RESUMO
We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
Assuntos
Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Proteínas Serina-Treonina Quinases/genética , População Branca/genética , Idoso , Alelos , Substituição de Aminoácidos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Ativação Enzimática , Feminino , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/epidemiologia , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , NF-kappa B/metabolismo , Fenótipo , Proteínas Serina-Treonina Quinases/metabolismo , Deleção de SequênciaRESUMO
BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare autosomal-recessive lysosomal storage disorder caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene. METHODS: In a prospective, observational cohort study, all Bulgarian patients diagnosed with NP-C to date (since 2010) underwent detailed neurological examination and neuro-ophthalmological, neuropsychological and psychiatric evaluations, as well as brain MRI, abdominal ultrasound and hearing tests. Plasma chitotriosidase was also measured, when possible. RESULTS: The Bulgarian national NP-C cohort comprised 11 patients who were diagnosed based on molecular genetic analysis (n = 9) and/or filipin staining of skin fibroblasts (n = 3). The mean age at onset was 14.4 (SD 8.3). Diagnoses were achieved 1-23 years after initial clinical presentation. All patients who underwent genetic mutation analysis were compound heterozygotes: a total of 12 NPC1 mutations were recorded, 5 of which were novel. Two patients had late-infantile onset, 4 had juvenile onset, and the remaining 5 had the adult-onset form of NP-C. Initial symptoms were neurological in 9 patients, visceral in one, and predominantly psychiatric in another. Vertical gaze palsy was present in all patients. Dysarthria, pyramidal involvement, cognitive impairment, and organomegaly with varied severity were observed in 10 of them. Ataxia was present in 9 and dystonia in 7. Four patients had epileptic seizures, and gelastic cataplexy was reported in 5. Brain MRI revealed hyperintense white matter lesions in 5 patients and cortical and/or cerebellar atrophy in 4. CONCLUSIONS: This Bulgarian NP-C cohort showed wide variability in terms of NPC1 mutations and predominant forms of neurological involvement. Diagnosing NP-C is challenging, and it was often delayed in this cohort due to the heterogeneity of patients' clinical signs and symptoms.
Assuntos
Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/patologia , Adulto , Idade de Início , Bulgária , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Exame Neurológico , Estudos ProspectivosRESUMO
We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion.
Assuntos
Degeneração Lobar Frontotemporal/epidemiologia , Degeneração Lobar Frontotemporal/genética , Instabilidade Genômica , Proteínas/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/genética , Sequência de Bases , Proteína C9orf72 , Cromossomos Humanos Par 9/genética , Estudos de Coortes , Expansão das Repetições de DNA , Europa (Continente)/epidemiologia , Finlândia/epidemiologia , Estudo de Associação Genômica Ampla/métodos , Alemanha/epidemiologia , Haplótipos , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Prevalência , Espanha/epidemiologia , Suécia/epidemiologiaRESUMO
Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
Assuntos
Esclerose Lateral Amiotrófica , Adulto , Criança , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/terapia , Estudos de Viabilidade , Europa (Continente) , Bases de Dados Factuais , PrevalênciaRESUMO
The hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an autosomal dominant genetic disease characterized by amyloid formation in different tissues due to pathogenic variants in the TTR gene. Great heterogeneity in the penetrance and manifestation of ATTRv amyloidosis is observed. In Bulgaria, the most common TTR pathogenic variant is Glu89Gln. Other TTR pathogenic variants are also found - Val30Met, Ser77Phe, Gly47Glu and Ser52Pro. There is a proven founder effect for the Glu89Gln variant, thus the aim of the present study is to investigate the founder effect for the other TTR pathogenic variants in Bulgaria. Haplotype analysis was performed by using microsatellite markers close to the TTR gene. DNA samples from ATTRv amyloidosis patients and their healthy relatives were analyzed. Theoretical haplotype reconstruction was done with Arlequin v.3.01 software. The age of the most recent common ancestor (hypothetical founder) for the studied variants was calculated with the DMLE 2.2 software. In addition, DBS screening among 100 Roma newborns was done for the Gly47Glu TTR variant via direct Sanger sequencing. The reconstructed haplotypes of the patients were compared to their healthy relatives and to a control group of 40 healthy individuals. The results showed a possible founder effect for each of the studied variants. The Val30Met haplotype was compared to published haplotype data for this variant and no similarity was found. The result from the DBS screening showed no pathogenic TTR variants in exon 2 of the gene, so we considered the presence of the Gly47Glu variant in our population a sporadic event. With this study, we succeeded to gain a more complete picture of the population genetics of ATTRv amyloidosis in Bulgaria and made another step towards a more detailed understanding of the disease epidemiology.
Assuntos
Neuropatias Amiloides Familiares , Pré-Albumina , Neuropatias Amiloides Familiares/genética , Bulgária , Efeito Fundador , Humanos , Recém-Nascido , Pré-Albumina/genéticaRESUMO
Transthyretin amyloid (ATTR) amyloidosis is an adult-onset, rare systemic disorder characterized by the accumulation of misfolded fibrils in the body, including the peripheral nerves, the heart and the gastrointestinal tract. Gastrointestinal manifestations are common in hereditary (ATTRv) amyloidosis and are present even before the onset of the polyneuropathy in some cases. Delays in diagnosis of ATTRv amyloidosis with gastrointestinal manifestations commonly occur because of fragmented knowledge among gastroenterologists and general practitioners, as well as a shortage of centers of excellence and specialists dedicated to disease management. Although the disease is becoming well-recognized in the societies of Neurology and Cardiology, it is still unknown for most gastroenterologists. This review presents the recommendations for ATTRv amyloidosis with gastrointestinal manifestations elaborated by a working group of European gastroenterologists and neurologists, and aims to provide digestive health specialists with an overview of crucial aspects of ATTRv amyloidosis diagnosis to help facilitate rapid and accurate identification of the disease by focusing on disease presentation, misdiagnosis and management of gastrointestinal symptoms.
Assuntos
Neuropatias Amiloides Familiares , Gastroenteropatias , Adulto , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/terapia , Gastroenteropatias/diagnóstico , Gastroenteropatias/etiologia , Gastroenteropatias/terapia , Humanos , Pré-AlbuminaRESUMO
Over 40 mutations in the GDAP1 gene have been shown to segregate with Charcot-Marie-Tooth disease (CMT). Among these, only two mutations, i.e., S194X and Q163X have been reported in a sufficient number of CMT families to allow for the construction of reliable phenotype-genotype correlations. Both the S194X and Q163X mutations have been shown to segregate with an early-onset and severe neuropathy resulting in loss of ambulance at the beginning of the second decade of life. In this study, we identified the L239F mutation in the GDAP1 gene in one Bulgarian and five Polish families. We hypothesized that the L239F mutation may result from a founder effect in the European population since this mutation has previously been reported in Belgian, Czech, and Polish patients. In fact, we detected a common disease-associated haplotype within the 8q13-q21 region in the Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously detected "regional" S194X and Q163X mutations, respectively present in Maghreb countries and in patients of Spanish descent, the L239F mutation seems to be the most common GDAP1 pathogenic variant in the Central and Eastern European population. Given the likely presence of a common ancestor harboring the L239F mutation, we decided to compare the phenotypes of the CMT (L239F) patients collected in this study with those of previously reported cases. In contrast to CMT4A caused by the S194X and Q163X mutations, the CMT phenotype resulting from the L239F substitution represents a milder clinical entity with a long-preserved period of ambulance at least until the end of the second decade of life.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Efeito Fundador , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Idade de Início , Doença de Charcot-Marie-Tooth/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 8/genética , Europa (Continente) , Feminino , Estudos de Associação Genética , Loci Gênicos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Mutação , Proteínas/genética , Adulto JovemRESUMO
Transthyretin amyloid (ATTR) amyloidosis is a rare systemic disorder characterized by amyloid deposits formed by misfolded monomers of the transthyretin. Gastrointestinal (GI) manifestations are common in ATTR amyloidosis; however, their pathogenesis is not fully elucidated. In the present study, we aim to evaluate the diagnostic role of fecal calprotectin (FC) in ATTR amyloidosis patients with GI manifestations.We recruited 21 consecutive ATTR amyloidosis patients and 42 sex and age-matched healthy controls. The presentation of GI symptoms and the severity of peripheral neuropathy were evaluated. Colonoscopy and FC assessment were performed in all subjects.Mean levels of FC in ATTR amyloidosis patients (184âµg/g [30-430]) were significantly higher thаn those of controls (40âµg/g [30-70]), Pâ<â.001. Receiver operating characteristic curve analysis indicated a FC cut-off level of 71âµg/g, which differentiates ATTR amyloidosis with GI manifestations from healthy subjects with 91% sensitivity, 100% specificity, 100% positive predictive value, 95% negative predictive value and 97% overall accuracy. FC values were significantly associated with the presence of neutrophilic granulocytic infiltration in the colonic mucosa (Pâ=â.002), with the presence of amyloid deposits in rectal mucosa (Pâ=â.007) and the presence of diarrhea (Pâ=â.046).FC levels are elevated in patients with ATTR amyloidosis with GI manifestations, which suggests an inflammatory component in the pathogenesis of the disease. The presence of elevated FC concentrations could help gastroenterologists to include ATTR amyloidosis in their diagnostic work-up.
Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Gastroenteropatias/diagnóstico , Complexo Antígeno L1 Leucocitário/metabolismo , Adulto , Idoso , Neuropatias Amiloides Familiares/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Colonoscopia , Fezes/química , Feminino , Gastroenteropatias/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos ProspectivosRESUMO
Appropriate testing strategies and strict model for Center Of Excellence (CoE) support are essential for the correct diagnosis, follow-up strategy and treatment plan for transthyretin (ATTR) amyloidosis. CoE is defined as a programme within a healthcare institution established to provide an exceptionally high concentration of expertise and related resources centred on a particular area of medicine, delivering associated care in a comprehensive, interdisciplinary fashion to afford the best patient outcome. Ideally, CoEs provide regular education and training for healthcare professionals and share knowledge and learning with other CoEs and specialists to ensure the highest standards of care. CoEs and testing strategies are of significant value to those with rare diseases and their families, as there is naturally low awareness among healthcare professionals, a phenomenon that potentially delays diagnosis and treatment. In this review, we focus on the importance of performing the most appropriate testing strategies for ATTR amyloidosis and establishing a CoE for this rare disease. We highlight our experience in establishing a CoE in Sofia, Bulgaria and define the fundamental steps needed to successfully launch a programme.
Assuntos
Neuropatias Amiloides Familiares , Neuropatias Amiloides Familiares/diagnóstico , Atenção à Saúde , Humanos , Pré-Albumina , Padrões de ReferênciaRESUMO
BACKGROUND: Hereditary transthyretin amyloidosis is a systemic infiltrative disease, caused by a mutation in the transthyretin gene. p.Glu89Gln is the most common mutation in the Balkan countries. METHODS: We evaluated the clinical manifestations, cardiac involvement, morbidity and mortality in 78 patients with p.Glu89Gln mutation, verified through a DNA analysis. Clinical assessment, electrocardiogram and echocardiography were performed at the time of diagnosis. The patients have been followed for 30 months. RESULTS: All included patients were Caucasian, 39 (50%) - men, with median age at diagnosis of 56 years (42-73), median age at onset -- 53 years (35-69), starting significantly earlier in men (4.36, Pâ=â0.004). Cardiac and neurological involvement was found in 74 (95%) patients. Pathological ECG was present in 65 (84%) patients, infarct pattern in 43 (56%), low voltage in 24 (31%). Echocardiography revealed an infiltrative cardiomyopathy with restrictive filling in 31 (40%) and ejection fraction less than 50% in 20 (27%) patients. Twenty-two patients (28%) died: 14 (64%) because of advanced heart failure, 6 (27%) died suddenly, 2 (9%) from an ischemic stroke. The median age at death was 58.5 years (52-72). No statistically significant sex difference in survival was observed; a significant difference in survival was found for the New York Heart Association class, familial amyloidotic polyneuropathy stage, ejection fraction, filling pattern and tafamidis treatment. CONCLUSION: Cardiac involvement is common and has significant prognostic implications in the evaluated patients with p.Glu89Gln mutation. Heart failure and rhythm disturbances are the main causes of death. An earlier identification of the disease is crucial to improve prognosis.
Assuntos
Neuropatias Amiloides Familiares/genética , Cardiomiopatias/genética , Mutação , Pré-Albumina/genética , Adulto , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/mortalidade , Neuropatias Amiloides Familiares/fisiopatologia , Arritmias Cardíacas/mortalidade , Arritmias Cardíacas/fisiopatologia , Cardiomiopatias/diagnóstico , Cardiomiopatias/mortalidade , Cardiomiopatias/fisiopatologia , Causas de Morte , Progressão da Doença , Feminino , Predisposição Genética para Doença , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
There are few reports on pregnancies in sporadic and familial amyotrophic lateral sclerosis (ALS). We report on a young woman with sporadic ALS who gave birth twice during the course of her disease. The first pregnancy occurred 13 months after the onset of symptoms, and one month after diagnosis. The pregnancy was uncomplicated and resulted in vaginal delivery of a healthy boy. Fifteen months later, when she was already bed-ridden, she became pregnant again. She received a percutaneous endoscopic gastrostomy in the 21st gestational week and underwent early Caesarean section in the 34th week of gestation. The child was ventilated for 72 h in a neonatological unit. The patient was tracheotomized and ventilated two months later, i.e. 47 months after symptom onset, and died nine months later from gastrointestinal haemorrhage. Her two children have developed without abnormalities to date. This case confirms that pregnancies in early-stage ALS can develop normally and may result in uncomplicated vaginal delivery. Pregnancies in late stages may be critical for mother and child, and early delivery by Caesarean section may become necessary although neonatal outcome can be good.
Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Complicações na Gravidez , Gravidez , Adulto , Cesárea , Parto Obstétrico , Evolução Fatal , Feminino , Idade Gestacional , Humanos , Masculino , Resultado da GravidezRESUMO
Transthyretin amyloidosis (ATTR) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene. Due to the phenotypic heterogeneity, ATTR is difficult to recognize and it is often diagnosed very late. In ATTR gastrointestinal (GI) disorders play an important role in the patients' morbidity and mortality. In some cases, GI symptoms are present even before the onset of the peripheral polyneuropathy. However, the complaints are various and it is really difficult to differentiate them from other GI disorders. We present a 61-year old male referred for diarrhea, unintentional weight loss and early satiety. He had hypotension after longstanding hypertension, numbness and tingling in the feet. We considered a broad differential diagnosis spectrum of chronic diarrhea syndrome and performed numerous laboratory, biochemical, imaging, endoscopic, histological and genetic tests. Transthyretin amyloidosis with a Glu89Gln mutation was diagnosed. Transthyretin amyloidosis is frequently misdiagnosed, representing a diagnostic challenge in GI practice. The presence of certain clinical combinations could help gastroenterologists to include ATTR in their diagnostic work-up.
Assuntos
Neuropatias Amiloides Familiares/complicações , Diarreia/etiologia , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/genética , Benzoxazóis/uso terapêutico , Doença Crônica , Análise Mutacional de DNA , Diagnóstico Diferencial , Diarreia/diagnóstico , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pré-Albumina/genética , Valor Preditivo dos TestesRESUMO
Hereditary transthyretin amyloidosis is an autosomal dominant genetic disorder caused by missense mutations in the TTR gene resulting in amyloid formation of the transthyretin protein. Depending on the system affection, the manifestations may be different and high heterogeneity in the penetrance is observed. An endemic region in Bulgaria exists where the TTR mutation Glu89Gln is found with high frequency. This is a rare mutation and was probably introduced in the population by a common ancestor. This phenomenon, called "founder effect" was proved in carrier families by haplotype analysis of microsatellite markers showing linkage disequilibrium. Allele frequencies were analyzed and haplotype reconstruction was done with Arlequin v.3.01 software. The common ancestry of the carriers was demonstrated using additional data for their genealogies and microsatellite data from a control group of non-affected individuals. The results show that the mutation Glu89Gln is linked to one haplotype, called "hypothetical founder haplotype" which was compared to published haplotype data from other European patients and no similarity was found. Further population genetics studies of carriers of the Glu89Gln mutation from other endemic regions are required in order to clarify the geographical distribution of the mutation.
Assuntos
Neuropatias Amiloides Familiares/genética , Efeito Fundador , Ácido Glutâmico/genética , Glutamina/genética , Pré-Albumina/genética , Adulto , Idoso , Neuropatias Amiloides Familiares/epidemiologia , Bulgária/epidemiologia , Feminino , Haplótipos , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , MutaçãoRESUMO
Diagnosis in the early stages of hereditary transthyretin (ATTR) amyloidosis is imperative to support timely treatment to prevent or delay disease progression. Genetic testing in the setting of genetic counselling enables identification of carriers of a TTR gene mutation who are therefore at risk of developing TTR-associated disease. Knowledge of different genotypes and how they manifest in symptomatic disease should facilitate development of a structured and targeted approach to enable diagnosis of symptomatic disease in ATTR amyloidosis mutation carriers on the first manifestation of the earliest detectable sign or symptom. A group of experts from across Europe, Israel and Japan met to reach a consensus on such an approach. The proposed approach involves establishing a baseline for key clinical parameters, determination of the timing and frequency of follow-up in TTR mutation carriers based on a predicted age of disease onset, and recognition of the likely initial clinical signs and symptoms aligned with the phenotype of the specific TTR gene mutation and family history. Minimum criteria for diagnosis of symptomatic disease have been agreed, which it is hoped will ensure diagnosis of ATTR amyloidosis at the earliest possible stage in people with a known TTR mutation.
Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Mutação , Guias de Prática Clínica como Assunto , Pré-Albumina/genética , Idade de Início , Diagnóstico Precoce , Testes Genéticos , Humanos , AnamneseRESUMO
AIMS: In the current study we aimed to explore the prevalence of gastrointestinal (GI) manifestations in hereditary transthyretin amyloid (hATTR) amyloidosis associated with Glu89Gln mutation. METHODS: We recruited 78 patients with hATTR amyloidosis associated with Glu89Gln mutation. The diagnosis of hATTR was defined by a documented transthyretin mutation through DNA analysis. Symptoms were recorded as present or absent at the time of enrollment into the study. The gastrointestinal (GI) symptoms checklist included the following items: early satiety, nausea, vomiting, constipation, alternating diarrhea/ constipation, diarrhea, fecal incontinence and unintentional weight loss. RESULTS: Forty-two patients (53.8%) reported at least one GI symptom or sign. Diarrhea was the most frequently reported (30.8%), followed by unintentional weight loss (28.2%) and nausea (21.8%). Fecal incontinence (3.8%) was the least common one. No significant gender related difference in overall GI symptom prevalence was found (females 52.16%, males 55%, p = 0.834). Type of disease onset was not related to GI prevalence (earlyonset 50%, late-onset 55.6%, p=0.650). After dividing the patients into groups with a disease duration of <5 years, 5-10 years and >10 years, respectively, the prevalence of GI symptoms was found to be significantly higher in later stages (26.3% vs. 55.0% vs. 78.9%, p = 0.005; OR 2.450, 95% CI 1.084-5.538). Gastrointestinal manifestations had no impact on survival (p=0.193). CONCLUSIONS: Gastrointestinal manifestations are very common in hATTR patients with Glu89Gln mutation and increase with disease duration. They are not associated with gender and onset of the disease and have no impact on patient survival. These results highlight the importance of a thorough evaluation of the GI function in patients with ATTR amyloidosis and should stimulate further studies on the phenotypic differences related to genotype and geographic origin.
Assuntos
Neuropatias Amiloides Familiares/complicações , Gastroenteropatias/etiologia , Ácido Glutâmico/genética , Glutamina/genética , Mutação , Pré-Albumina/genética , Adulto , Idoso , Neuropatias Amiloides Familiares/genética , Diarreia/etiologia , Feminino , Gastroenteropatias/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Náusea/genética , Estudos Prospectivos , Redução de Peso/genéticaRESUMO
TTR-related amyloidosis (ATTR) is manifested in two allelic forms: familial amyloid polyneuropathy (TTR-FAP) and cardiomyopathy (TTR-FAC), both caused by mutations in the TTR gene. The most prevalent mutation in Bulgaria is p.Glu89Gln. Markedly different age at onset and disease penetrance is noticed in Bulgarian p.Glu89Gln cases even in a single family or between genetically identical twins. The present study aimed to evaluate the transcription profile of the TTR gene in order to better understand the difference in disease onset and penetrance. Six p.Glu89Gln positive families were selected from our registry, based on intrafamilial differences in disease onset and penetrance. Plasma and urine specimens were collected from 13 patients and subjected to transcription analysis. Both mutant and wild type transcripts were visualized in a mixed transcription profile, which is the traditional model of autosomal gene expression. The results from a relative quantification of the mutant versus wild type transcript showed presence of the mutant transcript between 0.14 and 1.14 times against the wild type. In addition, monoallelic expression signature was also detected. Based on our results we propose a model of natural selection, which includes age-related allele exclusion or suppression: predominant expression of a wild type (at an early age) and mutant (at the process of ageing) alleles. The intrafamilial differences in disease onset and penetrance need to be considered in genetic counselling and in follow-up of mutation carriers.
Assuntos
Substituição de Aminoácidos , Neuropatias Amiloides Familiares/genética , Cardiomiopatias/genética , Penetrância , Pré-Albumina/genética , Adulto , Idade de Início , Alelos , Bulgária , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Seleção GenéticaRESUMO
OBJECTIVE: To systematically study peripheral nerve morphology in patients with transthyretin (TTR) amyloidosis and TTR gene mutation carriers using high-resolution ultrasonography (US). METHODS: In this prospective cross-sectional study we took a structured history, performed neurological examination, and measured peripheral nerve cross-sectional areas (CSAs) bilaterally at 28 standard locations using US. Demographic and US findings were compared to controls. RESULTS: Peripheral nerve CSAs were significantly larger in 33 patients with familial amyloid polyneuropathy (FAP) compared to 50 controls, most dramatically at the common entrapment sites (median nerve at the wrist, ulnar nerve at the elbow), and in the proximal nerve segments (median nerve in the upper arm, sciatic nerve in the thigh). Findings in 21 asymptomatic TTR gene mutation carriers were less marked compared to controls, with CSAs being larger only in the median nerve in the upper arm. Nerve CSAs correlated with abnormalities on nerve conduction studies. CONCLUSION: Using US, we confirmed previous pathohistological and imaging reports in FAP of the most pronounced peripheral nerve thickening in the proximal limb segments. SIGNIFICANCE: Similar to US findings in diabetic and vasculitic neuropathies these predominantly proximal locations of nerve thickening may be attributed to ischaemic nerve damage caused by poor perfusion in the watershed zones along proximal limb segments.
Assuntos
Neuropatias Amiloides Familiares/diagnóstico por imagem , Nervos Periféricos/diagnóstico por imagem , Adolescente , Adulto , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pré-Albumina/genética , UltrassonografiaAssuntos
Neuropatias Amiloides Familiares , Fezes/química , Gastroenteropatias , Complexo Antígeno L1 Leucocitário/análise , Adulto , Idoso , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/etiologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
UBQLN2 and PFN1 were recently associated with amyotrophic lateral sclerosis (ALS). We investigated a role for these ALS genes in frontotemporal lobar degeneration (FTLD). We screened 328 FTLD, 17 FTLD-ALS, and 157 ALS patients. Patients originated from Flanders-Belgium except for 26 Bulgarian ALS patients. The frequency of UBQLN2 and PFN1 genetic variants in the FTLD patients was low at 0.30% and 0.91% respectively. Moreover, the biological relevance to disease of the variants was questionable. In UBQLN2, we identified p.S346C outside of the PXX domain in 1 FTLD patient. Yet, a closely located serine substitution, p.S340I, was observed in a neurologically healthy control individual. In PFN1, we observed the previously reported p.E117G mutation in 3 FTLD patients and in 3 control individuals. In the ALS patient cohort, we detected UBQLN2 variants in 1.27% of patients. These involved 2 novel UBQLN2 missense mutations, p.S400G and p.P440L, that were also present in unaffected relatives (i.e., the p.S400G carrier's son [70 years] and daughter [65 years]) and the p.P440L carrier's mother (67 years). No mutations were observed in PFN1. In summary, we conclude that genetic variations in UBQLN2 and PFN1 in a predominantly Flanders-Belgian cohort of FTLD and ALS patients are extremely rare.