muscle extracts revealed decreased activities of complexes I+II and I+III, while CoQ10 concentration was less than 25% of normal. With a brief course of CoQ10 (150 mg daily), the patient reported subjective improvement. The triad of CNS involvement, recurrent myoglobinuria, and ragged-red fibers should alert clinicians to the possibility of CoQ., deficiency.

Expanding the phenotypes of the Pro56Ser VAPB mutation: Proximal SMA with dysautonomia

The phenotype of 16 members of a family affected by a late‐onset, dominant, progressive, motor and autonomic disorder is described. The VAPB (Pro56Ser) mutation was detected in Brazilian families with different phenotypes of motor neuron disorders. In this family, proximal and axial muscle weakness and atrophy, associated with abdominal protrusion, defined the motor phenotype. Death occurred in 10–15 years due to respiratory insufficiency. Tone and tendon reflexes were decreased and a distal tremor was common. Sensation was preserved. Autonomic abnormalities were also present, including choking, chronic intestinal constipation, sexual dysfunction, and sudomotor abnormalities, and on nerve morphology there was involvement of unmyelinated fibers. Electromyography disclosed ongoing denervation and reinnervation. Isolated dysfunction of motor and autonomic neurons is unusual among the spinal muscular atrophies. On this basis, this condition seems to represent a new category of disease. Muscle Nerve, 2006

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.

Hand weakness in Duchenne muscular dystrophy and its relation to physical disability

The purpose of this study was to determine the age of hand involvement in Duchenne muscular dystrophy (DMD), since various types of hand dynamometry have been applied to evaluate patients in clinical trials. We studied 40 patients with DMD from our university hospital clinic and 80 healthy, age-matched controls. Hand strength was evaluated by handgrip and pinch dynamometries, and by manual testing. Physical disability was measured with a functional scale. Hand weakness was present since early stages in patients with DMD. However, hand strength tended to increase with age in the first decade, although never reaching the control values. Decrease of strength occurred later. Handgrip and pinch dynamometry values were significantly correlated with global hand strength, which were inversely correlated with functional capacity only in the group older than 10 years. Hand dynamometry should be applied with caution as an outcome measure in therapeutical trials in young patients with DMD.

Validação da escala motora funcional EK para a língua portuguesa

OBJECTIVE: To validate a Portuguese version of the EK scale (Egen Klassifikation), that was developed in Denmark for patients with Duchenne muscular dystrophy, and spinal muscular atrophy. METHODS: An English version of the EK scale was translated into the Portuguese language as spoken in Brazil. This scale was applied to 26 male patients (mean age = 12.7 ± 4.0 years) with Duchenne muscular dystrophy. Patients also answered questions of a Portuguese version of the Barthel index questionnaire, and had their right and left hand grip forces measured with a dynamometer. RESULTS: The mean total EK scale score was 8.1 ± 7.3 and the Barthel index 54.0 ± 26.2. The mean hand grip force was 12.7 ± 17.2 % predicted for the right hand, and 14.6 ± 19.8 % predicted for the left hand. The EK scale scores showed highly significant statistical correlations with age (r= 0.596, p= 0.0013), right hand grip force (r= -0.556, p= 0.0032), left hand grip force (r= -0.623, p=0.0007), and Barthel index (r= -0.928, p < 0.0001). CONCLUSION: This translated Portuguese version of the EK scale is an adequate tool to be used for Brazilian Duchenne muscular dystrophy patients.

Compound Charcot-Marie-Tooth disease may determine unusual and milder phenotypes

Compound forms of Charcot-Marie-Tooth (CMT) disease have been recently associated with unusually severe neuropathies, an observation that prompted the proposition that the additive effects of two mutations should be searched in patients whose clinical severity falls outside the common CMT phenotypes. In this report, we present a father and a daughter with a very mild and unusual disease that segregates with two mutations in PMP22 gene, the 17p11.2-p12 duplication and a Ser72Leu point mutation. We propose that the deleterious effects of each mutation are partially compensated by the functional effect of the other.

Leigh-like syndrome with the T8993G mutation in the mitochondrial ATPase 6 gene: long-term follow-up discloses a slowly progressive course

We describe the long-term clinical outcome of a patient with Leigh-like syndrome presenting as an early onset encephalopathy and peripheral neuropathy caused by the T8993G mutation in the mitochondrial DNA (mtDNA). Clinical follow-up for 20 years revealed a peculiar pattern of slow disease progression, characterized by the addition of new minor deficits, while worsening of previous symptoms was mild. Brain MRI revealed cerebellar atrophy, diffuse demyelination of corona radiata and parietal white matter, and bilateral and symmetrical putaminal lesions. The proportion of mutant mtDNAs in blood was 72% (+/-0.02%) and in skeletal muscle was 81% (+/-0.4%). Leigh-like syndrome caused by the T8993G mtDNA mutation is a progressive disease, although not necessarily associated with an aggressive clinical course.

Episodic migraine associated with postural orthostatic tachycardia syndrome and vasovagal syncope: migraine triggers neuromediated syncope

Dr. Elcio Juliato Piovesan – Hospital de Clínicas da UFPR Rua General Carneiro 181 / 12 andar / Sala 1236 80060-900 Curitiba PR Brasil. E-mail: piovesan@avalon.sul.com.br Migraine is a common episodic headache disorder characterized by attacks consisting of various combinations of headache, neurologic, gastrointestinal and autonomic symptoms. Autonomic symptoms, such as a cold feeling, increased urination, anorexia, diarrhea, constipation and fluid retention, can occur during the premonitory phase, and nausea, vomiting, diarrhea, cutaneous vasoconstriction (pallor), vasodilation (flushing), piloerection and diaphoresis can occur during the pain phase. Migraine patients with accompanying autonomic symptoms seem to experience their pain more unilateral and more severe than non autonomic migraine patients. Studies of autonomic nervous system dysfunction in migraine have been performed. Cardiovascular tests, vasomotor reactions to temperature changes and responses to pharmacological tests, and changes in biochemical parameters suggest abnormalities (hypoor hyperfunctioning) of both the sympathetic and parasympathetic nervous systems. These inconsistent findings may be explained by different types of autonomic dysregulation. Syncope and migraine are both highly prevalent in the general population. Both disorders occur together more frequently than chance would predict, i.e., they are comorbid. Studies using the orthostatic (tilt) test suggest that migraine patients have vagal hyperactivity and α-sympathetic system hypoactivity. Migraineurs may have a genetic predisposition leading to autonomic nervous system (ANS) dysfunction. The link between migraine and abnormal ANS function is unclear. ANS dysfunction may be involved in both increased susceptibility to migraine headaches and increased response to triggers. Migraine patients with typical autonomic symptoms, such as postural orthostatic tachycardia syndrome (POTS) and vasovagal syncope (VS), as well as patients with migraine with prolonged aura, are potential candidates for genetic studies. Mitochondrial dysfunction may play a role in migraine pathophysiology. It is not known whether the mitochondrion (encoded by the nuclear and mitochondrial genomes) is the primary site of the dysfunction, or whether the mitochondrial disturbance occur secondary to another cause. Mitochondria may play a role in the genesis of migraine, especially in these groups (migraine plus autonomic symptoms). Connecting networks exist between pain and autonomic functions in the brain (Fig 1); thus pain can produce autonomic symptoms. We describe a group of patients in whom autonomic symptoms (POTS and VS) occurred only during migraine attacks. We also studied the presence of the mitochondrial DNA (mtDNA) A3243G point mutation, common in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).

Brazilian consensus on Duchenne muscular dystrophy. Part 1: diagnosis, steroid therapy and perspectives

Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD. The main recommendations: 1) genetic testing in diagnostic suspicious cases should be the first line for diagnostic confirmation; 2) patients diagnosed with DMD should have steroids prescribed; 3) lack of published results for phase 3 clinical trials hinders, for now, the recommendation to use exon skipping or read-through agents.

Idiopathic hyperCKemia and malignant hyperthermia susceptibility

PurposeHyperCKemia is a persistent rise in serum creatine kinase (CK) levels of at least 1.5 times the normal value, as evidenced by a minimum of two measurements at 30-day intervals. One of the neuromuscular diseases associated with hyperCKemia is malignant hyperthermia (MH). This study investigated the susceptibility to MH in patients with hyperCKemia via in vitro contracture testing (IVCT) and a search of mutations in the RYR1 gene.MethodsPatients in an MH centre were followed from 1997-2012, and their epidemiologic, clinical, and laboratory data were analyzed, including IVCT, muscle histochemical analysis, and next-generation sequencing molecular analysis.ResultsThere were nine patients (eight male) in our study with a mean (SD) age of 33 (12) yr. Four patients were Caucasian and five were African Brazilian. Most complained about myalgia or cramps, but all had a normal neurological examination. They persistently presented with hyperCKemia from three months to ten years, with a mean (SD) CK value of 788 (507) IU·L−1 ranging from 210-1,667 IU·L−1. These values corresponded to a 1.5- to nine-fold increase in the normal value (mean increase, 3.7-fold). Six patients were MH susceptible (MHS) after a positive IVCT. Histopathological muscular analysis disclosed unspecified changes in four of the MHS patients. Mitochondrial proliferation was observed in the other two MHS patients and in three MH negative patients. No pathogenic mutations were identified in the RYR1 gene in the five patients evaluated.ConclusionWhen investigating patients with idiopathic hyperCKemia, susceptibility to MH should be taken into account, and guidance should be offered to prevent anesthetic complications in the family.RésuméObjectifL’hyperCKémie est définie comme étant l’élévation persistante des taux sériques de créatine kinase (CK) d’au moins 1,5 fois les valeurs normales, tel qu’attesté par un minimum de deux mesures prises à 30 jours d’intervalle. L’une des maladies neuromusculaires associées à l’hyperCKémie est l’hyperthermie maligne (HM). Cette étude a évalué la susceptibilité à l’HM de patients atteints d’hyperCKémie via un test de contracture in vitro (ou IVCT, pour in vitro contracture testing) et une recherche des mutations du gène RYR1.MéthodeDes patients d’un centre d’HM ont été suivis entre 1997 et 2012 et leurs données épidémiologiques, cliniques et de laboratoire ont été analysées, notamment par IVCT, par analyse histochimique musculaire et par analyse moléculaire séquentielle de nouvelle génération.RésultatsNeuf patients (huit hommes) ont été inclus dans notre étude, d’un âge moyen (ÉT) de 33 (12) ans. Quatre patients étaient d’origine caucasienne et cinq d’origine afro-brésilienne. La plupart se plaignaient de myalgie ou de crampes, mais l’examen neurologique était normal chez tous les patients. Ils ont présenté de façon persistante une hyperCKémie allant de trois mois à dix ans, avec une valeur moyenne de CK (ÉT) de 788 (507) IU·L−1, allant de 210 à 1667 IU·L−1. Ces valeurs correspondent à une augmentation de 1,5 à 9 fois les valeurs normales (augmentation moyenne, 3,7 fois). Six patients étaient susceptibles à l’HM (SHM) après un IVCT positif. L’analyse musculaire histopathologique a révélé des changements non spécifiés chez quatre des patients SHM. Une prolifération mitochondriale a été observée chez les deux autres patients SHM et chez trois patients négatifs à l’HM. Aucune mutation pathogénique n’a été identifiée sur le gène RYR1 chez les cinq patients évalués.ConclusionLorsqu’on étudie des patients atteints d’hyperCKémie idiopathique, la susceptibilité à l’HM devrait être prise en compte, et il convient de conseiller ces patients afin de prévenir les complications anesthésiques dans la famille.