Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines.

The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South-Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed-field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre-implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial-readiness for FSHD.

Genetic diversity in hereditary axonal neuropathy: Analyzing 53 Brazilian children.

BACKGROUND AND AIMS: The genetic epidemiology of inherited neuropathies in children remains largely unknown. In this study, we specifically investigated the genetic profile of a Brazilian cohort of pediatric patients with pure or complex axonal neuropathies, a crucial knowledge in the near future for establishing treatment priorities and perspectives for this group of patients. METHODS: Fifty-three pediatric patients who were assessed prior to reaching the age of 20, and who had clinical diagnoses of axonal hereditary neuropathy or presented with axonal neuropathy as the primary clinical feature, were included in the study. The recruitment of these cases took place from January 1, 2018, to December 31, 2020. The diagnosis was based on clinical and electrophysiological data. A molecular assessment was made using target-gene panel or whole-exome sequencing. Subsequently, segregation analysis was performed on available family members, and all candidate variants found were confirmed through Sanger. RESULTS: A molecular diagnosis was reached in 68% of the patients (n = 36/53), considering only pathogenic and probably pathogenic variants. Variants in MFN2 (n = 15) and GJB1 (n = 3) accounted for half of the genetically confirmed patients (50%; n = 18/36). The other 18 genetically diagnosed patients had variants in several less common genes. INTERPRETATION: Apart from MFN2 and GJB1 genes, universally recognized as a frequent cause of axonal neuropathies in most studied population, our Brazilian cohort of children with axonal neuropathies showed an important genetic heterogeneity, probably reflecting the multi ethnicity of the Brazilian population. Diagnostic, counseling, and future interventions should consider this characteristic.

Generation of percentile curves for strength and functional abilities for boys with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Considering the heterogeneity of the clinical manifestations of Duchenne muscular dystrophy (DMD), it is important to describe their various clinical profiles. Thus, in this study we aimed to develop percentile curves for DMD using a battery of measures to define the patterns of functional abilities, timed tests, muscle strength, and range of motion (ROM). METHODS: This retrospective data analysis was based on the records of patients with DMD using the Motor Function Measure (MFM) scale, isometric muscle strength (IS), dorsiflexion ROM, 10-meter walk test (10 MWT), and 6-minute walk test (6 MWT). Percentile curves (25th, 50th, and 75th percentiles) with MFM, IS, ROM, 10 MWT, and 6 MWT on the y axis and patient age on the x axis were constructed using the generalized additive model for location, scale, and shape, with Box-Cox power exponential distribution. RESULTS: There were records of 329 assessments of patients between 4 and 18 years of age. The MFM percentiles showed a gradual reduction in all dimensions. Muscle strength and ROM percentiles showed that the knee extensors were the most affected from 4 years of age, and dorsiflexion ROM negative values were noted from the age of 8 years. The 10 MWT showed a gradual increase in performance time with age. For the 6 MWT, the distance curve remained stable until 8 years, with a subsequent progressive decline. DISCUSSION: In this study we generated percentile curves that can help health professionals and caregivers follow the trajectory of disease progression in DMD patients.

Inter-rater reliability of the Rasch-modified medical research council scoring criteria for manual muscle testing in neuromuscular diseases.

It was argued that researchers and clinicians are not able to make judgments between most categories of the original Medical Research Council (MRC) scale and that a modified short version would reach higher agreement levels. We aimed to assess the inter-rater reliability for both the original and the Rasch-modified MRC scoring criteria of Manual Muscle Strength tests (MMSt) in patients with neuromuscular diseases. Two MRC scoring criteria were used to score muscle strength using MMSt in 40 muscle groups of the upper and lower limbs in patients with neuromuscular disorders. Three investigators performed the evaluations; the order of the MMSt and the use of the scales were performed according to the preferences of the investigators. The agreement coefficient (Gwet's AC2 ) was used to compute the reliability. Sixty patients (mean age of 39.3 years ± 15.2) with neuromuscular diseases were included. The mean AC2 for the muscle groups of the upper limbs ranged from 0.82 to 0.96 using the modified MRC scale and from 0.86 to 0.96 using the original MRC scale. The AC2 for the lower limb muscle groups ranged from 0.80 to 0.91 (modified MRC scale) and from 0.87 to 0.93 (original MRC scale). These values might be interpreted as "almost perfect agreement" with no significant differences between the scales. The results indicate that both MRC scoring criteria have significant reliability among trained observers. Moreover, the Rasch-modified MRC scale is as reliable as the original MRC scale and can be used in future clinical studies.

Alternative instrument for the evaluation of handgrip strength in Duchenne muscular dystrophy.

BACKGROUND: The commonly used dynamometers can be ineffective in evaluating handgrip in patients with Duchenne muscular dystrophy (DMD), especially children with generalized muscle weakness. The aim of this study was to analyze whether the modified sphygmomanometer is an effective instrument for handgrip strength evaluation in patients with DMD, during different stages of the disease. METHOD: The handgrip strength of 33 patients was evaluated by the Jamar dynamometer and the modified sphygmomanometer. Motor function was evaluated by the Motor Function Measurement (MFM) scale. Four evaluations, with a six-month interval between each, were performed: Evaluation 1 (N = 33), Evaluation 2 (N = 24), Evaluation 3 (N = 15), and Evaluation 4 (N = 8). A linear regression model with mixed effects was used for the longitudinal data and descriptive analysis of strength for all four evaluations. RESULT: The first evaluation data presented very high correlations between the dynamometer and the modified sphygmomanometer (r = 0.977; p < 0.001). The longitudinal analysis showed a significant difference between Evaluation 1 and the other handgrip strength evaluations obtained using the dynamometer (p < 0.05) but not the modified sphygmomanometer (p > 0.05). Null values were obtained only when using the dynamometer device. CONCLUSION: The modified sphygmomanometer seems to be more suitable than the dynamometer for measuring handgrip strength in all stages of DMD.

Acetyl-CoA-driven respiration in frozen muscle contributes to the diagnosis of mitochondrial disease.

BACKGROUND: Freezing human biopsies is common in clinical practice for storage. However, this technique disrupts mitochondrial membranes, hampering further analyses of respiratory function. To contribute to laboratorial diagnosis of mitochondrial diseases, this study sought to develop a respirometry approach using O2k (Oroboros Ins.) to measure the whole electron transport chain (ETC) activity in homogenates of frozen skeletal muscle biopsies. PATIENTS AND METHODS: We enrolled 16 patients submitted to muscle biopsy in the process of routine diagnostic investigation: four with mitochondrial disease and severe mitochondrial dysfunction; seven with exercise intolerance and multiple deletions of mitochondrial DNA, presenting mild to moderate mitochondrial dysfunction; five without mitochondrial disease, as controls. Whole homogenates of muscle fragments were prepared using grinder-type equipment. O2 consumption rates were normalized using citrate synthase activity. RESULTS: Transmission electron microscopy confirmed mitochondrial membrane discontinuation, indicating increased permeability of mitochondrial membranes in homogenates from frozen biopsies. O2 consumption rates in the presence of acetyl-CoA lead to maximum respiratory rates sensitive to rotenone, malonate and antimycin. This protocol of acetyl-CoA-driven respiration (ACoAR), applied in whole homogenates of frozen muscle, was sensitive enough to identify ETC abnormality, even in patients with mild to moderate mitochondrial dysfunction. We demonstrated adequate repeatability of ACoAR and found significant correlation between O2 consumption rates and enzyme activity assays of individual ETC complexes. CONCLUSIONS: We present preliminary data on a simple, low cost and reliable procedure to measure respiratory function in whole homogenates of frozen skeletal muscle biopsies, contributing to diagnosis of mitochondrial diseases in humans.

Clinicogenetic lessons from 370 patients with autosomal recessive limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophies (LGMD) are a group of genetically heterogeneous disorders characterized by predominantly proximal muscle weakness. We aimed to characterize epidemiological, clinical and molecular data of patients with autosomal recessive LGMD2/LGMD-R in Brazil. A multicenter historical cohort study was performed at 13 centers, in which index cases and their affected relatives' data from consecutive families with genetic or pathological diagnosis of LGMD2/LGMD-R were reviewed from July 2017 to August 2018. Survival curves to major handicap for LGMD2A/LGMD-R1-calpain3-related, LGMD2B/LGMD-R2-dysferlin-related and sarcoglycanopathies were built and progressions according to sex and genotype were estimated. In 370 patients (305 families) with LGMD2/LGMD-R, most frequent subtypes were LGMD2A/LGMD-R1-calpain3-related and LGMD2B/LGMD-R2-dysferlin-related, each representing around 30% of families. Sarcoglycanopathies were the most frequent childhood-onset subtype, representing 21% of families. Five percent of families had LGMD2G/LGMD-R7-telethonin-related, an ultra-rare subtype worldwide. Females with LGMD2B/LGMD-R2-dysferlin-related had less severe progression to handicap than males and LGMD2A/LGMD-R1-calpain3-related patients with truncating variants had earlier disease onset and more severe progression to handicap than patients without truncating variants. We have provided paramount epidemiological data of LGMD2/LGMD-R in Brazil that might help on differential diagnosis, better patient care and guiding future collaborative clinical trials and natural history studies in the field.

Idiopathic hyperCKemia and malignant hyperthermia susceptibility.

PURPOSE: HyperCKemia 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. METHODS: Patients 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. RESULTS: There 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. CONCLUSION: When 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.

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.

Whole-Exome Sequencing Study of Fibroblasts Derived From Patients With Cerebellar Ataxia Referred to Investigate CoQ10 Deficiency.

Background and Objectives: Coenzyme Q10 (CoQ10)-deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ10 biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ10 supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic variants, and assess CoQ10 levels, in fibroblasts from patients with undiagnosed cerebellar ataxia referred to investigate CoQ10 deficiency. Methods: WES was performed on genomic DNA extracted from 16 patients. Sequencing data were filtered using a virtual panel of genes associated with CoQ10 deficiency and/or cerebellar ataxia. CoQ10 levels were measured by high-performance liquid chromatography in 14 patient-derived fibroblasts. Results: A definite genetic etiology was identified in 8 samples of 16 (diagnostic yield = 50%). The identified genetic causes were pathogenic variants of the genes COQ8A (ADCK3) (n = 3 samples), ATP1A3 (n = 2), PLA2G6 (n = 1), SPG7 (n = 1), and MFSD8 (n = 1). Five novel mutations were found (COQ8A n = 3, PLA2G6 n = 1, and MFSD8 n = 1). CoQ10 levels were significantly decreased in 3/14 fibroblast samples (21.4%), 1 carrying compound heterozygous COQ8A pathogenic variants, 1 harboring a homozygous pathogenic SPG7 variant, and 1 with an unknown molecular defect. Discussion: This work confirms the importance of COQ8A gene mutations as a frequent genetic cause of cerebellar ataxia and CoQ10 deficiency and suggests SPG7 mutations as a novel cause of secondary CoQ10 deficiency.

Update of the Brazilian consensus recommendations on Duchenne muscular dystrophy.

In the last few decades, there have been considerable improvements in the diagnosis and care of Duchenne muscular dystrophy (DMD), the most common childhood muscular dystrophy. International guidelines have been published and recently reviewed. A group of Brazilian experts has developed a standard of care based on a literature review with evidence-based graded recommendations in a two-part publication. Implementing best practice management has helped change the natural history of this chronic progressive disorder, in which the life expectancy for children of the male sex in the past used to be very limited. Since the previous publication, diagnosis, steroid treatment, rehabilitation, and systemic care have gained more significant insights with new original work in certain fields. Furthermore, the development of new drugs is ongoing, and some interventions have been approved for use in certain countries. Therefore, we have identified the need to review the previous care recommendations for Brazilian patients with DMD. Our objective was to create an evidence-based document that is an update on our previous consensus on those topics.

Nas últimas décadas, houve progressos significativos no diagnóstico e no tratamento da distrofia muscular de Duchenne (DMD), considerada a distrofia muscular mais comum na infância. Diretrizes internacionais foram publicadas e revisadas recentemente. Um grupo de especialistas brasileiros desenvolveu um padrão de atendimento baseado em revisão de literatura, com recomendações graduadas pautadas em evidências compiladas em uma publicação dividida em duas partes. A implementação de melhores práticas de manejo ajudou a modificar a história natural desta doença crônica, progressiva, que, no passado, oferecia uma expectativa de vida muito limitada para crianças do sexo masculino. Desde a publicação desse consenso anterior, o diagnóstico, o tratamento com esteroides, a reabilitação e os cuidados sistêmicos ganharam novas possibilidades a partir da divulgação dos resultados de trabalhos originais em algumas dessas áreas. Além disso, as pesquisas e o desenvolvimento de novos fármacos estão em andamento, e algumas intervenções já foram aprovadas para uso em determinados países. Nesse contexto, identificamos a necessidade de rever as recomendações anteriores sobre o manejo dos pacientes brasileiros com DMD. Nosso objetivo principal foi elaborar uma atualização baseada em evidências sobre esses tópicos do consenso.

The cross-cultural adaptation, construct validity, and intra-rater reliability of the functional mobility scale in Brazilian Portuguese for children and adolescents with spina bifida.

PURPOSE: The purpose of this study was to perform a cross-cultural adaptation of the Functional Mobility Scale (FMS) to Brazilian Portuguese and analyse its construct validity and intra-rater reliability in a sample of caregivers of children and adolescents with spina bifida (SB). MATERIAL AND METHODS: The cross-cultural adaptation followed five stages: two forward translations, synthesis, back-translation, committee review and pre-testing (n = 20). Construct validity was assessed by comparing the FMS with the classifications of Hoffer and Schoenmakers (n = 40). Intra-rater reliability was assessed by comparing the ratings of 14 caregivers, on two occasions. Kendall's tau correlation coefficient was used to test the construct validity of the FMS, while the kappa coefficient was used to test intra-rater reliability. RESULTS: Caregivers reported no difficulties with completing the FMS in Brazilian Portuguese. Construct validity tests showed positive correlations between the distances of 5 m (house), 50 m (school) and 500 m (community) in the FMS and the classifications of Hoffer (τ = 0.84; τ = 0.90; τ = 0.68; p < 0.01) and Schoenmakers (τ = 0.83; τ = 0.89; τ = 0.76; p < 0.01), respectively. Excellent intra-rater reliability (kappa = 0.9-1.0) was found for all three distances in the FMS. CONCLUSIONS: The FMS in Brazilian Portuguese showed acceptable intra-rater reliability and construct validity when used to measure the mobility level of patients with SB. We recommend its use in clinical practice and research.Implications for RehabilitationA valid and reliable instrument for assessing the mobility of patients with SB;A cross-cultural and adapted FMS in Brazilian Portuguese;An instrument for therapeutic and functional approaches outside the clinicalsetting;The FMS in the Brazilian Portuguese online version shows mistranslations.

Misdiagnoses in a Brazilian population with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. The correct diagnosis at the onset of the disease is sometimes very difficult, due to the symptoms being very similar to those of other neurological syndromes. OBJECTIVE: This study aimed to analyze the initial manifestations, the specialty of the first physician visited due the initial complaint, the misdiagnoses, as well as the unnecessary surgical interventions in a new ALS Brazilian population. METHODS: The medical records of 173 patients with typical ALS were reviewed. RESULTS: The present study demonstrated that other symptoms, besides weakness, were very frequent as initial presentation of ALS, and orthopedics was the medical specialty most sought by patients at the onset of symptoms. Our frequency of misdiagnoses was 69.7%, and in 7.1% of them, an unnecessary surgical intervention was performed. CONCLUSIONS: Amyotrophic lateral sclerosis presents a very large pool of signs and symptoms; therefore, there is an urgent need of increasing the disease awareness to other specialties due to the high frequency of misdiagnoses observed in clinical practice.

ANTECEDENTES: A esclerose lateral amiotrófica (ELA) é uma doença neurodegenerativa que afeta os neurônios motores superior e inferior. O diagnóstico correto no início da doença é, às vezes, muito difícil, pois os sintomas de início são muito semelhantes aos de outras síndromes neurológicas. OBJETIVO: Este estudo teve como objetivo analisar as manifestações iniciais, a especialidade do primeiro médico visitado devido à queixa inicial, os diagnósticos errôneos, bem como as intervenções cirúrgicas desnecessárias em uma nova população brasileira acometida por ELA. MéTODOS: Os prontuários médicos de 173 pacientes com ELA típica foram revisados. RESULTADOS: O presente estudo demonstrou que outros sintomas, além da fraqueza, foram muito frequentes como apresentação inicial da ELA, sendo a ortopedia a especialidade médica mais procurada pelos pacientes no início dos sintomas. Nossa frequência de diagnósticos errôneos foi de 69,7%, e em 7,1% deles foi realizada intervenção cirúrgica desnecessária. CONCLUSõES: A ELA apresenta um conjunto amplo de sinais e sintomas; portanto, há necessidade urgente de uma melhor educação de outras especialidades devido à alta frequência de diagnósticos equivocados observada na prática clínica.

Esophageal contractions in patients with chronic progressive external ophthalmoplegia.

BACKGROUND: Chronic progressive external ophthalmoplegia is a mitochondrial myopathy that causes muscular or multisystem symptoms and has dysphagia as one manifestation. AIM: To evaluate esophageal contractions in patients with chronic progressive external ophthalmoplegia. METHODS: We studied 14 patients with chronic progressive external ophthalmoplegia and 16 asymptomatic volunteers. The diagnosis of the disease was established by the clinical picture and by mitochondrial DNA analysis in skeletal muscle. We used the manometric method with a perfusion catheter that recorded the esophageal contractions at 2, 7, 12, 17, and 22 cm from the lower esophageal sphincter (LES). All subjects performed in the supine position 20 swallows of a 5-ml bolus of water at room temperature, ten every 30 s and ten every 10 s. RESULTS: The amplitude, duration, and area under the curve of contractions at 17 and 22 cm from the LES were lower in patients than in volunteers for swallows performed at 10-s and 30-s intervals (P<0.01). There was no difference in contractions at 7 and 2 cm, except for the contractions at 2 cm after swallows performed at 30-s intervals. The interval between the onset of contractions between 7 and 2 cm and between 22 and 2 cm was lower in patients than in volunteers, with swallows performed every 10 s and every 30 s. CONCLUSION: There is impairment of esophageal contractions in patients with chronic progressive external ophthalmoplegia, mainly in the proximal esophageal body.

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.

Brow motility in mitochondrial myopathy.

PURPOSE: To quantify the range of brow excursion in patients with mitochondrial myopathy and chronic progressive external ophthalmoplegia (CPEO). METHODS: Comparative case series. Digital image processing techniques were used to quantify the upper eyelid resting position, brow excursion, and monocular eye movements (ductions) in 19 patients with mitochondrial myopathy and CPEO and in 27 healthy control subjects. RESULTS: All patients with CPEO had ptosis ranging from 0.6 to 8 mm. For most patients, eye motility limitation was symmetrical. Elevation was the most affected eye movement. Patient's brow motility was on average 56.7% of the motility seen in the control group, and did not correlate with age or eye motility in any direction. Seventy-six percent of the brows displayed more than 2 mm of excursion. CONCLUSIONS: In patients with CPEO, the occipitofrontalis muscle is less affected than the extraocular muscles. Most patients display a useful degree of brow excursion that theoretically can be used to clear the visual axis after a conservative brow suspension.

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.

Clinical and molecular findings in a cohort of ANO5-related myopathy.

OBJECTIVE: ANO5-related myopathy is an important cause of limb-girdle muscular dystrophy (LGMD) and hyperCKemia. The main descriptions have emerged from European cohorts, and the burden of the disease worldwide is unclear. We provide a detailed characterization of a large Brazilian cohort of ANO5 patients. METHODS: A national cross-sectional study was conducted to describe clinical, histopathological, radiological, and molecular features of patients carrying recessive variants in ANO5. Correlation of clinical and genetic characteristics with different phenotypes was studied. RESULTS: Thirty-seven patients from 34 nonrelated families with recessive mutations of ANO5 were identified. The most common phenotype was LGMD, observed in 25 (67.5%) patients, followed by pseudometabolic presentation in 7 (18.9%) patients, isolated asymptomatic hyperCKemia in 4 (10.8%) patients, and distal myopathy in a single patient. Nine patients presented axial involvement, including one patient with isolated axial weakness. The most affected muscles according to MRI were the semimembranosus and gastrocnemius, but paraspinal and abdominal muscles, when studied, were involved in most patients. Fourteen variants in ANO5 were identified, and the c.191dupA was present in 19 (56%) families. Sex, years of disease, and the presence of loss-of-function variants were not associated with specific phenotypes. INTERPRETATION: We present the largest series of anoctaminopathy outside Europe. The most common European founder mutation c.191dupA was very frequent in our population. Gender, disease duration, and genotype did not determine the phenotype.

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.

A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome.

The most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE. The c.130dupG mutation was found in 32 patients (23 families), with 26 patients (19 families, 26.3%) in homozygosis, confirming its high prevalence in different regions of Brazil. Among the homozygous patients, the following characteristics were frequent: onset of symptoms before 2 years of age (92.3%), little functional restriction (92.3%), fluctuating symptoms (100%), ocular muscle impairment (96.1%), ptosis (100%), limb weakness (88.4%), response to pyridostigmine (100%), facial involvement (77%), and bulbar symptoms (70.8%). The pretest probability of finding at least one allele harbouring the c.130dupG mutation was 38.1%. Selecting only patients with impaired eye movement together with limb weakness and improvement with pyridostigmine, the probability increases to 72.2%. This clinical pre-selection of patients is likely a useful tool for regions where CHRNE mutations have a founder effect. In conclusion, the CHRNE mutation c.130dupG leads to fairly benign natural course of the disease with relative homogeneity.