LUSTR: a new customizable tool for calling genome-wide germline and somatic short tandem repeat variants.

BACKGROUND: Short tandem repeats (STRs) are widely distributed across the human genome and are associated with numerous neurological disorders. However, the extent that STRs contribute to disease is likely under-estimated because of the challenges calling these variants in short read next generation sequencing data. Several computational tools have been developed for STR variant calling, but none fully address all of the complexities associated with this variant class. RESULTS: Here we introduce LUSTR which is designed to address some of the challenges associated with STR variant calling by enabling more flexibility in defining STR loci, allowing for customizable modules to tailor analyses, and expanding the capability to call somatic and multiallelic STR variants. LUSTR is a user-friendly and easily customizable tool for targeted or unbiased genome-wide STR variant screening that can use either predefined or novel genome builds. Using both simulated and real data sets, we demonstrated that LUSTR accurately infers germline and somatic STR expansions in individuals with and without diseases. CONCLUSIONS: LUSTR offers a powerful and user-friendly approach that allows for the identification of STR variants and can facilitate more comprehensive studies evaluating the role of pathogenic STR variants across human diseases.

Marked neuropsychiatric involvement and dysmorphic features in nemaline myopathy.

BACKGROUND: Inherited nemaline myopathy is one of the most common congenital myopathies. This genetically heterogeneous disease is defined by the presence of nemaline bodies in muscle biopsy. The phenotypic spectrum is wide and cognitive involvement has been reported, although not extensively evaluated. METHODS: We report two nemaline myopathy patients presenting pronounced central nervous system involvement leading to functional compromise and novel facial and skeletal dysmorphic findings, possibly expanding the disease phenotype. RESULTS: One patient had two likely pathogenic NEB variants, c.2943G > A and c.8889 + 1G > A, and presented cognitive impairment and dysmorphic features, and the other had one pathogenic variant in ACTA1, c.169G > C (p.Gly57Arg), presenting autism spectrum disorder and corpus callosum atrophy. Both patients had severe cognitive involvement despite milder motor dysfunction. CONCLUSION: We raise the need for further studies regarding the role of thin filament proteins in the central nervous system and for a systematic cognitive assessment of congenital myopathy patients.

Clinical Manifestation of Nebulin-Associated Nemaline Myopathy.

Background and Objectives: Nemaline myopathy (NM) is a genetically heterogeneous inherited myopathy related with at least 12 genes, whereas pathogenic variants in NEB gene are the most common genetic cause. The clinical spectrum of NM caused by NEB pathogenic variants (NM-NEB) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar involvement. There is currently not enough data regarding the progression of the disease. In this study, we present a genotypic and phenotypic spectrum of 33 patients with NM caused by NEB variants (NM-NEB) classified according to age groups and the use of ventilatory support. We focused on interventional support, genotype-phenotype correlation, and association between respiratory, bulbar, and motor systems in groups of patients stratified by age and by the use of ventilatory support (VS). Methods: Clinical and genetic data from patients with NM-NEB followed up in one specialized center were collected through regular consultations. Patients were evaluated regarding motor, bulbar, and respiratory functions. Results: Thirty-three patients with NM-NEB were evaluated consisting of 15 females and 18 males with an average age of 18 (±12) years and a median of 17 (±11) years. 32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS. Scoliosis and dysphagia were more common among patients who used VS. Described for the first time, half of the patients presented tongue atrophy in a triple furrow pattern, and the presence of the atrophy was associated with dysphagia. Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains. In addition to that, we showed that VS use was associated with scoliosis and dysphagia. Discussion: NM-NEB is a very debilitating disease. There is an association between scoliosis and respiratory dysfunction while patients using VS have more often scoliosis than the no-VS group. Triple furrow tongue atrophy is a novel and frequent finding, which is directly associated with dysphagia. Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities. All observations are relevant in the management care of patients with NM.

Effect of the COVID-19 pandemic on patients with inherited neuromuscular disorders.

BACKGROUND: The COVID-19 pandemic has brought substantial challenges for current practices in treating hereditary neuromuscular disorders (hNMDs). However, this infection has not been the only concern for these patients. Social distancing has compromised multidisciplinary assistance and physical activity, and has brought about several mental health issues. We presented a follow-up on 363 patients with hNMDs at a Brazilian tertiary center during the peak of the COVID-19 pandemic. OBJECTIVE: We aimed to show the frequency and severity of SARS-CoV-2 infection among hNMD patients and to demonstrate the effects of the pandemic on life habits, disease progression and multidisciplinary supportive care status. METHODS: Three hundred and sixty-three patients (58% male and 42% female) were followed for three months through three teleconsultations during the peak of the COVID-19 pandemic in Brazil. RESULTS: There were decreases in the numbers of patients who underwent physical, respiratory and speech therapies. For several patients, their appetite (33%) and sleep habits (25%) changed. Physical exercises and therapies were interrupted for most of the patients. They reported new onset/worsening of fatigue (17%), pain (17%), contractions (14%) and scoliosis (7%). Irritability and sleep, weight and appetite changes, and especially diminished appetite and weight loss, were more frequent in the group that reported disease worsening. There was a low COVID-19 contamination rate (0.8%), and all infected patients had a mild presentation. CONCLUSION: The isolation by itself was protective from a COVID-19 infection perspective. However, this isolation might also trigger a complex scenario with life habit changes that are associated with an unfavorable course for the NMD.

The Location of Disease-Causing DES Variants Determines the Severity of Phenotype and the Morphology of Sarcoplasmic Aggregates.

Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES cause desminopathy, a disorder affecting the heart and skeletal muscles. We aimed to analyze the clinical features, morphology, and distribution of desmin aggregates in skeletal muscle biopsies of patients with desminopathy and to correlate these findings with the type and location of disease-causing DES variants. This retrospective study included 30 patients from 20 families with molecularly confirmed desminopathy from 2 neuromuscular referral centers. We identified 2 distinct patterns of desmin aggregates: well-demarcated subsarcolemmal aggregates and diffuse aggregates with poorly delimited borders. Pathogenic variants located in the 1B segment and the tail domain of the desmin molecule are more likely to present with early-onset cardiomyopathy compared to patients with variants in other segments. All patients with mutations in the 1B segment had well-demarcated subsarcolemmal aggregates, but none of the patients with variants in other desmin segments showed such histological features. We suggest that variants located in the 1B segment lead to well-shaped subsarcolemmal desmin aggregation and cause disease with more frequent cardiac manifestations. These findings will facilitate early identification of patients with potentially severe cardiac syndromes.

Effect of the COVID-19 pandemic on patients with inherited neuromuscular disorders / Efeito da pandemia do COVID-19 em pacientes com doenças neuromusculares hereditárias

ABSTRACT Background The COVID-19 pandemic has brought substantial challenges for current practices in treating hereditary neuromuscular disorders (hNMDs). However, this infection has not been the only concern for these patients. Social distancing has compromised multidisciplinary assistance and physical activity, and has brought about several mental health issues. We presented a follow-up on 363 patients with hNMDs at a Brazilian tertiary center during the peak of the COVID-19 pandemic. Objective We aimed to show the frequency and severity of SARS-CoV-2 infection among hNMD patients and to demonstrate the effects of the pandemic on life habits, disease progression and multidisciplinary supportive care status. Methods Three hundred and sixty-three patients (58% male and 42% female) were followed for three months through three teleconsultations during the peak of the COVID-19 pandemic in Brazil. Results There were decreases in the numbers of patients who underwent physical, respiratory and speech therapies. For several patients, their appetite (33%) and sleep habits (25%) changed. Physical exercises and therapies were interrupted for most of the patients. They reported new onset/worsening of fatigue (17%), pain (17%), contractions (14%) and scoliosis (7%). Irritability and sleep, weight and appetite changes, and especially diminished appetite and weight loss, were more frequent in the group that reported disease worsening. There was a low COVID-19 contamination rate (0.8%), and all infected patients had a mild presentation. Conclusion The isolation by itself was protective from a COVID-19 infection perspective. However, this isolation might also trigger a complex scenario with life habit changes that are associated with an unfavorable course for the NMD.

RESUMO Antecedentes: A Pandemia por COVID-19 tem trazido desafios subtanciais para a prática clínica no tratamento das doenças neuromusculares hereditárias (DNMh). A infecção não tem sido a única preocupação para os pacientes. O distanciamento social tem comprometido a assistência multidisciplinar, atividade física e tem trazido problemas mentais em decorrência do próprio isolamento. Nós apresentamos aqui um seguimento de 363 pacientes com DNMh de um centro terciário Brasileiro durante o pico da Pandemia de Covid-19. Objetivos: Mostrar a frequência e gravidade da infecção por Sars-Cov-2 em pacientes com DNMh e demonstrar os efeitos da pandemia nos hábitos de vida, na progressão da doença e no cuidado multidisciplinary. Métodos Trezentos e sessenta e três pacientes (58% homens and 42% mulheres) foram acompanhados por 3 meses através de 3 teleconsultas durante o pico da Pandemia de Covid-19 no Brasil. Resultados Houve um decréscimo no número de pacientes que faziam terapia física, respiratória e fonoaudiológica. Em muitos pacientes, o apetite (33%) e hábitos do sono (25%) se alteraram. Exercícios físicos e terapias foram interrompidas pela maioria dos pacientes. Physical exercises and therapies were interrupted for most of the patients. Eles relataram piora ou aparecimento de fadiga (17%), dor (17%), retrações (14%), e escoliose (7%). Irritabilidade, mudanças no sono, peso e apetite, sendo principalmente diminuição do apetite e peso foram mais frequentemente encontrados em pacientes que apresentaram piora clinica da doença. Houve uma baixa taxa de contaminação por Covid-19 (0.8%), e todos os pacientes infectado apresentaram quadro clinico leve. Conclusão O isolamento por si só se mostrou protetor na perspectiva de infecção por Covid-19, mas pode desencadear um cenário complexo com mudanças nos hábitos de vida e curso desfavorável da doença de base.

Myasthenia Gravis Related to Thymic Carcinoma: A Case Study.

Myasthenia gravis and thymoma are often presented in association with ∼10% of myasthenic cases having concomitant thymoma. Thymic carcinoma is one of the rarest/aggressive human epithelial tumors and has no correlation with myasthenia gravis hitherto. Here is provided a clinical case and review of literature on a very rare association of thymic carcinoma (with no sign of thymoma) and myasthenia gravis (antiacetylcholine receptor antibody positive). Two years after thymectomy, clinical evolution was satisfactory. This clinical case elicits hypothesis that thymic carcinoma may be related with myasthenia gravis, what may have good prognostic from oncologic and neurologic perspectives.

Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital.

BACKGROUND: More than one-third of COVID-19 patients present neurological symptoms ranging from anosmia to stroke and encephalopathy. Furthermore, pre-existing neurological conditions may require special treatment and may be associated with worse outcomes. Notwithstanding, the role of neurologists in COVID-19 is probably underrecognized. OBJECTIVE: The aim of this study was to report the reasons for requesting neurological consultations by internists and intensivists in a COVID-19-dedicated hospital. METHODS: This retrospective study was carried out at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, a 900-bed COVID-19 dedicated center (including 300 intensive care unit beds). COVID-19 diagnosis was confirmed by SARS-CoV-2-RT-PCR in nasal swabs. All inpatient neurology consultations between March 23rd and May 23rd, 2020 were analyzed. Neurologists performed the neurological exam, assessed all available data to diagnose the neurological condition, and requested additional tests deemed necessary. Difficult diagnoses were established in consensus meetings. After diagnosis, neurologists were involved in the treatment. RESULTS: Neurological consultations were requested for 89 out of 1,208 (7.4%) inpatient COVID admissions during that period. Main neurological diagnoses included: encephalopathy (44.4%), stroke (16.7%), previous neurological diseases (9.0%), seizures (9.0%), neuromuscular disorders (5.6%), other acute brain lesions (3.4%), and other mild nonspecific symptoms (11.2%). CONCLUSIONS: Most neurological consultations in a COVID-19-dedicated hospital were requested for severe conditions that could have an impact on the outcome. First-line doctors should be able to recognize neurological symptoms; neurologists are important members of the medical team in COVID-19 hospital care.

Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital / Consultas neurológicas e diagnósticos em um grande hospital universitário dedicado a COVID-19

ABSTRACT Background: More than one-third of COVID-19 patients present neurological symptoms ranging from anosmia to stroke and encephalopathy. Furthermore, pre-existing neurological conditions may require special treatment and may be associated with worse outcomes. Notwithstanding, the role of neurologists in COVID-19 is probably underrecognized. Objective: The aim of this study was to report the reasons for requesting neurological consultations by internists and intensivists in a COVID-19-dedicated hospital. Methods: This retrospective study was carried out at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, a 900-bed COVID-19 dedicated center (including 300 intensive care unit beds). COVID-19 diagnosis was confirmed by SARS-CoV-2-RT-PCR in nasal swabs. All inpatient neurology consultations between March 23rd and May 23rd, 2020 were analyzed. Neurologists performed the neurological exam, assessed all available data to diagnose the neurological condition, and requested additional tests deemed necessary. Difficult diagnoses were established in consensus meetings. After diagnosis, neurologists were involved in the treatment. Results: Neurological consultations were requested for 89 out of 1,208 (7.4%) inpatient COVID admissions during that period. Main neurological diagnoses included: encephalopathy (44.4%), stroke (16.7%), previous neurological diseases (9.0%), seizures (9.0%), neuromuscular disorders (5.6%), other acute brain lesions (3.4%), and other mild nonspecific symptoms (11.2%). Conclusions: Most neurological consultations in a COVID-19-dedicated hospital were requested for severe conditions that could have an impact on the outcome. First-line doctors should be able to recognize neurological symptoms; neurologists are important members of the medical team in COVID-19 hospital care.

RESUMO Introdução: Mais de um terço dos pacientes com COVID-19 apresentam sintomas neurológicos que variam de anosmia a AVC e encefalopatia. Além disso, doenças neurológicas prévias podem exigir tratamento especial e estar associadas a piores desfechos. Não obstante, o papel dos neurologistas na COVID-19 é provavelmente pouco reconhecido. Objetivo: O objetivo deste estudo foi relatar os motivos para solicitar consultas neurológicas por clínicos e intensivistas em um hospital dedicado à COVID-19. Métodos: Estudo retrospectivo realizado no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brasil, um centro dedicado à COVID-19 com 900 leitos (incluindo 300 leitos para unidades de terapia intensiva). O diagnóstico de COVID-19 foi confirmado por SARS-CoV-2-RT-PCR em swabs nasais. Todas as interconsultas de neurologia hospitalar entre 23 de março e 23 de maio de 2020 foram analisadas. Os neurologistas realizaram o exame neurológico, avaliaram todos os dados disponíveis para diagnosticar a patologia neurológica e solicitaram exames adicionais conforme necessidade. Diagnósticos difíceis foram estabelecidos em reuniões de consenso. Após o diagnóstico, os neurologistas participaram da condução dos casos. Resultados: Foram solicitadas consultas neurológicas para 89 de 1.208 (7,4%) em pacientes internados por COVID-19 durante o período. Os principais diagnósticos neurológicos incluíram: encefalopatia (44,4%), acidente vascular cerebral (16,7%), doenças neurológicas prévias (9,0%), crises epilépticas (9,0%), transtornos neuromusculares (5,6%), outras lesões encefálicas agudas (3,4%) e outros sintomas leves inespecíficos (11,2%). Conclusões: A maioria das consultas neurológicas em um hospital dedicado à COVID-19 foi solicitada para condições graves que poderiam afetar o desfecho clínico. Os médicos na linha de frente devem ser capazes de reconhecer sintomas neurológicos. Os neurologistas são membros importantes da equipe médica no atendimento hospitalar à COVID-19.

Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital / Consultas neurológicas e diagnósticos em um grande hospital universitário dedicado a COVID-19

Background: More than one-third of COVID-19 patients present neurological symptomsranging from anosmia to stroke and encephalopathy. Furthermore, pre-existingneurological conditions may require special treatment and may be associated with worseoutcomes. Notwithstanding, the role of neurologists in COVID-19 is probablyunderrecognized. Objective: The aim of this study was to report the reasons forrequesting neurological consultations by internists and intensivists in a COVID-19-dedicated hospital. Methods: This retrospective study was carried out at Hospital dasClínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, a 900-bedCOVID-19 dedicated center (including 300 intensive care unit beds). COVID-19 diagnosiswas confirmed by SARS-CoV-2-RT-PCR in nasal swabs. All inpatient neurologyconsultations between March 23rd and May 23rd, 2020 were analyzed. Neurologistsperformed the neurological exam, assessed all available data to diagnose theneurological condition, and requested additional tests deemed necessary. Difficultdiagnoses were established in consensus meetings. After diagnosis, neurologists wereinvolved in the treatment. Results: Neurological consultations were requested for 89 outof 1,208 (7.4%) inpatient COVID admissions during that period. Main neurologicaldiagnoses included: encephalopathy (44.4%), stroke (16.7%), previous neurologicaldiseases (9.0%), seizures (9.0%), neuromuscular disorders (5.6%), other acute brainlesions (3.4%), and other mild nonspecific symptoms (11.2%). Conclusions: Mostneurological consultations in a COVID-19-dedicated hospital were requested for severeconditions that could have an impact on the outcome. First-line doctors should be able torecognize neurological symptoms; neurologists are important members of the medicalteam in COVID-19 hospital care.

Introdução: Mais de um terço dos pacientes com COVID-19 apresentam sintomasneurológicos que variam de anosmia a AVC e encefalopatia. Além disso, doençasneurológicas prévias podem exigir tratamento especial e estar associadas a pioresdesfechos. Não obstante, o papel dos neurologistas na COVID-19 é provavelmentepouco reconhecido. Objetivo: O objetivo deste estudo foi relatar os motivos para solicitarconsultas neurológicas por clínicos e intensivistas em um hospital dedicado à COVID-19. Métodos: Estudo retrospectivo realizado no Hospital das Clínicas da Faculdade deMedicina da Universidade de São Paulo, Brasil, um centro dedicado à COVID-19 com900 leitos (incluindo 300 leitos para unidades de terapia intensiva). O diagnóstico deCOVID-19 foi confirmado por SARS-CoV-2-RT-PCR em swabs nasais. Todas asinterconsultas de neurologia hospitalar entre 23 de março e 23 de maio de 2020 foramanalisadas. Os neurologistas realizaram o exame neurológico, avaliaram todos os dadosdisponíveis para diagnosticar a patologia neurológica e solicitaram exames adicionaisconforme necessidade. Diagnósticos difíceis foram estabelecidos em reuniões deconsenso. Após o diagnóstico, os neurologistas participaram da condução dos casos.Resultados: Foram solicitadas consultas neurológicas para 89 de 1.208 (7,4%) empacientes internados por COVID-19 durante o período. Os principais diagnósticosneurológicos incluíram: encefalopatia (44,4%), acidente vascular cerebral (16,7%),doenças neurológicas prévias (9,0%), crises epilépticas (9,0%), transtornosneuromusculares (5,6%), outras lesões encefálicas agudas (3,4%) e outros sintomasleves inespecíficos (11,2%). Conclusões: A maioria das consultas neurológicas em umhospital dedicado à COVID-19 foi solicitada para condições graves que poderiam afetaro desfecho clínico. Os médicos na linha de frente devem ser capazes de reconhecersintomas neurológicos. Os neurologistas são membros importantes da equipe médica noatendimento hospitalar à COVID-19.

Facial myokymia in inherited peripheral nerve hyperexcitability syndrome.

Peripheral nerve hyperexcitability syndrome comprises a heterogeneous group of diseases, clinically characterised by myokymia, fasciculation, muscle cramps and stiffness. The causes are either immune mediated or non-immune mediated. Non-immune-mediated forms are mostly genetic, relating to two main genes: KCNQ2 and KCNA1 Patients with KCNQ2 gene mutations typically present with epileptic encephalopathy, benign familial neonatal seizures and myokymia, though occasionally with purely peripheral nerve hyperexcitability. We report a woman with marked facial myokymia and distal upper limb contractures whose mother also had subtle facial myokymia; both had the c.G620A (p.R207Q) variant in the KCNQ2 gene. Patients with familial myokymia and peripheral nerve hyperexcitability syndrome should be investigated for KCNQ2 variants. This autosomal dominant condition may respond to antiepileptic medications acting at potassium channels.

Clinical features of collagen VI-related dystrophies: A large Brazilian cohort.

OBJECTIVES: Collagen VI-related dystrophies (COL6-RDs) have a broad clinical spectrum and are caused by mutations in the COL6A1, COL6A2 and COL6A3 genes. Despite the clinical variability, two phenotypes are classically recognized: Bethlem myopathy (BM, milder form) and Ullrich congenital muscular dystrophy (UCMD, more severe form), with many patients presenting an intermediate phenotype. In this work, we present clinical and genetic data from 28 patients (27 families), aged 6-38 years (mean of 16.96 years), with COL6-RDs. PATIENTS AND METHODS: Clinical, muscle histology and genetic data are presented. COL6A1, COL6A2 and COL6A3 genes were analyzed by next-generation sequencing (NGS). RESULTS: Homozygous or heterozygous variants were found in COL6A1 (12 families), COL6A2 (12 families) and COL6A3 (3 families). Patients with the severe UCMD phenotype (three cases) had a homogeneous clinical picture characterized by neonatal onset of manifestations, no gait acquisition and a stable course, but with severe respiratory involvement. Most of the patients with the mild UCMD phenotype had neonatal onset of manifestations (88.8 %), delayed motor development (66.6 %), slowly progressive course, pulmonary involvement (55.5 %) and loss of the walking capacity before the age of 10 (66.6 %). In the intermediate group (nine patients), some children had neonatal onset of manifestations (44.5 %) and delayed motor development (88.9 %); but all of them achieved the ability to walk and were still ambulatory. Some patients that had the BM phenotype presented neonatal manifestations (57.1 %); however, all of them had normal motor development and normal pulmonary function. Only one patient from the group of BM lost the walking capacity during the evolution of the disease. Other frequent findings observed in all groups were joint retractions, spinal deformities, distal hyperextensibility, congenital hip dislocation and keloid formation. CONCLUSION: COL6-RDs present variable clinical manifestations, but common findings are helpful for the clinical suspicion. NGS is a valuable approach for diagnosis, providing useful information for the genetic counseling of families.

Congenital fiber type disproportion caused by TPM3 mutation: A report of two atypical cases.

Congenital fiber type disproportion (CFTD) is a rare congenital myopathy subtype defined by slow type 1 hypotrophy in the absence of any other major structural findings such as rods, central nuclei or cores. Dominant missense changes in slow alpha-tropomyosin coded by TPM3 gene are the main cause of the CFTD. There are only a few reports of recessive loss-of-function mutations in TPM3 causing severe Nemaline Myopathy and CFTD. We present two patients harboring TPM3 mutations. The first is a novel homozygous missense variant with a mild CFTD clinical phenotype inherited in a recessive fashion. The second is a previously reported heterozygous mutation presenting within pronounced early axial involvement and dropped head. This report expands the genotype-phenotype correlation in the TPM3 myopathy showing a recessive mutation causing a mild clinical phenotype and also shows that TPM3 mutations should be part of the investigation in patients with dropped head.

Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil.

Mutations in RAPSN are an important cause of congenital myasthenic syndrome (CMS), leading to endplate acetylcholine receptor deficiency. We present three RAPSN early-onset CMS patients (from a Brazilian cohort of 61 CMS patients). Patient 1 and patient 2 harbor the mutation p.N88K in homozygosity, while patient 3 harbors p.N88K in compound heterozygosity with another pathogenic variant (p.V165M; c.493G ≥ A). At onset, patient 3 presented with more severe symptoms compared to the other two, showing generalized weakness and repeated episodes of respiratory failure in the first years of life. During adolescence, she became gradually less symptomatic and does not require medication anymore, presenting better long-term outcomes than patients 1 and 2. This case series illustrates the variability of RAPSN early-onset CMS, with patient 3, despite severe onset, revealing an almost complete reversal of myasthenic symptoms, not limited to apneic episodes. Moreover, it suggests that RAPSN CMS may be underdiagnosed in non-European countries.

Clinical and imaging hallmarks of the MYH7-related myopathy with severe axial involvement.

INTRODUCTION: MYH7 gene mutations are related to a heterogeneous group of skeletal and cardiac myopathies. METHODS: We evaluated clinical and muscle MRI changes in patients with mutations in the rod domain of MYH7, including 1 with mosaicism and 3 with novel missense mutations. RESULTS: Patients presented in childhood with a distal and axial phenotype. Biopsy findings were variable. Half of the cases displaying some type of core pathology, including minicores and eccentric cores. Most patients demonstrated internal bands of infiltration ("inverted-collagen-VI sign") in multiple muscles, particularly the soleus, and prominent atrophy and fatty infiltration of the tongue and the paraspinal, gluteus minimus, sartorius, gracilis, tibialis anterior, and extensor digitorum longus muscles. DISCUSSION: Muscle imaging findings in patients with axial involvement provide significant clues permitting the distinction between MYH7-related myopathies and other axial myopathies such as those related to SEPN1 and LMNA genes. Muscle Nerve 58: 224-234, 2018.