Central Core Disease: Facial Weakness Differentiating Biallelic from Monoallelic Forms.

Central Core Disease (CCD) is a genetic neuromuscular disorder characterized by the presence of cores in muscle biopsy. The inheritance has been described as predominantly autosomal dominant (AD), and the disease may present as severe neonatal or mild adult forms. Here we report clinical and molecular data on a large cohort of Brazilian CCD patients, including a retrospective clinical analysis and molecular screening for RYR1 variants using Next-Generation Sequencing (NGS). We analyzed 27 patients from 19 unrelated families: four families (11 patients) with autosomal dominant inheritance (AD), two families (3 patients) with autosomal recessive (AR), and 13 sporadic cases. Biallelic RYR1 variants were found in six families (two AR and four sporadic cases) of the 14 molecularly analyzed families (~43%), suggesting a higher frequency of AR inheritance than expected. None of these cases presented a severe phenotype. Facial weakness was more common in biallelic than in monoallelic patients (p = 0.0043) and might be a marker for AR forms. NGS is highly effective for the identification of RYR1 variants in CCD patients, allowing the discovery of a higher proportion of AR cases with biallelic mutations. These data have important implications for the genetic counseling of the families.

Muscle fat replacement and modified ragged red fibers in two patients with reversible infantile respiratory chain deficiency.

Reversible infantile respiratory chain deficiency is a severe neonatal mitochondrial myopathy that resolves spontaneously. It is caused by the homoplasmic m.14674T>C mtDNA mutation and additional nuclear variants in genes interacting with mt-tRNAGlu have been detected in some patients. We present detailed clinical, imaging, and muscle biopsy findings in a boy and a girl with neonatal hypotonia, feeding difficulties, lactic acidosis, and ragged red fibers. Both patients show fat replacement on muscle imaging, which was mild in the boy, but severe in the girl, affecting mostly the posterior leg muscles. In addition to the homoplasmic m.14674T>C, both patients carried heterozygous variants in QRSL1 (c. 686T>G; p.Val299Gly) and EARS2 (c.358C>T; p.Arg120Trp), respectively. It is very important to recognize the clinical and morphological signs of reversible infantile respiratory chain deficiency as patients should receive intensive supportive care in the first 6 months of life. Understanding the mechanism of the spontaneous recovery may lead to novel therapeutic perspectives in other mitochondrial diseases.

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.

Limb Length Discrepancy on an 11-Month-Old Boy with Osteoid Osteoma.

Osteoid osteoma is a benign bone tumor that frequently occurs between the ages of 10 and 25 years old; in about 80% of the patients, it is associated with intense pain. The present article describes the case of an 11-month-old infant with claudication, right lower limb shortening, and painless right leg volume increase. Image studies demonstrated an osteolytic lesion with small ossifications within, involved by cortical thickening of the right tibial diaphysis. The diagnostic hypotheses were osteoid osteoma, chronic osteomyelitis (Brodie abscess), Ewing sarcoma, and Langerhans cell histiocytosis. Microorganism cultures were negative and the histopathological exam demonstrated osteoid osteoma. The present report expands the knowledge on osteoid osteoma as a cause of painless limping and lower limb shortening in infancy. The early differential diagnosis is important, as surgical excision is curative and prevents further complications.

Limb Length Discrepancy on an 11-Month-Old Boy with Osteoid Osteoma / Discrepância de membros em menino de 11 meses de idade associada a osteoma osteoide

Abstract Osteoid osteoma is a benign bone tumor that frequently occurs between the ages of 10 and 25 years old; in about 80% of the patients, it is associated with intense pain. The present article describes the case of an 11-month-old infant with claudication, right lower limb shortening, and painless right leg volume increase. Image studies demonstrated an osteolytic lesion with small ossifications within, involved by cortical thickening of the right tibial diaphysis. The diagnostic hypotheses were osteoid osteoma, chronic osteomyelitis (Brodie abscess), Ewing sarcoma, and Langerhans cell histiocytosis. Microorganismcultures were negative and the histopathological exam demonstrated osteoid osteoma. The present report expands the knowledge on osteoid osteoma as a cause of painless limping and lower limb shortening in infancy. The early differential diagnosis is important, as surgical excision is curative and prevents further complications.

Resumo Osteoma osteoide é umtumor ósseo benigno,mais frequentedos 10aos 25anos de idadee, em cerca de 80% dos pacientes, está associado a dor forte. O presente artigo descreve um pacientemasculino apresentando claudicação, encurtamento domembro inferior direito e aumento de volume indolor da perna direita desde os 11 meses de idade. Os exames de imagem demonstraram lesão osteolítica contendo pequenas ossificações de permeio, envolvidas por espessamento cortical da diáfise da tíbia direita. As hipóteses diagnósticas de osteoma osteoide, de osteomielite crônica (abscesso de Brodie), de sarcoma de Ewing e de histiocitose de células de Langerhans foram levantadas. As culturas para microrganismos foram negativas e o exame histopatológico demonstrou osteoma osteoide. O presente relato expande o conhecimento sobre osteoma osteoide como causa de claudicação e discrepância demembros inferiores indolor emlactente.Odiagnóstico diferencial precoce é importante, pois a exérese da lesão é curativa e previne sequelas futuras.

The relative frequency of common neuromuscular diagnoses in a reference center.

The diagnostic procedure in neuromuscular patients is complex. Knowledge of the relative frequency of neuromuscular diseases within the investigated population is important to allow the neurologist to perform the most appropriate diagnostic tests. OBJECTIVE: To report the relative frequency of common neuromuscular diagnoses in a reference center. METHODS: A 17-year chart review of patients with suspicion of myopathy. RESULTS: Among 3,412 examinations, 1,603 (46.98%) yielded confirmatory results: 782 (48.78%) underwent molecular studies, and 821 (51.21%) had muscle biopsies. The most frequent diagnoses were: dystrophinopathy 460 (28.70%), mitochondriopathy 330 (20.59%), spinal muscular atrophy 158 (9.86%), limb girdle muscular dystrophy 157 (9.79%), Steinert myotonic dystrophy 138 (8.61%), facioscapulohumeral muscular dystrophy 99 (6.17%), and other diagnoses 261 (16.28%). CONCLUSION: Using the presently-available diagnostic techniques in this service, a specific limb girdle muscular dystrophy subtype diagnosis was reached in 61% of the patients. A neuromuscular-appropriate diagnosis is important for genetic counseling, rehabilitation orientation, and early treatment of respiratory and cardiac complications.

The relative frequency of common neuromuscular diagnoses in a reference center / Frequência relativa de diagnósticos neuromusculares comuns em um serviço de referência

ABSTRACT The diagnostic procedure in neuromuscular patients is complex. Knowledge of the relative frequency of neuromuscular diseases within the investigated population is important to allow the neurologist to perform the most appropriate diagnostic tests. Objective: To report the relative frequency of common neuromuscular diagnoses in a reference center. Methods: A 17-year chart review of patients with suspicion of myopathy. Results: Among 3,412 examinations, 1,603 (46.98%) yielded confirmatory results: 782 (48.78%) underwent molecular studies, and 821 (51.21%) had muscle biopsies. The most frequent diagnoses were: dystrophinopathy 460 (28.70%), mitochondriopathy 330 (20.59%), spinal muscular atrophy 158 (9.86%), limb girdle muscular dystrophy 157 (9.79%), Steinert myotonic dystrophy 138 (8.61%), facioscapulohumeral muscular dystrophy 99 (6.17%), and other diagnoses 261 (16.28%). Conclusion: Using the presently-available diagnostic techniques in this service, a specific limb girdle muscular dystrophy subtype diagnosis was reached in 61% of the patients. A neuromuscular-appropriate diagnosis is important for genetic counseling, rehabilitation orientation, and early treatment of respiratory and cardiac complications.

RESUMO O procedimento diagnóstico neuromuscular é complexo. O conhecimento da frequência relativa das doenças neuromusculares em uma população é importante para utilização dos testes diagnósticos mais apropriados. Objetivo: Relatar a frequência relativa de doenças neuromusculares em um centro de referência. Métodos: Revisão de prontuários de pacientes com suspeita de miopatia em 17 anos. Resultados: Dentre 3412 exames, 1603 (46,98%) foram confirmatórios: 782 (48,78%) estudos moleculares e 821 (51,21%) biópsias musculares. Os diagnósticos mais frequentes foram: distrofinopatia 460 (28,70%), mitocondriopatia 330 (20.59%), atrofia muscular espinhal 158 (9,86%), distrofia muscular cintura-membros 157 (9,79%), distrofia miotônica de Steinert 138 (8,61%), distrofia muscular face-escápulo-umeral 99 (6,17%) e outros diagnósticos 261 (16,28%). Conclusão: Utilizando as técnicas diagnósticas atualmente disponíveis em nosso serviço, o diagnóstico específico do subtipo de distrofia muscular cintura-membros foi obtido em 61% dos pacientes. O diagnóstico neuromuscular apropriado é importante para o aconselhamento genético, orientações de reabilitação e tratamento precoce de complicações respiratórias e cardíacas.

Phenotypic Variability of Dystrophinopathy Symptomatic Female Carriers.

BACKGROUND: Dystrophinopathies are X-linked muscular dystrophies characterized by pathogenic mutations in the dystrophin gene. Symptomatic dystrophinopathy female carriers may present with limb-girdle weakness. The diagnosis may be challenging in the absence of affected male relatives. We aimed to describe the phenotypic variability in a series of molecular-confirmed female dystrophinopathy patients. METHODS: This is a retrospective analysis of medical records from 1997 to 2015. RESULTS: Ten female dystrophinopathy patients were selected, two with unusual phenotypes: one with early joint contractures muscular dystrophy and the other with very late onset myopathy. Muscle imaging studies demonstrated predominant asymmetric fat replacement. Muscle biopsy immunohistochemistry demonstrated clear mosaic pattern in two cases and only subtle reduction of dystrophin intensity in three. CONCLUSIONS: Adequate diagnosis is fundamental for genetic counseling and cardiologic follow-up. Female patients with dystrophinopathy may present unusual phenotypes such as early contractures and very late onset myopathy.

Limb girdle muscular dystrophy type 2G with myopathic-neurogenic motor unit potentials and a novel muscle image pattern.

BACKGROUND: Limb girdle muscular dystrophy type 2G (LGMD2G) is a subtype of autosomal recessive muscular dystrophy caused by mutations in the telethonin gene. There are few LGMD2G patients worldwide reported, and this is the first description associated with early tibialis anterior sparing on muscle image and myopathic-neurogenic motor unit potentials. CASE PRESENTATION: Here we report a 31 years old caucasian male patient with progressive gait disturbance, and severe lower limb proximal weakness since the age of 20 years, associated with subtle facial muscle weakness. Computed tomography demonstrated soleus, medial gastrocnemius, and diffuse thigh muscles involvement with tibialis anterior sparing. Electromyography disclosed both neurogenic and myopathic motor unit potentials. Muscle biopsy demonstrated large groups of atrophic and hypertrophic fibers, frequent fibers with intracytoplasmic rimmed vacuoles full of autophagic membrane and sarcoplasmic debris, and a total deficiency of telethonin. Molecular investigation identified the common homozygous c.157C > T in the TCAP gene. CONCLUSION: This report expands the phenotypic variability of telethoninopathy/ LGMD2G, including: 1) mixed neurogenic and myopathic motor unit potentials, 2) facial weakness, and 3) tibialis anterior sparing. Appropriate diagnosis in these cases is important for genetic counseling and prognosis.

Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype.

Common recessive limb girdle muscular dystrophies differential diagnosis: why and how? / Diagnóstico diferencial das distrofias musculares cintura-membros recessivas comuns: como e por quê?

Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype.

As distrofias musculares progressivas cintura-membros são desordens neuromusculares hereditárias autossômicas heterogêneas. Elas produzem alterações distróficas à biópsia muscular e estão associadas a mutações em diversos genes envolvidos na estrutura e função muscular. Fluxograma diagnóstico, fotos, tabelas e diagramas ilustrados dos aspectos clínicos, laboratoriais e de imagem são apresentados para o diagnóstico diferencial de distrofias musculares cintura-membros autossômicas recessivas comuns, diagnosticadas atualmente em um centro de referência no Brasil. Exames de imagem pré-operatórios direcionam o local da biópsia muscular. O padrão de envolvimento muscular difere de acordo com o subtipo de distrofia muscular cintura-membros. A substituição fibroadiposa do tecido muscular é mais acentuada no compartimento posterior da coxa na calpainopatia e proteinopatia relacionada à fukutina; anterior da coxa na sarcoglicanopatia; difusa na coxa na disferlinopatia e teletoninopatia. O diagnóstico diferencial preciso das distrofias musculares cintura-membros é importante para o aconselhamento genético, orientação prognóstica, tratamento cardíaco e respiratório. Além disso poderá, no futuro, provavelmente, propiciar terapias gênicas específicas para cada subtipo.

Schwannomatose - primeiros casos relatados no Brasil / Schwannomatosis - first reported cases in Brazil

A dor neuropática pode ser decorrente de diversas causas, entre elas a schwannomatose (SCH), uma doença que acomete cerca de cinco mil brasileiros. A SCH é caracterizada por schwannomas múltiplos e intensamente dolorosos. O diagnóstico diferencial de SCH inclui especialmente as neurofibromatoses do tipo 1 e 2. Um caso típico de SCH, provavelmente o primeiro registrado no Brasil, é apresentado e discutido em detalhes e dois outros casos subsequentes são comparados quanto a determinados aspectos clínicos e radiológicos. Paciente feminina de 33 anos de idade foi admitida com queixas de dor e diminuição progressivada força no membro inferior esquerdo, havia cinco anos, associadas ao surgimento de nodulações muito dolorosas naquela região. Apresentava também duas manchas café com leite (<1 cm). A RNM detectou tumores de partes moles em região subcutânea e intracavitárias. Foram realizadas duas biópsias em regiões distintas e o exame microscópico de dois nódulos revelou células de Schwann envoltas por abundante estroma mixóide. O exame imuno-histoquímico mostrou marcação forte e difusa para proteína S-100. O exame ultraestrutural demonstrou nas áreas centrais células de Schwann, com restos membranosos intracitoplasmáticos e, focalmente, membrana basal redundante. A sintomatologia álgica, o padrão de crescimento neoplásico intraneural, com acentuado edema peritumoral, hialinização vascular e reatividade imuno-histoquímica para proteína S-100 nas células de Schwann no centro das lesões possibilitaram o diagnóstico de schwannomatose. O tratamento farmacológico para a dor foi a opção possível, obtendo-se remissão parcial da dor...

Neuropathic pain stems various sources including schwannomatosis (SCH), a disease that affects about five thousand Brazilians. SCH is characterized by multiple and intensely painful schwannomas. Differential diagnosis of SCH includes, especially, neurofibromatosis types 1 and 2. A typical case of SCH, possibly the first recorded in Brazil, is presented and discussed in detail and compared with two other subsequent cases with regards to selected clinical and radiological aspects. A 33 year-old female patient was admitted with pain and progressive loss of strength in the left lower limb for the past five years. These complaints were associated withthe appearance of very painful nodules in the same region. She also had two light brown (café-au-lait) spots (<1 cm). MRI detected soft tissue tumors in the subcutaneous and intracavitary regions. Two distinct biopsies of different regions and microscopic examination of two nodulesrevealed Schwann cells surrounded by abundant myxoid stroma. Immunohistochemical examination showed strong and diffuse markers of S-100 protein. Ultrastructural examination showed Schwann cells in the core areas with traces of intracytoplasmic membranes and foci of redundant basement membrane. The pain symptoms, the pattern of intraneural neoplastic growth with marked peritumoral edema, vascular hyalinization, and immunohistochemical reactivity for S-100 protein in Schwann cells in lesion cores suggested the diagnosis of schwannomatosis. Pharmacological pain treatment achieved partial remission of pain...

Dificuldades diagnósticas no osteoma osteoide do cotovelo: estudo clínico, radiológico e histopatológico / Diagnostic difficulties in osteoid osteoma of the elbow: clinical, radiological and histopathological study

OBJETIVO: Descrever os aspectos clínicos e de imagem que podem auxiliar no diagnóstico correto do osteoma osteoide no cotovelo. MATERIAIS E MÉTODOS: Realizado estudo retrospectivo de sete pacientes com diagnóstico de osteoma osteoide no cotovelo confirmado histologicamente por biópsia óssea. Eles tiveram seus prontuários médicos e exames de imagem revisados. RESULTADOS: Do total de 142 pacientes identificados em nossos arquivos, 4,9 por cento apresentavam a lesão no cotovelo, com predomínio no sexo masculino (2,5:1) e idade média de 25 anos. Dor e limitação de movimento foram os sintomas mais comuns. Cinco pacientes (71,4 por cento) receberam outro diagnóstico clínico prévio. A duração média dos sintomas foi de 21 meses. As radiografias não demonstraram o nidus em 42,8 por cento dos casos. A tomografia computadorizada e a ressonância magnética mostraram claramente o nidus. Derrame articular foi um achado constante. O aspecto histológico observado foi o usual. A ressecção cirúrgica promoveu alívio dos sintomas e/ou melhora funcional em todos os casos. CONCLUSÃO: É importante considerar a possibilidade de osteoma osteoide em paciente adulto jovem com dor, limitação do movimento e sinais de sinovite no cotovelo, refratária ao tratamento conservador. Esclerose óssea, espessamento cortical e/ou reação periosteal detectados na radiografia permitem direcionar a tomografia computadorizada para a visualização precisa do nidus.

OBJECTIVE: To describe the clinical and imaging findings that may aid in correctly diagnosing osteoid osteoma of the elbow. MATERIALS AND METHODS: The authors have retrospectively evaluated seven patients diagnosed with osteoid osteoma of the elbow histologically confirmed by bone biopsy. The patients' medical records and imaging studies were reviewed. RESULTS: Among the 142 patients with osteoid osteoma identified in the archives of the institutions, 4.9 percent had the lesion in the elbow, predominantly in men (2.5:1), with a mean age of 25 years. Pain and limitation of movement were the most common symptoms. Five of the patients (71.4 percent) had previously received a different clinical diagnosis. The mean duration of symptoms was 21 months. Radiography did not demonstrate the nidus in 42.8 percent of cases. Computed tomography and magnetic resonance imaging clearly demonstrated the nidus. Joint effusion was a constant finding. The histological findings corresponded to the ones usually observed in such cases. Surgical resection has brought relief of symptoms and/or functional improvement in all of the cases. CONCLUSION: It is important to consider the possibility of osteoid osteoma in young adult patients with pain, limitation of movement and signs of synovitis in the elbow refractory to conservative treatment. The detection of bone sclerosis, cortical thickening and/or periosteal reaction at radiography allows directing computed tomography towards the accurate identification of the nidus.

Mastite granulomatosa / Granulomatous mastitis

A mastite granulomatosa, doença rara que acomete mulheres jovens em idade fértil, foi caracterizada pela primeira vez por Kessler e Wollocb, em 1972, como uma entidade definida, isolando-a de outras mastites com as quais muitas vezes era confundida. Poucos casos foram descritos na literatura estrangeira (pouco mais de 50 casos) e näo encontramo relato de nenhum cso na literatura nacional. Nosso objetivo é chamar a atençäo para esta entidade, que muitas vezes é clinicamente confundida com cacinoma e cujo diagnóstico é relativamente fácil e de prognóstico benigno

Importância da detecçåo do Mobiluncus sp. nas gardnereloses resistentes ao tratamento com metronidazol / The importance of Mobiluncus sp. detection in vaginal infections caused by Gardnerella sp. which are results to metronidazole

O objetivo principal do trabalho é ressaltar o papel do citopatologista na detecçåo do bacilo curvo, móvel, anaeróbico, Gram-negativo e Gram-variável (Mobiluncus sp.) nas vaginoses bacterianas associadas principalmente à gardnerelose resistente. De um total de 506 exames citológicos rotineiros, vistos em um mês, foram detectados 77 esfregaços com flora bacteriana sugestiva de Gardnerella vaginalis. Utilizando-se lente de imersåo (o que rotineiramente nåo é feito pelo citopatologista), foi possível verificar a associaçåo de Mobiluncus sp. em 25 destas pacientes, quatro delas com resistência ao tratamento com metronidazol