RESUMO
AIMS: Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. METHODS: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. RESULTS: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. CONCLUSIONS: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.
Assuntos
Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Músculo Esquelético/patologia , Adolescente , Adulto , Idoso , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/ultraestrutura , Fenótipo , Adulto JovemRESUMO
In this article we address the relevance of rare diseases and their peculiarities with respect to pain therapy. Towards this end, four rare diseases (hemophilia, Morbus Fabry, dermatomyositis, and facioscapulohumeral dystrophy (FSHD)) will be presented and fundamental aspects of their pain therapies described. The diseases were chosen to showcase a pain therapy based on the WHO-step-by-step plan (hemophilia), a complex but established pain therapy (M. Fabry), and two less well established, individually adapted pain therapies (dermatomyositis, FSHD).
Assuntos
Distrofia Muscular Facioescapuloumeral , Manejo da Dor , Doenças Raras , Humanos , Distrofia Muscular Facioescapuloumeral/terapia , Doenças Raras/complicaçõesRESUMO
As Pompe disease glycogen storage disease type 2 with a severely reduced life expectancy is now a treatable disorder, accurate diagnostic procedures and evidence-based indications for therapy are mandatory. We screened the literature for consensus reports and published trial data of late-onset Pompe disease. These data were summarized in a Delphi consensus method approach. The clinical suspicion of late-onset Pompe disease should be substantiated by the validated dry blood spot test measurement for acid α-glucosidase activity. Alternatively, enzyme activity analysis in lymphocytes is also feasible. Glucosidase α gene sequencing for verifying the diagnosis is recommended. A muscle biopsy including measurements of acid α-glucosidase activity and glycogen concentration is warranted for differential diagnosis in selected cases. The confirmed diagnosis should lead to a multidisciplinary treatment approach, possibly including enzyme replacement therapy.
Assuntos
Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Adulto , Fatores Etários , Biópsia , Comportamento Cooperativo , Estudos Transversais , Técnica Delphi , Diagnóstico Diferencial , Doença de Depósito de Glicogênio Tipo II/epidemiologia , Fidelidade a Diretrizes , Humanos , Comunicação Interdisciplinar , Imageamento por Ressonância Magnética , Músculo Esquelético/patologia , Exame Neurológico , Ensaios Clínicos Controlados Aleatórios como Assunto , alfa-Glucosidases/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Myotonic dystrophy type 2 (DM2) is an adult-onset progressive multisystem disease. There have been no reported risks for anesthesia in DM2. METHODS: We assess the frequency, type, and severity of peri-operative complications under general and local anesthesia in genetically proven DM2. A retrospective multicenter study was conducted. RESULTS: Out of 320 DM2 patients, 134 participated by completing questionnaires (41, 88%), which were delivered by mail, and their clinical records were reviewed (class III evidence). A total of 121 patients had 340 operations in general anesthesia at an average age of 40.5 years (range 18-82); 132 (38.8%) general anesthesia were performed prior to DM2 onset, 187 (55.9%) after disease onset. A total of 212 (62.4%) of the interventions were performed without known DM2 diagnosis. In 120 (35.3%) interventions, DM2 was already diagnosed. The locations of surgery were lower abdomen (47%), peripheral extremities (46.8%), upper abdomen (3.8%), thorax (1.8%), and brain (0.6%). The overall frequency of severe complications was 0.6% (2 of 340). One incident was a post-operative development of rhabdomyolysis, hyperthermia, muscle weakness and renal failure; the others, prolonged muscular weakness and renal failure. Minor complications related to a general anesthesia were reported by 27 participants (20.2%). In 116 patients (86.6%), 342 interventions were performed in regional anesthesia. Minor complications were reported by 20.2% participants such as nausea (6.7%), muscular weakness and pain (5.9%), prolonged anesthesia (5.2%), circulatory insufficiency (2.9%), and shortness of breath (2.9%). CONCLUSION: The overall lower risk seems to be predominantly related to the minor respiratory involvement in DM2, than in myotonic dystrophy type 1 (DM1).
Assuntos
Anestesia Geral/efeitos adversos , Anestesia Local/efeitos adversos , Distrofia Miotônica/complicações , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: Muscle magnetic resonance imaging (MRI) is the most sensitive method in the detection of dystrophic and non-dystrophic abnormalities within striated muscles. We hypothesized that in severe myotonia congenita type Becker muscle stiffness, prolonged transient weakness and muscle hypertrophy might finally result in morphologic skeletal muscle alterations reflected by MRI signal changes. AIM OF THE STUDY: To assess dystrophic and/or non-dystrophic alterations such as fatty or connective tissue replacement and muscle edema in patients with severe recessive myotonia congenita. METHODS: We studied three seriously affected patients with myotonia congenita type Becker using multisequence whole-body high-field MRI. All patients had molecular genetic testing of the muscle chloride channel gene (CLCN1). RESULTS: Molecular genetic analyses demonstrated recessive CLCN1 mutations in all patients. Two related patients were compound heterozygous for two novel CLCN1 mutations, Q160H and L657P. None of the patients showed skeletal muscle signal changes indicative of fatty muscle degeneration or edema. Two patients showed muscle bulk hypertrophy of thighs and calves in line with the clinical appearance. CONCLUSIONS: We conclude that (i) chloride channel dysfunction alone does not result in skeletal muscle morphologic changes even in advanced stages of myotonia congenita, and (ii) MRI skeletal muscle alterations in myotonic dystrophy must be clear consequences of the dystrophic disease process.
Assuntos
Canais de Cloreto/genética , Genes Recessivos , Músculo Esquelético/patologia , Miotonia Congênita/genética , Miotonia Congênita/patologia , Tecido Adiposo/patologia , Adolescente , Adulto , Tecido Conjuntivo/patologia , Edema , Feminino , Humanos , Hipertrofia/patologia , Perna (Membro)/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação , LinhagemRESUMO
OBJECTIVES AND METHODS: Mutations in the gene encoding dysferlin cause limb girdle muscular dystrophy type 2B (LGMD2B), distal Miyoshi myopathy (MM), and a rare form of distal anterior compartment myopathy. To study the correlations between clinical manifestations and muscle imaging changes we conducted a 3.0-T magnetic resonance imaging (MRI) study in six German patients with primary dysferlinopathies defined by absence of dysferlin expression in muscle (MM, n = 3; LGMD2B, n = 2; hyperCKemia without clinical symptoms, n = 1). RESULTS: Patients with manifest myopathy had widespread muscular pathology. In analogy to previous imaging studies, we confirmed an involvement of the anterior and posterior thigh compartments and a predominant involvement of posterior lower legs. However, our whole-body MRI study further provided evidence of signal alterations in the glutei, erector spinae and shoulder girdle muscles. Correlation of clinical findings with imaging demonstrated the potential of MRI to detect subclinical muscle pathology. CONCLUSIONS: Whole-body 3.0-T MRI is a non-invasive method to demonstrate various degrees of skeletal muscle alterations and disease progression in muscular dystrophies. Furthermore, whole-body high-field MRI may serve as a helpful diagnostic tool in differentiating primary dysferlinopathies from other forms of LGMD and distal myopathies.
Assuntos
Miopatias Distais/patologia , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Adulto , Progressão da Doença , Miopatias Distais/genética , Disferlina , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Imagem Corporal TotalRESUMO
This case concerns a 17-year-old boy, who was given the diagnosis of Alpers syndrome only postmortem when a homozygous 1399G-->A (A467T) mutation was found in the linker-region of POLG1. Serial muscle and liver biopsies as well as brain MRI scans in our patient ranging from early childhood to postmortem analyses showed that (i) routine diagnostic procedures can be normal in the early stage of the disorder and that (ii) central nervous system and further organ affection may only develop in the time course of the disease. Consecutive diagnostic examinations clearly reflected the devastating clinical course and cerebral deterioration evolving over time in Alpers syndrome.
Assuntos
Encéfalo/patologia , DNA Polimerase Dirigida por DNA/genética , Esclerose Cerebral Difusa de Schilder , Hepatopatias/etiologia , Músculos/patologia , Mutação/genética , Adolescente , DNA Polimerase gama , Esclerose Cerebral Difusa de Schilder/complicações , Esclerose Cerebral Difusa de Schilder/patologia , Progressão da Doença , Humanos , Hepatopatias/genética , Imageamento por Ressonância Magnética , MasculinoRESUMO
BACKGROUND: The main symptom of chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS) are upper eyelid ptosis and a slowly progressive weakness of the extraocular muscles. Mitochondrial disorders are much more frequent than previously assumed. Because of great phenotypic variability, early diagnosis may prove to be difficult. MATERIAL AND METHODS: Retrospective analysis of 30 patients with CPEO or KSS with regard to ophthalmological and neurological findings as well as molecular genetic background. RESULTS: Twenty-seven patients presented with upper eyelid ptosis as the first clinical symptom. In 11 of these patients, ptosis was either unilateral or asymmetric. External ophthalmoplegia was present in only three patients initially; however, it developed in 27 patients in the later course of the disease. Diplopia was found to be more frequent than previously assumed. Twenty-six patients showed characteristic histological hallmarks in skeletal muscle biopsy. In 22 patients, molecular genetic testing revealed mitochondrial DNA mutations. CONCLUSIONS: Mitochondrial disorders should be included in the early differential diagnosis of patients with etiologically unclear acquired isolated unilateral or bilateral ptosis, atypical eye movement disorders, or diplopia. A correct diagnosis is mandatory for qualified counseling and the management of potentially life-threatening complications, such as cardiac involvement.
Assuntos
Síndrome de Kearns-Sayre/diagnóstico , Oftalmoplegia Externa Progressiva Crônica/diagnóstico , Equipe de Assistência ao Paciente , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Blefaroptose/etiologia , Criança , Deleção Cromossômica , Terapia Combinada , DNA Mitocondrial/genética , Feminino , Rearranjo Gênico/genética , Auxiliares de Audição , Humanos , Síndrome de Kearns-Sayre/genética , Síndrome de Kearns-Sayre/terapia , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmoplegia Externa Progressiva Crônica/terapia , Marca-Passo Artificial , Mutação Puntual/genética , Polimorfismo de Fragmento de Restrição/genética , Estudos Retrospectivos , Ubiquinona/uso terapêuticoRESUMO
In the present study we assessed the prevalence and nature of hearing loss in patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) due to single large-scale mitochondrial DNA (mtDNA) deletion or mtDNA tRNA (Leu (UUR)) A3243G point mutation (A3243G PM). 14 patients with mtDNA deletion and three patients with A3243G PM underwent audiological evaluation comprising pure-tone and speech audiometry as well as transient evoked otoacoustic emissions (OAE). Audiological evaluation revealed hearing impairment in 10/17 patients. Hearing loss was mild to moderate predominantly affecting high frequencies in five patients with subjective hearing problems (three patients with mtDNA deletions, two patients with A3243G PM). Subclinical hearing deficits restricted to high frequencies were seen in further five asymptomatic patients (four patients with mtDNA deletions, one patients with A3243G PM). Audiological findings suggested a cochlear origin of hearing loss in all subjects. Our results demonstrate that CPEO or KSS patients due to mtDNA deletion or A3243G PM are at high risk of developing sensorineural hearing deficits.
Assuntos
Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/etiologia , Síndrome de Kearns-Sayre/complicações , Oftalmoplegia Externa Progressiva Crônica/complicações , Adulto , Audiometria de Tons Puros , DNA Mitocondrial/genética , Potenciais Evocados Auditivos , Feminino , Deleção de Genes , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Síndrome de Kearns-Sayre/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Oftalmoplegia Externa Progressiva Crônica/fisiopatologia , Emissões Otoacústicas Espontâneas/fisiologia , PrevalênciaRESUMO
In order to study putative genotype phenotype correlations in mitochondrial disorders due to large-scale mtDNA deletions we performed a quantitative analysis of biochemical, morphological, and genetic findings in 20 patients. The size of the mtDNA deletions varied from 2 to 7.5 kb with a degree of heteroplasmy ranging from 16% to 78%. Applying improved methods for measuring respiratory chain enzyme activities, we found highly significant inverse correlations between the percentage of cytochrome c oxidase (COX)- negative fibers and citrate synthase (CS) normalized COX ratios. Significant correlations were also established between CS normalized complex I and complex IV ratios as well as between the degree of heteroplasmy of mtDNA deletions and the percentage of ragged red fibers, COX-negative fibers, and CS normalized complex I and complex IV ratios. Our results indicate that the degree of heteroplasmy of mtDNA deletions is mirrored on the histological as well as the biochemical level. Furthermore, our findings suggest that single large-scale deletions equally influence the activities of all mitochondrially encoded respiratory chain enzymes. Even low degrees of heteroplasmy of mtDNA deletions were found to result in biochemical abnormalities indicating the absence of any well-defined mtDNA deletion threshold in skeletal muscle.
Assuntos
DNA Mitocondrial/genética , Deleção de Genes , Mitocôndrias Musculares/genética , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/fisiopatologia , Músculo Esquelético/fisiopatologia , Adolescente , Adulto , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Síndrome de Kearns-Sayre/genética , Síndrome de Kearns-Sayre/metabolismo , Síndrome de Kearns-Sayre/patologia , Síndrome de Kearns-Sayre/fisiopatologia , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/patologia , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Oftalmoplegia Externa Progressiva Crônica/enzimologia , Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmoplegia Externa Progressiva Crônica/patologia , Oftalmoplegia Externa Progressiva Crônica/fisiopatologiaRESUMO
To assess dysphagia, the authors examined 12 patients with Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) deletion by videofluoroscopy and manometry. Cricopharyngeal achalasia was documented in nine of 12 patients (75%), whereas deglutitive coordination problems were found in one patient. Cricopharyngeal myotomy may be an effective treatment in selected cases with severe cricopharyngeal obstruction.
Assuntos
Transtornos de Deglutição/genética , Transtornos de Deglutição/fisiopatologia , Acalasia Esofágica/genética , Acalasia Esofágica/fisiopatologia , Esôfago/fisiopatologia , Encefalomiopatias Mitocondriais/complicações , Encefalomiopatias Mitocondriais/genética , Músculos Faríngeos/fisiopatologia , Adulto , DNA Mitocondrial/genética , Transtornos de Deglutição/etiologia , Esôfago/patologia , Feminino , Deleção de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Encefalomiopatias Mitocondriais/fisiopatologia , Músculos Faríngeos/patologiaRESUMO
OBJECTIVE: To report the metabotropic glutamate receptor 5 (mGluR5) as the autoantigen of antibodies from 2 patients with Hodgkin lymphoma (HL) and limbic encephalopathy (Ophelia syndrome). METHODS: Immunohistochemistry with brain tissue and cultures of rat hippocampal neurons were used to demonstrate antibodies. Immunoprecipitation, mass spectrometry, and mGluR5-null mice served to identify the antigen. HEK293 cells transfected with mGluR5 or mGluR1 were used to determine immunologic crossreactivity. RESULTS: Both patients developed symptoms consistent with limbic encephalopathy; one had MRI findings typical of this disorder and the other had more extensive radiologic involvement, including parietal and occipital cortex. Patients' sera had antibodies that predominantly reacted with the neuropil of hippocampus and cell surface of live hippocampal neurons. Immunoprecipitation from cultured neurons and mass spectrometry demonstrated that the antigen was mGluR5, a receptor involved in processes of learning and memory. The reactivity of patients' sera was abrogated in brain of mGluR5-null mice, further confirming the antibody specificity. Studies with a large number of controls including 2 patients with cerebellar ataxia and mGluR1 antibodies showed that mGluR5 was only identified by sera of the 2 patients with the Ophelia syndrome, and that despite the homology of this receptor with mGluR1 each autoantigen was specific for a distinct syndrome. CONCLUSIONS: Antibodies to mGluR5 should be considered in patients with symptoms of limbic encephalitis and HL (Ophelia syndrome). Recognition of this disorder is important because it can affect young individuals and is reversible.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Receptores de Glutamato Metabotrópico/imunologia , Adolescente , Animais , Células Cultivadas , Feminino , Células HEK293 , Hipocampo/citologia , Doença de Hodgkin/imunologia , Doença de Hodgkin/patologia , Humanos , Encefalite Límbica/imunologia , Encefalite Límbica/patologia , Masculino , Pessoa de Meia-Idade , Neurônios/citologia , Neurônios/metabolismo , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/genética , SíndromeAssuntos
Oftalmoplegia Externa Progressiva Crônica/genética , Polimorfismo Genético , RNA de Transferência de Leucina/genética , RNA/genética , Adolescente , Segregação de Cromossomos , Códon , Análise Mutacional de DNA , Feminino , Humanos , Músculo Esquelético/patologia , Oftalmoplegia Externa Progressiva Crônica/patologia , Mutação Puntual , RNA MitocondrialRESUMO
OBJECTIVE: To present 2 families with maternally inherited severe epilepsy as the main symptom of mitochondrial disease due to point mutations at position 616 in the mitochondrial tRNA(Phe) (MT-TF) gene. METHODS: Histologic stainings were performed on skeletal muscle slices from the 2 index patients. Oxidative phosphorylation activity was measured by oxygraphic and spectrophotometric methods. The patients' complete mitochondrial DNA (mtDNA) and the relevant mtDNA region in maternal relatives were sequenced. RESULTS: Muscle histology showed only decreased overall COX staining, while a combined respiratory chain defect, most severely affecting complex IV, was noted in both patients' skeletal muscle. Sequencing of the mtDNA revealed in both patients a mutation at position 616 in the MT-TF gene (T>C or T>G). These mutations disrupt a base pair in the anticodon stem at a highly conserved position. They were apparently homoplasmic in both patients, and had different heteroplasmy levels in the investigated maternal relatives. CONCLUSIONS: Deleterious mutations in the mitochondrial tRNA(Phe) may solely manifest with epilepsy when segregating to homoplasmy. They may be overlooked in the absence of lactate accumulation and typical mosaic mitochondrial defects in muscle.
Assuntos
DNA Mitocondrial/genética , Epilepsia/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Mutação/genética , RNA de Transferência de Fenilalanina/genética , Adolescente , Anticonvulsivantes/uso terapêutico , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Saúde da Família , Feminino , Humanos , Masculino , Músculo Esquelético/patologia , Polimorfismo de Fragmento de Restrição , Succinato Desidrogenase/metabolismo , Adulto JovemRESUMO
Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease. We here present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with various stages of disease severity. Alglucosidase alfa was given i.v. at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests (AFT), Walton Gardner Medwin scale (WGMS), timed 10-m walk tests, four-stair climb tests, modified Gowers' maneuvers, 6-min walk tests, MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels and SF-36 self-reporting questionnaires. All tests were performed at baseline and every 3 months for 12 months of ERT. We found significant changes from baseline in the modified Gowers' test, the CK levels and the 6-min walk test (341 +/- 149.49 m, median 342.25 m at baseline; 393 +/- 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests were unchanged. ERT over 12 months revealed minor allergic reactions in 10% of the patients. No serious adverse events occurred. None of the patients died or required de novo ventilation. Our clinical outcome data imply stabilization of neuromuscular deficits over 1 year with mild functional improvement.
Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Adulto , Idade de Início , Idoso , Creatina Quinase/metabolismo , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Doença de Depósito de Glicogênio Tipo II/enzimologia , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , População Branca , Adulto Jovem , alfa-Glucosidases/administração & dosagem , alfa-Glucosidases/efeitos adversosRESUMO
BACKGROUND: Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome c oxidase (COX)-deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease. METHODS: We reviewed the clinical, histochemical, and molecular genetics analysis of 33 unreported patients from 26 families together with all previous cases described in the literature to define the clinical phenotype associated with PEO1 mutations. RESULTS: Ptosis and ophthalmoparesis were almost universal clinical features among this cohort, with 52% (17/33) reporting fatigue and 33% (11/33) having mild proximal myopathy. Features consistent with CNS involvement were rarely described; however, in 24% (8/33) of the patients, cardiac abnormalities were reported. Mitochondrial histochemical changes observed in muscle showed remarkable variability, as did the secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Moreover, we report 7 novel PEO1 variants. CONCLUSIONS: Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of adPEO may well be underestimated. Direct sequencing of the PEO1 gene should be considered in adPEO patients prior to muscle biopsy.
Assuntos
DNA Helicases/genética , DNA Mitocondrial/genética , Mitocôndrias Musculares/genética , Músculo Esquelético/patologia , Oftalmoplegia Externa Progressiva Crônica/genética , Adolescente , Adulto , Idade de Início , Idoso , Criança , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/patologia , Proteínas Mitocondriais , Mutação/genética , Músculos Oculomotores/patologia , Oftalmoplegia Externa Progressiva Crônica/patologia , FenótipoRESUMO
To evaluate the potential value of somatostatin receptor scintigraphy (SRS) using 111In-DTPA (diethylenetriaminepenta acetic acid)-D-Phe1-octreotide (111In-pentetreotide) in patients with recurring or persisting symptoms of myasthenia gravis (MG), 14 consecutive cases with such supplemental receptor imaging during neurological routine follow-up were retrospectively evaluated in this study. All 14 patients underwent SRS in addition to chest computed tomography (CT). Mean follow-up after imaging was 34 months. Eight patients had previous thymectomy, and three patients were referred to surgery after scintigraphy and chest CT. SRS was positive in one of the 14 patients with local recurrence of thymoma and pleural invasion, and negative in the remaining 13 patients. CT was positive for thymoma in three patients, inconclusive in four patients and negative in seven patients. In conclusion, while SRS may be able to detect thymoma lesions including metastases, it seems of limited value in patients with inconspicuous CT findings. Our initial experience fails to point out a benefit of SRS in the management of persisting or recurring MG (with regard to detection of thymic disorders) compared to CT. Whether SRS is useful for differentiating thymoma from non-neoplastic thymic disease may be investigated by larger series. A predominant proportion of patients with unsatisfactory treatment response, however, continue to suffer an unfavourable clinical course despite absent evidence for thymic pathology.
Assuntos
Miastenia Gravis/diagnóstico por imagem , Receptores de Somatostatina/análise , Adulto , Idoso , Feminino , Seguimentos , Humanos , Radioisótopos do Iodo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Octreotida/análogos & derivados , Cintilografia , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
We report two patients with polyglycosan body disease manifesting in adulthood. Clinical, electrophysiological, and histopathological characteristics of their disorders are summarized, and diagnostic classification is discussed.
Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/deficiência , Sistema da Enzima Desramificadora do Glicogênio/deficiência , Doença de Depósito de Glicogênio Tipo III/genética , Doença de Depósito de Glicogênio Tipo IV/genética , Miosite de Corpos de Inclusão/genética , Enzima Ramificadora de 1,4-alfa-Glucana/genética , Idoso , Biópsia , Diagnóstico Diferencial , Feminino , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo III/diagnóstico , Doença de Depósito de Glicogênio Tipo III/patologia , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/patologia , Humanos , Masculino , Músculo Esquelético/patologia , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/patologia , Vacúolos/patologiaAssuntos
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Degeneração Neural/patologia , Nervo Sural/patologia , Capilares/metabolismo , Capilares/ultraestrutura , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Nervo Sural/metabolismoRESUMO
BACKGROUND: Patients with the karyotypic finding of a terminal deletion in the long arm of chromosome 18 (18q- syndrome) commonly display cerebral dysmyelination and developmental delay. To our knowledge, all reported cases characterized by molecular analysis who had no mental retardation as confirmed by neuropsychological testing had a chromosomal breakpoint within the two most distal bands, 18q22 or 18q23, leading to a deletion of 16 Mb or less. AIMS OF THE STUDY: It was the aim of this study to improve the karyotype-phenotype correlation in 18q- syndrome by thoroughly analyzing the deletion size and the mental and radiologic status in a 23-year-old woman with a terminal 18q deletion. We performed cytogenetic and molecular cytogenetic analysis, brain MRI, and extended neuropsychological testing. RESULTS: Molecular karyotyping revealed a 17 Mb deletion of terminal 18q with a breakpoint in 18q21.33 and no evidence for mosaicism. While brain MRI demonstrated severe global dysmyelination, the patient showed a neuropsychological pattern that allowed for normal psychosocial and job achievement. After delayed development in childhood, the patient caught up during puberty and showed normal verbal intelligence and skills at 23 years. However, visual, visual-spatial, visual-constructional, and executive functions were found to be severely impaired. CONCLUSION: Here, we present a patient with one of the largest terminal 18q deletions reported in an individual without obvious mental retardation. Our analysis extends the phenotypic spectrum for individuals with breakpoints in 18q21.33. In addition, this study highlights the fact that severe global dysmyelination may not be associated with general cognitive deficits.