RESUMO
OBJECTIVE: To investigate the involvement of the epidermal small sensory fibers in the neurodegenerative process in amyotrophic lateral sclerosis (ALS). METHODS: In the present study, skin biopsies of 28 patients with ALS were obtained at an average of 34 months after disease onset by history. Protein gene product 9.5 (PGP9.5) immunohistochemistry findings were compared to 17 age-matched controls. The primary endpoint of the study was to evaluate the decrease in the density of small intraepidermal nerve fibers and to compare the prevalence of small-fiber neuropathy in patients with ALS and in controls. RESULTS: We found a significant reduction in epidermal nerve fiber density in the distal calf of patients with ALS (4.8 ± 3.7 fibers/mm vs 12.2 ± 4.6 in age-matched controls, p<0.0001). The extent of fiber loss was age-dependent. Also, the number of subjects with small-fiber neuropathy was significantly higher in the ALS group than in the controls (79% vs 12%). Correspondingly, mild sensory symptoms including diffuse dysesthesias, paresthesias, and hypesthesia were found in 7 patients. In 17 biopsies of patients with ALS, but only in 2 controls, we saw larger (>1.5 µm in diameter) focal swellings of epidermal axons resembling spheroids, suggesting trafficking defects. CONCLUSIONS: These results indicate that small, distal epidermal nerve fibers are involved in this disease, supporting the concept of distal axonopathy in ALS.
Assuntos
Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/epidemiologia , Doenças do Sistema Nervoso Periférico/epidemiologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/patologia , Feminino , Neuropatia Hereditária Motora e Sensorial/epidemiologia , Neuropatia Hereditária Motora e Sensorial/etiologia , Neuropatia Hereditária Motora e Sensorial/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/epidemiologia , Doença dos Neurônios Motores/etiologia , Doença dos Neurônios Motores/patologia , Fibras Nervosas Mielinizadas/patologia , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/patologia , Células Receptoras Sensoriais/patologia , Dermatopatias/epidemiologia , Dermatopatias/etiologia , Dermatopatias/patologiaRESUMO
Weight loss is a common phenomenon and an independent prognostic factor in amyotrophic lateral sclerosis (ALS). Several potential causal mechanisms, including intrinsic hypermetabolism and deficient food intake, have been discussed. We investigated the influence of fasting serum glucose, cholesterol, and triglyceride levels at time of diagnosis on survival in ALS. Serum cholesterol (LDL, HDL, and LDL/HDL ratio), triglycerides, and glucose were investigated in 488 patients (age of onset = 57.6 ± 12.6 years) in relation to survival and revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS-FRS) data. High serum levels of both fasting cholesterol and triglycerides had a significantly positive effect on survival (p < 0.05). We found a median prolonged life expectancy by 14 months for patients with serum triglyceride levels above the median of 1.47 mmol/l. The results suggest that the lipid metabolism and the nutritional status of ALS patients are important prognostic factors. These parameters should be thoroughly monitored during the clinical management of these patients. In case of progressive loss of body weight, a diet rich in lipids and calories should be considered. However, the final decision whether a lipid-rich diet should be recommended to ALS patients can only be based on a double-blind placebo-controlled interventional trial. Our results further imply that lipid-lowering drugs, e.g., statins, should be applied carefully in ALS patients although individual risk considerations must be made.
Assuntos
Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/mortalidade , Colesterol/sangue , Triglicerídeos/sangue , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
BACKGROUND: In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), CSF biomarkers are increasingly studied to evaluate their relevance for differential diagnosis, disease progression, and understanding of pathophysiologic processes. OBJECTIVE: To identify a biomarker profile of neuronal and glial CSF proteins to discriminate ALS from other motor neuron diseases (MND) and to assess whether baseline levels of CSF measures in ALS are associated with the course of the disease. METHODS: A total of 122 consecutive subjects with MND were included in this cross-sectional study (ALS, n = 75; lower motor neuron syndrome, n = 39; upper motor neuron diseases, n = 8). Clinical follow-up included 76 patients. We determined baseline levels of protein tau and astroglial S100beta in CSF and microglial sCD14 in CSF and serum in relation to diagnosis, duration of disease, and survival. RESULTS: CSF tau was significantly elevated in ALS and upper motor neuron diseases as compared to lower motor neuron diseases and controls. CSF S100beta levels were significantly lower in lower motor neuron diseases as compared to other MND. CSF concentrations of S100beta and sCD14 correlated with the survival time in patients with ALS. CONCLUSIONS: In motor neuron diseases, CSF tau elevation indicates the degeneration of upper motor neurons, while S100 beta and sCD14 may indicate the activation of CNS glial cells. Because S100beta and sCD14 concentrations correlate with survival in amyotrophic lateral sclerosis (ALS), we suppose that the combination of both markers may be useful to obtain prognostic information in patients with ALS.
Assuntos
Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Fatores de Crescimento Neural/líquido cefalorraquidiano , Proteínas S100/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/mortalidade , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Feminino , Seguimentos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/sangue , Doença dos Neurônios Motores/líquido cefalorraquidiano , Fatores de Crescimento Neural/sangue , Prognóstico , Curva ROC , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/sangue , Taxa de Sobrevida , Proteínas tau/sangueRESUMO
Lipodystrophies represent a heterogeneous group of diseases characterized by altered body fat repartition and often metabolic alterations. Here we illustrate a 20 year old male with myositis in association with localized lipodystrophy. Immunohistochemical stainings revealed a regular pattern of dystrophin, dysferlin, sarcoglycans, and theletonin. Furtermore, there was no evidence of Lamin A/C deficiency. A nearly identical clinical and histological picture has been described in three patients up to now. Although it is difficult to speculate on a causative pathophysiological mechanism at this time, it is possible that this association represents an unrecognized condition.
Assuntos
Lipodistrofia/complicações , Miosite/etiologia , Adulto , Biomarcadores/metabolismo , Nádegas , Relação CD4-CD8 , Disferlina , Distrofina/metabolismo , Humanos , Lipodistrofia/tratamento farmacológico , Lipodistrofia/patologia , Masculino , Proteínas de Membrana/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Miosite/tratamento farmacológico , Miosite/patologia , Prednisolona/uso terapêutico , Sarcoglicanas/metabolismo , Falha de TratamentoRESUMO
OBJECTIVE: Hereditary spastic paraplegias (HSP) are genetically exceedingly heterogeneous. To date, 37 genetic loci for HSP have been described (SPG1-41), among them 16 loci for autosomal dominant disease. Notwithstanding, further genetic heterogeneity is to be expected in HSP, as various HSP families do not link to any of the known HSP loci. In this study, we aimed to map the disease locus in a German family segregating autosomal dominant complicated HSP. METHODS: A genome-wide linkage analysis was performed using the GeneChip Mapping 10Kv2.0 Xba Array containing 10,204 SNP markers. Suggestive loci were further analyzed by mapping of microsatellite markers. RESULTS: One locus on chromosome 12q23-24, termed SPG36, was confirmed by high density microsatellite fine mapping with a significant LOD score of 3.2. SPG36 is flanked by markers D12S318 and D12S79. Linkage to SPG36 was excluded in >20 additional autosomal dominant HSP families. Candidate genes were selected and sequenced. No disease-causing mutations were identified in the coding regions of ATXN2, HSPB8, IFT81, Myo1H, UBE3B, and VPS29. SPG36 is complicated by a sensory and motor neuropathy; it is therefore the eighth autosomal dominant subtype of complicated HSP. CONCLUSION: We report mapping of a new locus for autosomal dominant hereditary spastic paraplegia (HSP) (SPG36) on chromosome 12q23-24 in a German family with autosomal dominant HSP complicated by peripheral neuropathy.
Assuntos
Cromossomos Humanos Par 12/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Doenças do Sistema Nervoso Periférico/genética , Paraplegia Espástica Hereditária/genética , Adulto , Idoso , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , Testes Genéticos , Genótipo , Alemanha , Humanos , Padrões de Herança/genética , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Mutação/genética , Fases de Leitura Aberta/genética , Linhagem , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Progressive infantile spastic tetraparesis spans a wide spectrum of partially rare differential diagnoses. Based on a clinical example the differential diagnostic thoughts are discussed in detail. Though juvenile motor neuron disease is a rare entity, it has to be kept in mind for differential diagnostics in cases of slowly progressive spastic tetraparesis, especially when a pseudobulbar palsy or distal amyotrophies add to the clinical picture. Electromyography can be helpful for early detection of lower motor neuron involvement. The glutamate antagonist riluzole slows the disease progression, but a causal treatment is not available, yet. Therefore symptomatic treatment of disturbing symptoms like muscle cramps, spasticity, pseudobulbar affect, dyspnea or dysphagia are of major interest.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Quadriplegia/diagnóstico , Adulto , Idade de Início , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/fisiopatologia , Diagnóstico Diferencial , Eletromiografia , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Quadriplegia/genética , Quadriplegia/fisiopatologiaRESUMO
Here we illustrate a 74-year-old patient presenting with clinical signs of slowly progressive motor neuron disease. After electromyography demonstrated myopathic changes, a skeletal muscle biopsy was performed showing histological signs of granulomatous myositis. In extensive diagnostic workup underlying primary granulomas forming diseases were excluded and corticoid therapy was initiated, but without clinical effect. We want to point out that granulomatous myositis should be considered in the differential diagnosis of slowly progressive motor neuron diseases, especially in atypical clinical presentations.
Assuntos
Granuloma/diagnóstico , Miosite/diagnóstico , Idoso , Biópsia , Diagnóstico Diferencial , Feminino , Granuloma/metabolismo , Humanos , Imageamento por Ressonância Magnética , Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/patologia , Músculo Esquelético/patologia , Miosite/metabolismo , Neurônios/metabolismo , Sarcoidose/diagnósticoRESUMO
Granulomatous myositis is a rare neuromuscular disorder histologically characterized by the development of endomyseal and/or perimyseal granulomas. Clinical hallmarks are generalized muscle weakness, myalgias, and bulbar symptoms. The association of granulomatous myositis with sarcoidosis is well known; less recognized is the association with several infectious diseases, inflammatory bowel diseases, malignancy, thymoma, graft-vs-host disease, and myasthenia gravis. In absence of sarcoidosis or other underlying disorders, the diagnosis of isolated or primary granulomatous myositis must be considered. Therapeutic strategies focus on immunosuppression, whereas the therapy response is unpredictable. Here we discuss the clinical features, diagnosis, and differential diagnosis and therapeutic strategies of primary and secondary granulomatous myositis.
Assuntos
Granuloma/diagnóstico , Miosite/diagnóstico , Idoso , Biópsia , Transtornos de Deglutição/etiologia , Diagnóstico Diferencial , Feminino , Granuloma/etiologia , Granuloma/patologia , Humanos , Imageamento por Ressonância Magnética , Cãibra Muscular/etiologia , Debilidade Muscular/etiologia , Músculo Esquelético/patologia , Miosite/etiologia , Miosite/patologia , Exame Neurológico , Fatores de RiscoAssuntos
Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Doença dos Neurônios Motores/genética , Insuficiência Respiratória/genética , Paralisia Respiratória/genética , Atrofias Musculares Espinais da Infância/genética , Fatores de Transcrição/genética , Adulto , Idade de Início , Criança , Feminino , Testes Genéticos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/diagnóstico , Exame Neurológico , Fenótipo , Polimorfismo Genético/genética , Insuficiência Respiratória/diagnóstico , Paralisia Respiratória/diagnóstico , Atrofias Musculares Espinais da Infância/diagnósticoRESUMO
OBJECTIVES: Magnetic resonance imaging (MRI) is considered the most sensitive modality for evaluating spinal epidural lipomatosis (SEL) in vivo. The aim of this study was to compare the existing MRI classifications of SEL and to reevaluate the clinico-radiological correlation of SEL as a pathological entity. MATERIALS AND METHODS: Measurements of the cervical, thoracic and lumbar spine were performed in a retrospective setting within 1406 data sets from the digital MRI archives. RESULTS: It could be shown that the existing MRI classifications developed for different spinal regions complemented each other. However, there was no distinct correlation of these MRI findings with clinical symptoms because other morphological changes existed that probably caused the patients' complaints. CONCLUSION: Existing SEL classifications developed either for the lumbar or the thoracic spine were found to be applicable to both regions, but the very vague association with clinical symptoms should caution against premature conclusions with respect to the clinical significance of SEL.
Assuntos
Lipomatose/classificação , Lipomatose/diagnóstico , Imageamento por Ressonância Magnética , Doenças da Coluna Vertebral/classificação , Doenças da Coluna Vertebral/diagnóstico , Espaço Epidural , Feminino , Humanos , Lipomatose/patologia , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sacro/patologia , Doenças da Coluna Vertebral/patologiaRESUMO
In 9 patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with a P301S tau mutation, the predominant phenotype was frontotemporal dementia in 3 and parkinsonism in 6. Comparison of the tau genotype/haplotype carrying the mutation and the initial clinical sign showed association between H1/H1 and parkinsonism and between H1/H2 and personality change. Thus, the tau haplotype carrying the mutation and the tau genotype may be related to the clinical phenotype throughout the disease course.
Assuntos
Cromossomos Humanos Par 17/genética , Degeneração Lobar Frontotemporal/genética , Ligação Genética , Mutação/genética , Transtornos Parkinsonianos/genética , Proteínas tau/genética , Adulto , Feminino , Degeneração Lobar Frontotemporal/patologia , Genótipo , Haplótipos/genética , Humanos , Masculino , Transtornos Parkinsonianos/patologia , Adulto JovemRESUMO
Central core myopathy is a nonprogressive or only slowly progressive congenital muscle disease. In most cases, symptoms begin in childhood, but rare cases with adult onset are described. Regardless of its high variability, the clinical hallmarks are diffuse muscle weakness and the development of multiple bone deformities and contractures. Skeletal muscle biopsy is of high diagnostic significance. Due to a potential association with malignant hyperthermia, early diagnosis is of great importance. A curative treatment is not currently known. Here we discuss aetiology, pathogenesis, clinical features, diagnosis, differential diagnosis, therapeutic strategies, and prognosis of central core myopathy based on a clinical example with an atypical onset of symptoms in adulthood.
Assuntos
Anormalidades Múltiplas/diagnóstico , Osso e Ossos/anormalidades , Debilidade Muscular/diagnóstico , Miopatia da Parte Central/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Debilidade Muscular/terapia , Miopatia da Parte Central/terapiaRESUMO
After the oral administration of the COX 2 inhibitor rofecoxib (Vioxx) as part of an oral provocation test, a 64-year-old woman developed acute anterograde and retrograde amnesia which lasted for several hours. The patient did not show symptoms of anaphylaxis. Neurological examination did not reveal focal symptoms or an epileptic seizure. Diffusion-weighted magnetic resonance imaging only showed a small region of increased signal intensity in the left hippocampus. The patient thus had no anaphylactic drug reaction, but a transient global amnesia (TGA) or amnestic episode. TGA is an acute, reversible, cerebral dysfunctional state which lasts from 1 h up to maximally 24 h and which is associated with anterograde and retrograde amnesia. While about half of the cases appear to occur spontaneously, other cases are preceded by physically or emotionally stressful events. In our patient it may have been the emotional distress caused by the oral provocation testing that has triggered the TGA. When TGA occurs during oral challenge of drugs, we recommend repeating the oral challenge of the tested drug.
Assuntos
Amnésia Global Transitória/induzido quimicamente , Anti-Inflamatórios não Esteroides/efeitos adversos , Lactonas/efeitos adversos , Sulfonas/efeitos adversos , Urticária/induzido quimicamente , Administração Oral , Amnésia Global Transitória/diagnóstico , Anti-Inflamatórios não Esteroides/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hipocampo/patologia , Humanos , Lactonas/uso terapêutico , Memória de Curto Prazo/efeitos dos fármacos , Pessoa de Meia-Idade , Sulfonas/uso terapêutico , Urticária/diagnósticoRESUMO
Neuronal ceroid lipofuscinoses are a heterogenous group of genetic progressive neurodegenerative disorders. Curative therapeutic strategies are not known. These are largely diseases of childhood; adult-onset forms are rare and poorly characterized. The classical adult variant is CLN4 (Kufs' disease), in which autosomal-recessive and autosomal dominant forms are known. Furthermore the "classic infantile" CLN1, caused by a deficiency of the enzyme palmitoylprotein-thioesterase, may be of adult onset Neuronal ceroid lipofuscinoses in adulthood are multifaceted diseases. Their clinical picture is mainly characterized by progressive dementia, seizures, and extrapyramidal motor symptoms. In contrast to the infantile forms, visual loss is an uncommon feature that appears only in adult CLN1 but not CLN4, which may be helpful in clinical differential diagnosis.
Assuntos
Demência/diagnóstico , Lipofuscinoses Ceroides Neuronais/classificação , Lipofuscinoses Ceroides Neuronais/diagnóstico , Convulsões/diagnóstico , Transtornos da Visão/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , MasculinoRESUMO
Benign symmetric lipomatosis, also called Madelung's disease, is characterized by lipomata and fatty infiltrations. Involvement of the nervous system has occasionally been described, mitochondrial dysfunctions have been suggested. We report a 55 year old male suffering from benign symmetric lipomatosis with associated axonal neuropathy and hyperlipoproteinemia. He showed a remarkable phenotype of neuropathy i.e. no sensory disturbance, ubiquitous fasciculations and muscle cramps, furthermore reduced COX activity and abnormalities in specific mitochondrial tRNA regions.
Assuntos
Axônios/fisiologia , Hiperlipoproteinemias/genética , Lipomatose Simétrica Múltipla/genética , Doenças do Sistema Nervoso Periférico/genética , RNA de Transferência/genética , RNA/genética , Humanos , Hiperlipoproteinemias/complicações , Lipomatose Simétrica Múltipla/complicações , Masculino , Pessoa de Meia-Idade , Mutação , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/fisiopatologia , RNA MitocondrialRESUMO
BACKGROUND: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease. The most frequent cause of autosomal dominant HSP is mutation of SPAST (SPG4 locus), but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4. OBJECTIVE: To determine the frequency of genomic copy number aberrations of SPAST in autosomal dominant HSP. METHODS: We developed and validated a multiplex ligation-dependent probe amplification assay targeting SPAST and SPG3A, another gene frequently involved in autosomal dominant HSP. In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP, all of whom had previously been screened negative for SPAST mutations. Independent secondary samples, additional family members, and cDNA were analyzed to confirm positive findings. RESULTS: Aberrant MLPA profiles were identified in 12 cases (18%). They exclusively affect SPAST, represent deletions, segregate with the disease, and are largely pedigree specific. Internal SPAST deletions entail expression of correspondingly shortened transcripts, which vary in stability. Age at onset in SPAST deletion carriers does not differ from that associated with other SPAST mutations. CONCLUSIONS: Partial SPAST deletions, but not SPAST amplifications and SPG3A copy number aberrations, represent an underestimated cause of autosomal dominant hereditary spastic paraplegia. Partial SPAST deletions are likely to act via haploinsufficiency.
Assuntos
Adenosina Trifosfatases/genética , Deleção de Genes , Frequência do Gene/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Criança , Dosagem de Genes/genética , Haploidia , Humanos , Pessoa de Meia-Idade , Linhagem , EspastinaRESUMO
Hereditary spastic paraparesis (HSP) is a heterogeneous group of neurodegenerative disorders with progressive lower limb spasticity, categorized into pure (p-HSP) and complicated forms (c-HSP). The purpose of this study was to evaluate if brain volumes in HSP were altered compared with a control population. Brain volumes were determined in patients suffering from HSP, including both p-HSP (n = 21) and c-HSP type (n = 12), and 30 age-matched healthy controls, using brain parenchymal fractions (BPF) calculated from 3D MRI data in an observer-independent procedure. In addition, the tissue segments of grey and white matter were analysed separately. In HSP patients, BPF were significantly reduced compared with controls both for the whole patient group (P < 0.001) and for both subgroups, indicating considerable brain atrophy. In contrast to controls who showed a decline of brain volumes with age, this physiological phenomenon was less pronounced in HSP. Therefore, global brain parenchyma reduction, involving both grey and white matter, seems to be a feature in both subtypes of HSP. Atrophy was more pronounced in c-HSP, consistent with the more severe phenotype including extramotor involvement. Thus, global brain atrophy, detected by MRI-based brain volume quantification, is a biological marker in HSP subtypes.
Assuntos
Encéfalo/patologia , Imageamento Tridimensional/métodos , Paraplegia Espástica Hereditária/patologia , Adulto , Fatores Etários , Atrofia/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Myocardial involvement in motor neuron diseases (MND) is an uncommon feature. In amyotrophic lateral sclerosis (ALS) abnormalities of the autonomic nervous system affecting cardiac function have been described, for the hereditary spastic paraplegias (HSP) comparable manifestations are unknown. This study observed ALS and HSP patients with coexisting cardiomyopathy without major cardial risk factors. METHODS: Four patients with definite ALS and two pHSP patients. In all patients detailed clinical, cardiological, electrophysiological and laboratory data were analysed. In two ALS patients skeletal muscle biopsy was performed. RESULTS: In all investigated MND patients cardiomyopathy was present. Beside hyperlipoproteinaemia and mild hypertension in one case, none of the patients showed major cardiovascular risk factors. There was no evidence for a secondary cause of cardiomyopathy like coronary heart disease, myocarditis, or mitochondrial damage mimicking MND. CONCLUSION: This report could not conclude that the occurrence of cardiomyopathy is rare logically. Although an underlying pathophysiological cause was not obvious, it is proposed that in all MND patients a routine cardiological evaluation should be performed.