Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis.

OBJECTIVES: To present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis. METHODS: Suspected CMS patients were divided into three groups: group A (limb, bulbar or axial weakness, with or without ocular impairment, and all the following: clinical fatigability, electrophysiology compatible with neuromuscular junction involvement and anticholinesterase agents response), group B (limb, bulbar or axial weakness, with or without ocular impairment, and at least one of additional characteristics noted in group A) and group C (pure ocular syndrome). Individual clinical findings and the clinical groups were compared between the group with a confirmed molecular diagnosis of CMS and the group without molecular diagnosis or with a non-CMS molecular diagnosis. RESULTS: Seventy-nine patients (68 families) were included in the cohort: 48 in group A, 23 in group B and 8 in group C. Fifty-one were considered confirmed CMS (30 CHRNE, 5 RAPSN, 4 COL13A1, 3 DOK7, 3 COLQ, 2 GFPT1, 1 CHAT, 1 SCN4A, 1 GMPPB, 1 CHRNA1), 7 probable CMS, 5 non-CMS and 16 unsolved. The chance of a confirmed molecular diagnosis of CMS was significantly higher for group A and lower for group C. Some individual clinical features, alterations on biopsy and electrophysiology enhanced specificity for CMS. Muscle imaging showed at least mild alterations in the majority of confirmed cases, with preferential involvement of soleus, especially in CHRNE CMS. CONCLUSIONS: Stricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.

Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.

Severe brain involvement in 5q spinal muscular atrophy type 0.

Spinal muscular atrophy (SMA) type 0 is the most severe form of SMA, associated with the SMN1 gene and manifesting at birth. Most patients die in the first weeks of life. In this work, we present 3 patients with SMA type 0 who survived >1 year and presented diffuse and progressive brain abnormalities on magnetic resonance imaging, which are not usually seen in patients with SMA. Thus, severe brain involvement may likely be the full end manifestation of an already extreme SMA phenotype caused by substantial reduction of the SMN protein in the brain. ANN NEUROL 2019;86:458-462.

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.

Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1) and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor. METHODS: Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC), the Hammersmith Functional Motor Scale (HFMS), and the Barthel Index. RESULTS: After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period. CONCLUSION: Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01033331.

Real-World Data from Nusinersen Treatment for Patients with Later-Onset Spinal Muscular Atrophy: A Single Center Experience.

BackgroundSpinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness and motor disability.ObjectiveThis study aims to report the evaluation of nusinersen, an antisense oligonucleotide, on motor function in patients with SMA types 2 and 3.MethodsThis single-center retrospective observational study assessed nusinersen therapy outcomes, measured by HSMFSE or CHOP-INTEND scales, in patients with SMA types 2 and 3, compared to untreated patients, for at least 24 months.ResultsA total of 41 patients with SMA types 2 and 3 under nusinersen treatment were included. In 30 treated patients (mean age: 10.6 years; 14 with SMA type 2), the mean change in HFMSE scores was +1.47 points (SD = 0.4) and +1.60 points (SD = 0.6) after 12 and 24 months of treatment, respectively. In contrast, the control group (N = 37) (mean age: 10.2 years; 20 with SMA type 2) presented a mean change of -1.71 points (SD = 0.02) and -3.93 points (SD = 0.55) after 12 and 24 months of follow-up, respectively. The most severe patients under nusinersen treatment (N = 11) showed a change of +2.37 (SD = 1.13) on the CHOP-INTEND scale after 12 months of follow-up. Disease duration at the beginning of treatment was the main predictor of functional improvement. Despite functional gain and motor stabilization, treatment with nusinersen did not prevent the progression of scoliosis.ConclusionsOur data provide evidence for the long-term safety and efficacy of nusinersen use in the treatment of later-onset SMA, and patients with shorter disease duration showed better response to treatment.

Dominant or recessive mutations in the RYR1 gene causing central core myopathy in Brazilian patients.

Central Core Disease (CCD) is an inherited neuromuscular disorder characterized by the presence of cores in muscle biopsy. CCD is caused by mutations in the RYR1 gene. This gene encodes the ryanodine receptor 1, which is an intracellular calcium release channel from the sarcoplasmic reticulum to the cytosol in response to depolarization of the plasma membrane. Mutations in this gene are also associated with susceptibility to Malignant Hyperthermia (MHS). In this study, we evaluated 20 families with clinical and histological characteristics of CCD to identify primary mutations in patients, for diagnosis and genetic counseling of the families. We identified variants in the RYR1 gene in 19/20 families. The molecular pathogenicity was confirmed in 16 of them. Most of these variants (22/23) are missense and unique in the families. Two variants were recurrent in two different families. We identified six families with biallelic mutations, five compound heterozygotes with no consanguinity, and one homozygous, with consanguineous parents, resulting in 30% of cases with possible autosomal recessive inheritance. We identified seven novel variants, four of them classified as pathogenic. In one family, we identified two mutations in exon 102, segregating in cis, suggesting an additive effect of two mutations in the same allele. This work highlights the importance of using Next-Generation Sequencing technology for the molecular diagnosis of genetic diseases when a very large gene is involved, associated to a broad distribution of the mutations along it. These data also influence the prevention through adequate genetic counseling for the families and cautions against malignant hyperthermia susceptibility.

Sleep and neuromuscular disorders in children.

Children suffering from neuromuscular diseases are at an increased risk of sleep-related breathing disorders (SRBD) such as obstructive sleep apnea syndrome (OSAS) and hypoventilation as well as central sleep apnea, which is frequent in these patients due to diaphragmatic weakness. They are at higher risk for developing complications of nocturnal hypoxemia, including pulmonary hypertension, cor pulmonale and neurocognitive dysfunction. Neuromuscular disorders and OSAS are both prevalent disorders and frequently overlap. Sleep-related hypoventilation/hypoxemia due to neuromuscular diseases may be exacerbated in the presence of OSAS; these children are likely to experience greater severity and duration of sleep-related hypoxemia than are children with either disorder alone. Additionally, some of these children have reduced central neural chemoresponsiveness. The development of SRBD in these patients further impairs their quality of life and worsens their respiratory status. We review the literature on the diagnosis and treatment of SRBD in children with a variety of neuromuscular disorders.

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.

[Subependymal giant cell astrocytoma in patients with tuberous sclerosis: magnetic resonance imaging findings in ten cases]. / Astrocitoma subependimário de células gigantes em pacientes com esclerose tuberosa: achados em ressonância magnética de dez casos.

OBJECTIVE: To report the magnetic resonance imaging (MRI) findings in 10 patients with subependimal giant cell astrocytoma (SGCA) and tuberous sclerosis (TS). METHOD: Ten patients were retrospectively studied, presenting TS and histologically proven SGCA. Four patients were male and six female, with mean age 15.7 years. All patients underwent MRI, which was analyzed by two radiologists, final diagnosis was reached by consensus. The following findings were studied: topography, size, signal intensity on T1/T2-weighted images, contrast enhancement and associated findings. RESULTS: All patients presented a single lesion suggestive of SGCA, measuring between 1.5 cm and 8 cm in the largest diameter. Eight lesions were found near the foramen of Monro and two in the body of the lateral ventricles. The tumors showed preferentially intermediate signal on T1 (70%), high signal on T2-weighted images (100%), with intense enhancement after contrast administration (100%). CONCLUSION: SGCA in patients with TS usually presents as a single lesion near the foramen of Monro, with intermediate signal on T1, high signal on T2-weighted images and intense contrast enhancement.

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.

Rod distribution and muscle fiber type modification in the progression of nemaline myopathy.

Nemaline myopathy is a structural congenital myopathy associated with the presence of rodlike structures inside the muscle fibers and type I predominance. It may be caused by mutations in at least five genes: slow alpha-tropomyosin 3 (chromosome 1q22-23), nebulin (chromosome 2q21.1-q22), actin (chromosome 1q42), tropomyosin 2 (chromosome 9p13), and troponin T1 (chromosome 19q13.4). The effect of these mutations in the expression of the protein and the mechanism of rod formation is still under investigation. We analyzed the possibility of progressive alterations with time and/or disease evolution, such as transformation of type I to type II fiber and rod pattern and distribution in muscle fibers from patients with nemaline myopathy, through a morphometric and immunohistochemical analysis of different muscle protein isoforms. A tendency of diffuse rods to be organized in the subsarcolemmal region was observed in two patients who were submitted to subsequent biopsies after 10 and 13 years. Additionally, we observed the expression of type II protein isoforms in type I fibers and a higher proportion of type II fibers in the younger patient of a pair of affected sibs, giving further support to the hypothesis of progressive conversion of type II to type I fibers in nemaline myopathy.

Frontal foramina, Chiari II malformation, and hydrocephalus in a female.

Reported is a 4-year-old female with Chiari II malformation and congenital hydrocephalus associated with lumbosacral myelomeningocele who also presented with frontal calvarial foramina depicted by head computed tomographic scans with three-dimensional reconstructions. Magnetic resonance demonstrated bilateral and symmetric frontal lobe malformation-separated-lip clefts schizencephaly-adjacent to the bilateral frontal calvarial foramina. Because the different types of malformations evident in this patient do not share the same developmental origin, the association of findings is unusual and suggests the occurrence of an unknown prenatal factor acting along different stages of central nervous system development.

Clinical aspects of patients with sarcoglycanopathies under steroids therapy.

UNLABELLED: Patients with sarcoglycanopathies, which comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies, usually present with progressive weakness leading to early loss of ambulation and premature death, and no effective treatment is currently available. OBJECTIVE: To present clinical aspects and outcomes of six children with sarcoglycanopathies treated with steroids for at least one year. METHOD: Patient files were retrospectively analyzed for steroid use. RESULTS: Stabilization of muscle strength was noted in one patient, a slight improvement in two, and a slight worsening in three. In addition, variable responses of forced vital capacity and cardiac function were observed. CONCLUSIONS: No overt clinical improvement was observed in patients with sarcoglycanopathies under steroid therapy. Prospective controlled studies including a larger number of patients are necessary to determine the effects of steroids for sarcoglycanopathies.

Congenital muscular dystrophy with dropped head linked to the LMNA gene in a Brazilian cohort.

BACKGROUND: Congenital muscular dystrophy is a clinically and genetically heterogeneous group of myopathies. Congenital muscular dystrophy related to lamin A/C is rare and characterized by early-onset hypotonia with axial muscle weakness typically presenting with a loss in motor acquisitions within the first year of life and a dropped-head phenotype. METHODS: Here we report the clinical and histological characteristics of four unrelated Brazilian patients with dropped-head syndrome and mutations in the LMNA gene. RESULTS: All patients had previously described mutations (p.E358K, p.R249W, and p.N39S) and showed pronounced cervical muscle weakness, elevation of serum creatine kinase, dystrophic pattern on muscle biopsy, and respiratory insufficiency requiring ventilatory support. Three of the patients manifested cardiac arrhythmias, and one demonstrated a neuropathic pattern on nerve conduction study. CONCLUSION: Although lamin A/C--related congenital muscular dystrophy is a clinically distinct and recognizable phenotype, genotype/phenotype correlation, ability to anticipate onset of respiratory and cardiac involvement, and need for nutritional support remain difficult.

Motor function measure scale, steroid therapy and patients with Duchenne muscular dystrophy.

OBJECTIVE: To assess the evolution of motor function in patients with Duchenne muscular dystrophy (DMD) treated with steroids (prednisolone or deflazacort) through the Motor Function Measure (MFM), which evaluates three dimensions of motor performance (D1, D2, D3). METHODS: Thirty-three patients with DMD (22 ambulant, 6 non-ambulant and 5 who lost the capacity to walk during the period of the study) were assessed using the MFM scale six times over a period of 18 months. RESULTS: All the motor functions remained stable for 14 months in all patients, except D1 for those who lost their walking ability. In ambulant patients, D2 (axial and proximal motor capacities) motor functions improved during six months; an improvement in D3 (distal motor capacity) was noted during the total follow-up. D1 (standing posture and transfers) and total score were useful to predict the loss of the ability to walk. CONCLUSIONS: The use of the MFM in DMD patients confirms the benefits of the steroid treatment for slowing the progression of the disease.

Lung function monitoring in patients with duchenne muscular dystrophy on steroid therapy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a sex-linked inherited muscle disease characterized by a progressive loss in muscle strength and respiratory muscle involvement. After 12 years of age, lung function declines at a rate of 6 % to 10.7 % per year in patients with DMD. Steroid therapy has been proposed to delay the loss of motor function and also the respiratory involvement. METHOD: In 21 patients with DMD aged between seven and 16 years, the forced vital capacity (FVC) and the forced expiratory volume in one second (FEV1) were evaluated at three different times during a period of two years. RESULTS: We observed in this period of evaluation the maintenance of the FVC and the FEV1 in this group of patients independently of chronological age, age at onset of steroid therapy, and walking capacity. CONCLUSION: The steroid therapy has the potential to stabilize or delay the loss of lung function in DMD patients even if they are non-ambulant or older than 10 years, and in those in whom the medication was started after 7 years of age.

Anti-N-methyl D-aspartate receptor encephalitis in childhood.

OBJECTIVE: To discuss the differential diagnosis of encephalitis beyond that of infectious etiology and to inform pediatricians about the possibility of anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis in children by highlighting its most important clinical features. DESCRIPTION: Three patients presented with an initial neuropsychiatric syndrome followed by encephalopathy and movement disorder. The initial neuropsychiatric features which developed over days to weeks included a change in personality, anxiety, confusion, and speech regression. This was followed by a choreoathetoid or dystonic movement disorder affecting the orofacial region and the limbs. After the exclusion of the major causes of encephalitis, NMDAr antibodies were identified in serum and cerebrospinal fluid, and neoplasm screening did not detect any tumor. Patients were submitted to immunosuppression, and two of them had a full neurological recovery. One of them still presents a mild dystonic posture in a limb. COMMENTS: Clinical signs of anti-NMDAr encephalitis in children are similar to those previously described in adults. Tumors are not usually detected by this age. The diagnosis of anti-NMDAr encephalitis must be addressed only after the exclusion of infectious and other recognizable causes of encephalitis. Pediatricians should be aware of this treatable autoimmune condition.