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PURPOSE OF REVIEW: Hereditary sensory and autonomic neuropathies (HSANs) are a clinically heterogeneous group of inherited neuropathies featuring prominent sensory and autonomic involvement. Classification of HSAN is based on mode of inheritance, genetic mutation, and phenotype. In this review, we discuss the recent additions to this classification and the important updates on management with a special focus on the recently investigated disease-modifying agents. RECENT FINDINGS: In this past decade, three more HSAN types were added to the classification creating even more diversity in the genotype-phenotype. Clinical trials are underway for disease-modifying and symptomatic therapeutics, targeting mainly HSAN type III. Obtaining genetic testing leads to accurate diagnosis and guides focused management in the setting of such a diverse and continuously growing phenotype. It also increases the wealth of knowledge on HSAN pathophysiologies which paves the way toward development of targeted genetic treatments in the era of precision medicine.
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Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Humanos , Mutação , FenótipoRESUMO
Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases. For this reason, our present proposals for updating and simplifying the classification of some of these conditions (Charcot-Marie-Tooth diseases, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, hereditary spastic ataxias, hereditary spastic paraplegias and hereditary spastic ataxias) are expounded here.
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Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Ataxia Cerebelar/classificação , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Estudos de Associação Genética , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Humanos , Mutação , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/classificação , Doenças Neurodegenerativas/genética , Paraplegia Espástica Hereditária/classificação , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genéticaRESUMO
Inherited neuropathy is a genetically and clinically heterogeneous group of neuropathies, the main category becomes Charcot-Marie-Tooth neuropathy (CMT), also known as hereditary motor and sensory neuropathy (HMSN), distal hereditary motor neuropathy (dHMN), and hereditary sensory autonomic neuropathy (HSAN). At least 80 genes have been associated with CMT, HMN or HSAN, a precise molecular diagnosis is often needed to make a clinical diagnosis accurately, enable genetic counseling of the patient and understanding of their molecular mechanisms. To identify the mutation in each patient, using a high-throughput NGS, we established a diagnostic procedure involving screening of disease causing genes in CMT, HMN or HSAN.
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Neuropatias Hereditárias Sensoriais e Autônomas/genética , Atrofia Muscular Espinal/genética , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Diagnóstico Diferencial , Testes Genéticos/métodos , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Humanos , Atrofia Muscular Espinal/classificação , Atrofia Muscular Espinal/diagnóstico , Patologia Molecular , Análise de Sequência de DNA/métodosRESUMO
Congenital insensitivity to pain is a rare hereditary sensory and autonomic neuropathy (HSAN). This disorder is an autosomal recessive condition: since 1996, mutations attributed to this entity have been found in the neurotrophin tyrosine-kinase gene receptor on chromosome 1. The authors report 3 cases of congenital insensitivity to pain. In these 3 sisters of consanguineous parents, the clinical investigation showed total absence of pain and temperature sensations with preservation of all other sensory modalities, mental retardation, but in contrast to HSAN type IV, there was no anhidrosis. The neurophysiological investigation revealed an isolated axonal sensory polyneuropathy in the 3 patients. The clinical and neurophysiological investigations were normal in both parents and the brother. The physiopathology of this entity is discussed. We suggest a particular form of HSAN type IV with preservation of transpiration or a new entity of congenital insensitivity to pain, which should be analyzed genetically.
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Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Insensibilidade Congênita à Dor/diagnóstico , Adolescente , Adulto , Criança , Consanguinidade , Deficiências do Desenvolvimento/etiologia , Feminino , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Humanos , Deficiência Intelectual/etiologia , Masculino , Marrocos , Condução Nervosa , Insensibilidade Congênita à Dor/classificação , Insensibilidade Congênita à Dor/genética , Linhagem , Polineuropatias/etiologia , Reflexo AnormalRESUMO
The inherited neuropathies are a clinically and genetically heterogeneous group of disorders in which there have been rapid advances in the last two decades. Molecular genetic testing is now an integral part of the evaluation of patients with inherited neuropathies. In this chapter we describe the genes responsible for the primary inherited neuropathies. We briefly discuss the clinical phenotype of each of the known inherited neuropathy subgroups, describe algorithms for molecular genetic testing of affected patients and discuss genetic counseling. The basic principles of careful phenotyping, documenting an accurate family history, and testing the available genes in an appropriate manner should identify the vast majority of individuals with CMT1 and many of those with CMT2. In this chapter we also describe the current methods of genetic testing. As advances are made in molecular genetic technologies and improvements are made in bioinformatics, it is likely that the current time-consuming methods of DNA sequencing will give way to quicker and more efficient high-throughput methods, which are briefly discussed here.
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Predisposição Genética para Doença/genética , Testes Genéticos , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Animais , Genótipo , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , HumanosRESUMO
Recessively transmitted predominantly motor neuropathies are rare and show a severe phenotype. They are frequently observed in populations with a high rate of consanguineous marriages. At least 15 genes and six loci have been found to be associated with autosomal recessive CMT (AR-CMT) and X-linked CMT (AR-CMTX) and also distal hereditary motor neuronopathy (AR-dHMN). These disorders are genetically heterogeneous but the clinical phenotype is relatively homogeneous. Distal muscle weakness and atrophy predominating in the lower extremities, diminished or absent deep tendon reflexes, distal sensory loss, and pes cavus are the main clinical features of this disorder with occasional cranial nerve involvement. Although genetic diagnosis of some of subtypes of AR-CMT are now available, rapid advances in the molecular genetics and cell biology show a great complexity. Animal models for the most common subtypes of human AR-CMT disease provide clues for understanding the pathogenesis of CMT and also help to reveal possible treatment strategies of inherited neuropathies. This chapter highlights the clinical features and the recent genetic and biological findings in these disorders based on the current classification.
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Neuropatias Hereditárias Sensoriais e Autônomas , Família Multigênica/genética , Animais , Aberrações Cromossômicas , Genes Recessivos , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/genética , HumanosRESUMO
Hereditary sensory and autonomic neuropathies (HSN/HSAN) are clinically and genetically heterogeneous disorders of the peripheral nervous system that predominantly affect the sensory and autonomic neurons. Hallmark features comprise not only prominent sensory signs and symptoms and ulcerative mutilations but also variable autonomic and motor disturbances. Autosomal dominant and autosomal recessive inheritance has been reported. Molecular genetics studies have identified disease-causing mutations in 11 genes. Some of the affected proteins have nerve-specific roles but underlying mechanisms have also been shown to involve sphingolipid metabolism, vesicular transport, structural integrity, and transcription regulation. Genetic and functional studies have substantially improved the understanding of the pathogenesis of the HSN/HSAN and will help to find preventive and causative therapies in the future.
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Neuropatias Hereditárias Sensoriais e Autônomas , Família Multigênica/genética , Mutação/genética , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Proteínas de Membrana/genética , Metiltransferases/genética , Receptor trkA/genéticaRESUMO
OBJECTIVE: To describe the clinical and neurophysiologic phenotype of a family with hereditary sensory and autonomic neuropathy type 1 (HSANI) due to a novel mutation in SPTLC2 and to characterize the biochemical properties of this mutation. METHODS: We screened 107 patients with HSAN who were negative for other genetic causes for mutations in SPTLC2. The biochemical properties of a new mutation were characterized in cell-free and cell-based activity assays. RESULTS: A novel mutation (A182P) was found in 2 subjects of a single family. The phenotype of the 2 subjects was an ulcero-mutilating sensory-predominant neuropathy as described previously for patients with HSANI, but with prominent motor involvement and earlier disease onset in the first decade of life. Affected patients had elevated levels of plasma 1-deoxysphingolipids (1-deoxySLs). Biochemically, the A182P mutation was associated with a reduced canonical activity but an increased alternative activity with alanine, which results in largely increased 1-deoxySL levels, supporting their pathogenicity. CONCLUSION: This study confirms that mutations in SPTLC2 are associated with increased deoxySL formation causing HSANI.
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Neuropatias Hereditárias Sensoriais e Autônomas/genética , Mutação/genética , Serina C-Palmitoiltransferase/genética , Esfingolipídeos/sangue , Adulto , Neuropatias Hereditárias Sensoriais e Autônomas/sangue , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Linhagem , Fenótipo , Análise de Sequência de DNARESUMO
Hereditary neuropathies belong to the most common neurogenetic disorders. They appear mostly as sensory and motor neuropathies but there are also pure sensory, pure motor as well as sensory and autonomic hereditary neuropathies. In clinical practice, knowledge of hereditary neuropathies is important in order to recognize them among polyneuropathies and achieve a successful genetic diagnosis. The molecular genetics of hereditary neuropathies are very heterogeneous with currently more than 40 known disease-causing genes. The 4 most common genes account for almost 90% of the genetically diagnosed hereditary neuropathies. In this review article we provide an overview of the currently known genes and propose a rational genetic work-up protocol of the most common genes.
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Doenças do Sistema Nervoso/genética , Algoritmos , Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Estudos Transversais , Avaliação da Deficiência , Testes Genéticos , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatia Hereditária Motora e Sensorial/classificação , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/epidemiologia , Neuropatia Hereditária Motora e Sensorial/genética , Humanos , Doenças do Sistema Nervoso/classificação , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/epidemiologia , Exame Neurológico , Polineuropatias/classificação , Polineuropatias/diagnóstico , Polineuropatias/epidemiologia , Polineuropatias/genética , PrognósticoRESUMO
Hereditary sensorimotor neuropathies, or Charcot-Marie-Tooth disease (CMT) comprise a group of diseases with heterogeneous clinical, electrophysiological and genetic expression. They are classified by the mode of inheritance (autosomal dominant, X-linked dominant, autosomal recessive) and their electrophysiological characteristics taking into account the speed of motor conduction of the median nerve (demyelinating, intermediary and axonal forms). Certain purely motor forms are called spinal CMT or hereditary distal motor neuropathy, or distal spinal amyotrophy. CMT involving an important sensorial component, trophic disorders, or signs of dysautonomia are included in the classification of hereditary sensory and autonomic neuropathies.
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Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , Fenômenos Eletrofisiológicos , Proteínas de Ligação ao GTP/genética , Genes Ligados ao Cromossomo X , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Humanos , Nervo Mediano/fisiopatologia , Proteínas de Membrana/genética , Condução NervosaRESUMO
Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogeneous group of disorders of the PNS. Progressive degeneration, predominantly of sensory and autonomic neurons, is the main pathological feature in patients with HSAN, and causes prominent sensory loss and ulcerative mutilations in combination with variable autonomic and motor disturbances. Advances in molecular genetics have enabled identification of disease-causing mutations in 12 genes, and studies on the functional effects of these mutations are underway. Although some of the affected proteins--such as nerve growth factor and its receptor--have obvious nerve-specific roles, others are ubiquitously expressed proteins that are involved in sphingolipid metabolism, vesicular transport, transcription regulation and structural integrity. An important challenge in the future will be to understand the common molecular pathways that result in HSANs. Unraveling the mechanisms that underlie sensory and autonomic neurodegeneration could assist in identifying targets for future therapeutic strategies in patients with HSAN. This Review highlights key advances in the understanding of HSANs, including insights into the molecular mechanisms of disease, derived from genetic studies of patients with these disorders.
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Proteínas de Transporte/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Animais , Modelos Animais de Doenças , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/terapia , HumanosRESUMO
The genetic neuropathies are a clinically and genetically heterogeneous group of diseases of which the most common types are Charcot-Marie-Tooth disease (CMT), the hereditary sensory and autonomic neuropathies and the distal hereditary motor neuropathies. More than 30 causative genes have been described, making an accurate genetic diagnosis increasingly possible. Although no specific therapies are yet available, research into their pathogenesis has revolutionised our understanding of the peripheral nervous system and allowed the development of rational approaches to therapy. The first therapeutic trials in CMT are currently underway. This review will suggest an approach to the diagnosis of these disorders and provide an update on new therapies.
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Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/terapia , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/terapia , Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/terapia , Terapia Genética , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatia Hereditária Motora e Sensorial/classificação , Neuropatia Hereditária Motora e Sensorial/genéticaRESUMO
Currently more than 30 genes are known to be responsible for genetically determined neuropathies. Charcot-Marie-Tooth (CMT) disease is the most frequent of these hereditary neuropathies, with a prevalence of 4.7 to 36 per 100 000. In its demyelinating forms (CMT1), approximately 70% of cases are associated with a duplication of the PMP22gene. In its axonal forms (CMT2), 10-20% of the cases may be associated with a mutation of the MFN2gene. For North African patients with recessive transmission, a mutation of the LMNA gene must be sought. It is essential to stress the great variability of the phenotype--clinical, electrophysiological, and histologic--between and within families. A detailed analysis of these criteria, together with consideration of ethnic origin, may guide the search for the causal mutation. Whether the case involves certainly hereditary transmission or a sporadic form, it is desirable to be able to examine the maximum number of the patient's kin, both clinically and electrophysiologically. The forms with recessive transmission usually have a very early onset and are more serious than the dominant forms. The early- and very early-onset forms of CMT are increasingly better distinguished: congenital hypomyelination neuropathy (mutations of PMP22, MPZ or EGR2), or more axonal forms, including SMARD1 (Spinal muscle atrophy with respiratory distress; mutations of IGHMBP2) and EOHMSN (Early-onset hereditary motor and sensory neuropathy; mutations of MFN2). The prevention of cutaneous (ulcerations), bone, and amputation complications is very important in patients with hereditary sensory and autonomic neuropathies, because of the severity of the sensory disorders.
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Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatia Hereditária Motora e Sensorial/genética , Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/genética , Doenças Desmielinizantes/classificação , Doenças Desmielinizantes/genética , GTP Fosfo-Hidrolases , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatia Hereditária Motora e Sensorial/classificação , Humanos , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Mutação/genética , Proteínas da Mielina/genéticaRESUMO
BACKGROUND: To determine the features of the underlying destructive arthropathy in the peripheral joints of children with hereditary sensory and autonomic neuropathy (HSAN) type III and to compare and contrast this to the arthropathy noted in HSAN type IV, as both groups experience decreased pain perception. METHODS: From a database of 547 patients with HSAN type III and 32 patients with HSAN type IV, we performed a retrospective chart review and radiographic analysis of all patients who presented with joint swelling and deformity. Underlying joint pathology was classified as either osteonecrosis or Charcot arthropathy. RESULTS: In the HSAN type III population, 44 (8%; 22 males and 22 females) of the 547 patients had clinical evidence of arthropathy. In 42 patients, 48 joints demonstrated radiographic evidence of osteonecrosis; 45 (94%) of the 48 joints with osteonecrosis occurred in the lower extremity. In each case of osteonecrosis of the knee (n = 19), isolated involvement of the lateral distal femoral condyle was seen consisting of varying sizes of posterolateral osteochondral fragmentation. In the 32 patients comprising the HSAN type IV population, 18 (56%) were found to have radiographic findings consistent with Charcot arthropathy in a total of 30 affected joints. One patient demonstrated Charcot arthropathy of the spine and subsequent progressive spondylolisthesis. Nine patients (12 joints) also demonstrated osteomyelitis. CONCLUSIONS: In patients with HSAN type III, osteonecrosis is the initial lesion preceding destructive arthropathy. Osteonecrosis and osteochondral fragmentation were always isolated at the lateral distal femoral condyle in the knee. This pathology may be amenable to surgical reconstruction and fixation to stabilize the knee and prevent further degeneration. Hereditary sensory and autonomic neuropathy type IV was most commonly associated with Charcot arthropathy or joint subluxation and dislocation. Late secondary changes at the articular surface may make radiographic distinction difficult. Charcot arthropathy affected both sides of the involved joint with evidence of collapse and fragmentation. With osteonecrosis, the articular process was found to be more focal.
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Artropatia Neurogênica/etiologia , Neuropatias Hereditárias Sensoriais e Autônomas/complicações , Osteomielite/etiologia , Osteonecrose/etiologia , Adolescente , Adulto , Artropatia Neurogênica/diagnóstico por imagem , Artropatia Neurogênica/fisiopatologia , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Fêmur/patologia , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico por imagem , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Articulação do Joelho/patologia , Masculino , Osteomielite/diagnóstico por imagem , Osteomielite/fisiopatologia , Osteonecrose/diagnóstico por imagem , Osteonecrose/fisiopatologia , Dor/etiologia , Radiografia , Estudos Retrospectivos , Adulto JovemRESUMO
UNLABELLED: Ras-associated binding (Rab) proteins and Rab-associated proteins are key regulators of vesicle transport, which is essential for the delivery of proteins to specific intracellular locations. More than 60 human Rab proteins have been identified, and their function has been shown to depend on their interaction with different Rab-associated proteins regulating Rab activation, post-translational modification and intracellular localization. The number of known inherited disorders of vesicle trafficking due to Rab cycle defects has increased substantially during the past decade. This review describes the important role played by Rab proteins in a number of rare monogenic diseases as well as common multifactorial human ones. Although the clinical phenotype in these monogenic inherited diseases is highly variable and dependent on the type of tissue in which the defective Rab or its associated protein is expressed, frequent features are hypopigmentation (Griscelli syndrome), eye defects (Choroideremia, Warburg Micro syndrome and Martsolf syndrome), disturbed immune function (Griscelli syndrome and Charcot-Marie-Tooth disease) and neurological dysfunction (X-linked non-specific mental retardation, Charcot-Marie-Tooth disease, Warburg Micro syndrome and Martsolf syndrome). There is also evidence that alterations in Rab function play an important role in the progression of multifactorial human diseases, such as infectious diseases and type 2 diabetes. Rab proteins must not only be bound to GTP, but they need also to be 'prenylated'-i.e. bound to the cell membranes by isoprenes, which are intermediaries in the synthesis of cholesterol (e.g. geranyl geranyl or farnesyl compounds). This means that isoprenylation can be influenced by drugs such as statins, which inhibit isoprenylation, or biphosphonates, which inhibit that farnesyl pyrophosphate synthase necessary for Rab GTPase activity. CONCLUSION: Although protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents.
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Coroideremia/genética , Diabetes Insípido Nefrogênico/fisiopatologia , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/fisiologia , Coroideremia/fisiopatologia , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/metabolismo , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Prenilação/genética , Prenilação/fisiologia , Transporte Proteico/fisiologia , Síndrome , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumours like amelanotic melanoma. Management of HSN I follows the guidelines given for diabetic foot care (removal of pressure to the ulcer and eradication of infection, followed by the use of specific protective footwear) and starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. The disorder is slowly progressive and does not influence life expectancy but is often severely disabling after a long duration of the disease.
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Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Doenças do Pé/etiologia , Doenças do Pé/genética , Doenças do Pé/prevenção & controle , Ligação Genética/genética , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/terapia , Humanos , Mutação/genéticaAssuntos
Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatia Hereditária Motora e Sensorial/classificação , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/patologia , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Neuropatia Hereditária Motora e Sensorial/patologia , HumanosRESUMO
The authors report a Japanese patient with hereditary sensory and autonomic neuropathy type 2 (HSAN2) who has a new mutation of the HSN2 gene. The pathologic findings of the patient matched those of Canadian patients. They identified a homozygous 1134-1135 ins T mutation, resulting in a frameshift, and the subsequent premature stop codon at residue 378. These observations support the hypothesis that HSN2 is a causative gene for HSAN2.
Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas/genética , Proteínas do Tecido Nervoso/genética , Adulto , Povo Asiático/genética , Canadá , Mutação da Fase de Leitura , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Japão , Masculino , Antígenos de Histocompatibilidade Menor , Linhagem , Proteínas Serina-Treonina Quinases , Proteína Quinase 1 Deficiente de Lisina WNKRESUMO
OBJECTIVE: To present criteria for pathophysiological interpretation of motor and sensory nerve conduction studies and for pathophysiological classification of polyneuropathies suggested by a group of European neurophysiologists. METHODS: Since 1992 seven neurophysiologists from six European countries have collected random samples of their electrodiagnostic examinations for peer review medical audit in the ESTEEM (European Standardized Telematic tool to Evaluate Electrodiagnostic Methods) project. Based on existing criteria in the literature, the experience with a patient material of 572 peer reviewed electrodiagnostic examinations, and productive discussions between the physicians at workshops, the collaboration has produced a set of criteria now routinely used at the centres involved in the project. RESULTS: The first part of the paper considers pathophysiology of individual nerve segments. For interpretation of motor and sensory nerve conduction studies, figures showing change in amplitude versus change in conduction velocity/distal latency and change in F-wave frequency versus change in F-wave latency are presented. The suggested boundaries delimit areas corresponding to normal, axonal, demyelinated, or neuropathic nerve segments. Criteria for motor conduction block in upper and lower extremities are schematically depicted using the parameters CMAP amplitude and CMAP duration. The second part of the paper suggests criteria for classification of polyneuropathies into axonal, demyelinating, or mixed using the above-mentioned criteria. CONCLUSIONS: The suggested criteria are developed during many years of collaboration of different centres and may be useful for standardization in clinical neurophysiology. SIGNIFICANCE: Consistent interpretation of nerve conduction studies is an important step in optimising diagnosis and treatment of nerve disorders.
Assuntos
Eletrodiagnóstico/normas , Eletrofisiologia/normas , Condução Nervosa/fisiologia , Neurofisiologia/normas , Nervos Periféricos/fisiopatologia , Polineuropatias/diagnóstico , Polineuropatias/fisiopatologia , Axônios/fisiologia , Bases de Dados Factuais/tendências , Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/fisiopatologia , Educação , Eletrodiagnóstico/métodos , Eletrofisiologia/métodos , Europa (Continente) , Neuropatias Hereditárias Sensoriais e Autônomas/classificação , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Cooperação Internacional , Neurônios Motores/fisiologia , Exame Neurológico , Neurônios Aferentes/fisiologia , Neurofisiologia/métodos , Polineuropatias/classificação , Estudos Prospectivos , Tempo de Reação/fisiologia , Design de SoftwareRESUMO
BACKGROUND: Since the description of Charcot-Marie-Tooth disease over a century ago. it has now been recognized that these conditions are not caused by generalized metabolic defects but rather have various discrete genetic origins. These disorders can also have variable phenotypes due to dysfunction of peripheral nerve axons or their myelin due to the genetic defects that affect the formation of specific nerve proteins. REVIEW SUMMARY: This article summarizes the clinical presentation of various phenotypes of the hereditary motor sensory neuropathies and the hereditary sensory and autonomic neuropathies, genetic mutations, and their relevant protein products. Proper identification of the genetic defects provides the opportunity for better genetic counseling and hopefully therapies in the future.