RESUMO
BACKGROUND: Ataxia telangiectasia (A-T) is a neurodegenerative disorder. While patients with classic A-T generally die in their 20s, some patients with variant A-T, who have residual ataxia-telangiectasia mutated (ATM) kinase activity, have a milder phenotype. We noticed two commonly occurring ATM mutations that appeared to be associated with prolonged survival and decided to study patients carrying one of these mutations. METHODS: Data were retrospectively collected from the Dutch, Italian, German and French A-T cohorts. To supplement these data, we searched the literature for patients with identical genotypes. RESULTS: This study included 35 patients who were homozygous or compound heterozygous for the ATM c.3576G>A; p.(Ser1135_Lys1192del58) mutation and 24 patients who were compound heterozygous for the ATM c.8147T>C; p.(Val2716Ala) mutation. Compared with 51 patients with classic A-T from the Dutch cohort, patients with ATM c.3576G>A had a longer survival and were less likely to develop cancer, respiratory disease or immunodeficiency. This was also true for patients with ATM c.8147T>C, who additionally became wheelchair users later in life and had fewer telangiectasias. The oldest patient with A-T reported so far was a 78-year-old patient who was compound heterozygous for ATM c.8147T>C. ATM kinase activity was demonstrated in cells from all patients tested with the ATM c.8147T>C mutant protein and only at a low level in some patients with ATM c.3576G>A. CONCLUSION: Compared with classic A-T, the presence of ATM c.3576G>A results in a milder classic phenotype. Patients with ATM c.8147T>C have a variant phenotype with prolonged survival, which in exceptional cases may approach a near-normal lifespan.
Assuntos
Alelos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Estudos de Associação Genética , Genótipo , Mutação , Fenótipo , Ataxia Telangiectasia/mortalidade , Humanos , Prognóstico , Sítios de Splice de RNA , Deleção de Sequência , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To evaluate the effect of chenodeoxycholic acid treatment on disease progression in cerebrotendinous xanthomatosis (CTX). METHODS: In this retrospective cohort study, we report the clinical long-term follow-up characteristics of 56 Dutch patients with CTX. Age at diagnosis was correlated with clinical characteristics and with the course of modified Rankin Scale (mRS) and Expanded Disability Status Scale (EDSS) scores at follow-up. RESULTS: Median follow-up time was 8 years (6 months-31.5 years). Patients diagnosed and treated before the age of 24 years had a significantly better outcome at follow-up. When considering only patients with a good treatment adherence (n = 43), neurologic symptoms, if present, disappeared in all patients who were diagnosed before the age of 24 and treated since. Furthermore, treatment prevented the development of new neurologic symptoms during follow-up. In contrast, 61% of the patients diagnosed and treated after the age of 24 showed deterioration of the neurologic symptoms, with parkinsonism as a treatment-resistant feature. There was an improvement or stabilization in favor of patients diagnosed and treated before the age of 24 compared to those treated after the age of 24: 100% vs 58% for mRS scores and 100% vs 50% for EDSS scores, respectively. CONCLUSIONS: Treatment start at an early age can reverse and even prevent the development of neurologic symptoms in CTX. This study emphasizes the importance of early diagnosis in CTX and provides a rationale to include CTX in newborn screening programs.
Assuntos
Gerenciamento Clínico , Resultado do Tratamento , Xantomatose Cerebrotendinosa/terapia , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Colestanotriol 26-Mono-Oxigenase/genética , Colestanol/sangue , Estudos de Coortes , Avaliação da Deficiência , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação/genética , Doenças do Sistema Nervoso/etiologia , Fatores de Tempo , Xantomatose Cerebrotendinosa/sangue , Xantomatose Cerebrotendinosa/complicações , Xantomatose Cerebrotendinosa/genética , Adulto JovemRESUMO
Cerebrotendinous xanthomatosis (CTX) is an inborn error of cholesterol and bile acid metabolism, leading to neuropsychiatric and systemic manifestations. Movement disorders have rarely been reported in CTX, while a detailed appreciation of the full phenotypic spectrum is required in order to prevent underdiagnosis of this disease. This review focuses on the frequency of more unusual, non-ataxia and non-spasticity movement disorders reported in CTX. In total, 39 articles were reviewed, describing 55 CTX patients with a movement disorder. Additionally, we report on seven patients with parkinsonism out of our Dutch cohort of 79 (77 genetically proven) CTX patients. Mean age at onset of the movement disorder was 40⯱â¯12 years (median 40, range 13-62 years). Movement disorders can be considered a late disease manifestation. Parkinsonism was the most frequently reported movement disorder, followed by dystonia, myoclonus and postural tremor. Movement disorders were found to be mixed in 23% of patients and were usually part of a complex clinical picture, rather than a prominent symptom. Still, in 18% of the cases, a movement disorder was the presenting symptom. Unusual movement disorders represent a rare clinical feature in CTX, but CTX should be considered in the differential diagnosis of these movement disorders, particularly in case of early onset, and when associated with other neurological features (especially cognitive impairment, pyramidal and cerebellar signs) and/or with systemic features (such as diarrhoea, cataract and tendon xanthomas). CTX is a treatable disorder, stressing the importance of considering CTX as a potential cause of movement disorders.
Assuntos
Transtornos dos Movimentos/etiologia , Xantomatose Cerebrotendinosa/complicações , Adolescente , Adulto , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/epidemiologia , Países Baixos/epidemiologia , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/epidemiologia , Transtornos Parkinsonianos/etiologia , Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/epidemiologia , Adulto JovemRESUMO
Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.
Assuntos
Ataxia Telangiectasia/terapia , Ataxia Telangiectasia/diagnóstico , HumanosRESUMO
Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first.
Assuntos
Agamaglobulinemia/imunologia , Ataxia Telangiectasia/imunologia , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Imunoglobulina G/imunologia , Adolescente , Adulto , Agamaglobulinemia/complicações , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/mortalidade , Proteínas Mutadas de Ataxia Telangiectasia/genética , Causas de Morte , Criança , Estudos de Coortes , Feminino , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/complicações , Deficiência de IgA/complicações , Deficiência de IgA/imunologia , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Expectativa de Vida , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/etiologia , Neoplasias/genética , Razão de Chances , Fenótipo , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: The clinical syndrome of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) was first described 20 years ago, but it was only recently that whole exome sequencing unveiled the causative mutation in the ATP1A3 gene. We present four patients from the seventh and eighth family identified worldwide, provide a critical review of all patients published thus far, and speculate about the pathophysiologic processes underlying the acute neurological manifestations. CLINICAL OBSERVATIONS: The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness. An underlying c.2452G>A mutation in the ATP1A3 gene was found in all four individuals. Besides the persisting CAPOS features, other possibly related sequelae included dystonia, myoclonus, and emotional and behavioral changes. After initiation of acetazolamide in two patients, no further episodes occurred. CONCLUSION: Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia and in adults with a more or less stationary or slowly progressive cerebellar syndrome since childhood accompanied by mixed combinations of areflexia, pes cavus, profound visual impairment, and/or sensorineural hearing loss. Similar to some other types of episodic ataxia, acetazolamide may be considered in patients with CAPOS syndrome to prevent or attenuate bouts of ataxia, but this requires further study.
Assuntos
Ataxia Cerebelar/genética , Deformidades Congênitas do Pé/genética , Perda Auditiva Neurossensorial/genética , Atrofia Óptica/genética , Mutação Puntual , Reflexo Anormal/genética , ATPase Trocadora de Sódio-Potássio/genética , Adulto , Criança , Pré-Escolar , Família , Feminino , Humanos , MasculinoRESUMO
The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene-specific phenotype traits, and the relative frequency of the involvement of specific genes. To gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger-based sequencing (in 2011) and exome sequencing followed by targeted bioinformatics analysis (in 2012) for five different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite-stable colorectal cancer, this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost.
Assuntos
Exoma , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNA , Aconselhamento Genético , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Análise de Sequência de DNA/métodos , Análise de Sequência de DNA/normasRESUMO
Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk.
Assuntos
Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/patologia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adolescente , Adulto , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Criança , Proteínas de Ligação a DNA/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
BACKGROUND: The pathophysiology of primary focal dystonia remains insufficiently understood, but may be explained by a 'double-lesion' model, in which a particular trigger on top of an intrinsic susceptibility due to a certain genetic predisposition can induce dystonia. CASE-REPORT: Here, we describe a patient who developed cervical dystonia soon after ear surgery (revision stapedectomy), which had caused vestibular hypofunction. DISCUSSION: We also discuss other cases of dystonia associated with vestibular lesions and with other reported triggers, and put these into the context of the possible pathophysiology.
Assuntos
Procedimentos Cirúrgicos Otológicos/efeitos adversos , Complicações Pós-Operatórias/fisiopatologia , Torcicolo/etiologia , Idoso , Feminino , Lateralidade Funcional/fisiologia , Humanos , Otosclerose/cirurgiaAssuntos
Ataxia Telangiectasia/diagnóstico , Neoplasias da Mama/radioterapia , Adulto , Ataxia Telangiectasia/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Terapia Combinada , Diagnóstico Tardio , Evolução Fatal , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Tolerância a RadiaçãoRESUMO
The relevant clinical, genetic, and cell biologic aspects of the dominantly inherited spinocerebellar ataxias (SCAs) are reviewed in this article. SCAs are diseases of the entire nervous system; in addition to cerebellar ataxia, the central (but not obligate) disease feature, many noncerebellar complications can be present as well. There are over 35 genetic subtypes: although those caused by expanded CAG repeats are still the more common ones, the majority of the recent SCAs have been caused by more conventional mutations. Genotype-phenotype correlations do exist and are most clear for the repeat expansion, where repeat length partially explains age at onset, disease severity and progression, and the core clinical phenotype. Some common themes within the disease mechanisms seem to emerge, including misfolding and aggregation, impairment of the protein quality control system, abnormal protein interactions, disruption of gene transcription, RNA toxicity, and changes in glutamate and calcium signaling. Yet despite this exciting progress in the molecular genetic background and suggested corresponding pathways, there is still no drug available that is specifically designed for or targeted at the mechanisms at play.
Assuntos
Ataxias Espinocerebelares/genética , Transcrição Gênica/fisiologia , Genes Dominantes , Estudos de Associação Genética , Ácido Glutâmico/metabolismo , Humanos , Mutação , Peptídeos/genética , Fenótipo , Ataxias Espinocerebelares/fisiopatologia , Expansão das Repetições de TrinucleotídeosRESUMO
Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations provide incomplete coverage for genotyping of patients. By combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval with the use of next-generation sequencing technology, we identified a mutation in a gene and have shown its association with autosomal-recessive cerebellar ataxia. In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture. Prioritization of all detected sequence variants led to four candidate genes, one of which contained a variant with a high base pair conservation score (phyloP score: 5.26). This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10). The analysis of ANO10 by Sanger sequencing revealed three additional mutations: a homozygous mutation (c.1150_1151del [p.Leu384fs]) in a Serbian family and a compound-heterozygous splice-site mutation (c.1476+1G>T) and a frameshift mutation (c.1604del [p.Leu535X]) in a French family. This illustrates the power of using initial homozygosity mapping with next-generation sequencing technology to identify genes involved in autosomal-recessive diseases. Moreover, identifying a putative calcium-dependent chloride channel involved in cerebellar ataxia adds another pathway to the list of pathophysiological mechanisms that may cause cerebellar ataxia.
Assuntos
Ataxia Cerebelar/genética , Genes Recessivos , Homozigoto , Proteínas de Membrana/genética , Mutação , Proteínas de Neoplasias/genética , Anoctamina-1 , Canais de Cloreto , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Dystonia is a disabling movement disorder with a significant impact on quality of life. The current therapeutic armamentarium includes various drugs, botulinum toxin injections, and occasionally (neuro)surgery. In addition, many patients are referred for paramedical (including allied health care) interventions. An enormous variation in the paramedical treatment is provided, largely because evidence-based, accepted treatment regimes are not available. We have conducted a systematic review of studies that explored the effect of various paramedical interventions in primary dystonia. Only studies that have used clinical outcome measures were included. There were no class A1 or A2 studies and therefore, level 1 or 2 practice recommendations for a specific intervention could not be deducted. Many papers were case reports, mostly with a very limited number of patients and a clear publication bias for beneficial effects of a particular paramedical intervention. Some potentially interesting interventions come from class B studies, which include physical therapy in addition to botulinum toxin injections (BoNT-A) in cervical dystonia; sensorimotor training and transcutaneous electrical nerve stimulation (TENS) in writer's cramp; and speech therapy added to BoNT-A injections in laryngeal dystonia. Good quality clinical studies are therefore warranted, which should have the aim to be generally applicable. A design in which the paramedical intervention is added to a current gold standard, for example, BoNT-A injections in cervical dystonia, is recommended.
Assuntos
Distúrbios Distônicos/reabilitação , Modalidades de Fisioterapia , Bases de Dados Factuais/estatística & dados numéricos , Humanos , Terapia da Linguagem/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Fonoterapia/métodosRESUMO
We sought to explore the phenomenon of disproportionate antecollis in multiple system atrophy (MSA) and Parkinson's disease (PD). The etiology is much debated and the main issue is whether it represents a primary myopathy or is secondary to the underlying motor disorder. The clinical, electrophysiological, and biopsy data of MSA or PD patients with antecollis were reviewed. We reviewed 16 patients (7 MSA and 9 PD) who developed antecollis during the course of their disease. The interval between onset of motor symptoms and of antecollis was shorter in the MSA group (4.6 +/- 1.7 years vs. 10.5 +/- 7.0 years). In 6 patients, the antecollis developed subacutely, and in 2 the abnormal neck flexion was initially an off-period phenomenon. Two additional patients also showed some dopa-responsiveness. Clinically, the antecollis was characterized by a forward flexion and anterior shift of the neck, with prominent cervical paraspinal and levator scapulae muscles, usually without weakness of residual neck extension. Electromyography of cervical paraspinal muscles showed mixed myopathic, normal, and neurogenic units, without early recruitment. Cervical paraspinal muscle biopsy in 2 patients disclosed fibrosis and nonspecific myopathic changes. We suggest that, in the context of MSA or PD, the initiating event in antecollis could be a disproportionately increased tone in anterior neck muscles that leads to secondary fibrotic and myopathic changes. However, a primary but yet unexplained neck extensor myopathy still remains the alternative possibility and longitudinal studies are necessary to settle this issue.
Assuntos
Movimento/fisiologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Doença de Parkinson/fisiopatologia , Idoso , Antiparkinsonianos/uso terapêutico , Toxinas Botulínicas Tipo A/uso terapêutico , Eletromiografia , Eletrofisiologia , Feminino , Fibrose/patologia , Cabeça , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Atrofia de Múltiplos Sistemas/patologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Pescoço , Fármacos Neuromusculares/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologiaAssuntos
Ataxia Cerebelar/etiologia , Neoplasias Embrionárias de Células Germinativas/complicações , Degeneração Paraneoplásica Cerebelar/etiologia , Neoplasias Testiculares/complicações , Ataxia Cerebelar/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Degeneração Paraneoplásica Cerebelar/patologiaRESUMO
The discovery of the gene for Friedreich's ataxia (FRDA) has not only broadened the FRDA phenotype, but has also identified patients with early-onset cerebellar ataxia who resemble FRDA clinically but who do not carry a mutation in the frataxin gene. In order to identify subgroups that may represent a uniform underlying disorder, we performed neurophysiologic studies, including nerve conduction studies, electromyography, and transcranial magnetic stimulation, in 15 patients with a slowly progressive, unexplained, early-onset cerebellar ataxia (EOCA). In addition, sural nerve biopsy data were available in four patients. The neurophysiologic data identified three distinctive groups of EOCA patients: three patients with normal motor and sensory conduction velocities and borderline sensory amplitudes (group 1); three patients with a mild, predominantly motor, axonal neuropathy (group 2); and nine patients with a highly uniform syndrome characterized by pyramidal features and a severe sensory and motor axonal neuropathy (group 3). We conclude that, on the basis of neurophysiologic studies, distinctive groups of patients with EOCA can be delineated, and that differentiation between patients with EOCA can be useful for differential diagnostic consideration. Whether this splitting also reflects a fundamental phenotypic difference and, therefore, may direct future DNA studies, remains to be established.
Assuntos
Degenerações Espinocerebelares/classificação , Degenerações Espinocerebelares/diagnóstico , Adulto , Idade de Início , Eletromiografia , Humanos , Pessoa de Meia-Idade , Condução Nervosa , Exame Neurológico/métodos , Neurofisiologia/métodosRESUMO
We report a 28-year-old woman with a history of chronic immune-mediated hepatitis, in whom the simultaneous manifestation of dermatomyositis and myasthenia gravis resulted in severe neck extensor weakness and subacute respiratory insufficiency, followed by proximal muscle weakness and external ophthalmoplegia. Radiological signs of a thymoma were absent. The distinguishing clinical, electrophysiological, and biopsy findings are discussed. We suggest that an underlying immunoregulatory disorder was present, explaining the occurrence of three rare immune-mediated diseases in one patient.