RESUMO
Myotonic Dystrophies (DM, Dystrophia Myotonia) are autosomal dominant inherited myopathies with a high prevalence across different ethnic regions. Despite some differences, mainly due to the pattern of muscle involvement and the age of onset, both forms, DM1 and DM2, share many clinical and genetic similarities. In this study, we retrospectively analyzed the medical record files of 561 Greek patients, 434 with DM1 and 127 with DM2 diagnosed in two large academic centers between 1994-2020. The mean age at onset of symptoms was 26.2 ± 15.3 years in DM1 versus 44.4 ± 17.0 years in DM2 patients, while the delay of diagnosis was 10 and 7 years for DM1 and DM2 patients, respectively. Muscle weakness was the first symptom in both types, while myotonia was more frequent in DM1 patients. Multisystemic involvement was detected in the great majority of patients, with cataracts being one of the most common extramuscular manifestations, even in the early stages of disease expression. In conclusion, the present work, despite some limitations arising from the retrospective collection of data, is the first record of a large number of Greek patients with myotonic dystrophy and emphasizes the need for specialized neuromuscular centers that can provide genetic counseling and a multidisciplinary approach.
Assuntos
Miotonia , Distrofia Miotônica , Humanos , Distrofia Miotônica/epidemiologia , Distrofia Miotônica/genética , Estudos Transversais , Estudos Retrospectivos , Grécia/epidemiologiaRESUMO
PURPOSE: Τo evaluate the clinical relevance of CEACAM5mRNA-positive circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). METHODS: Peripheral blood was obtained from 436 patients with mCRC before the initiation of systemic therapy. A second sample was obtained on treatment assessment from 296 (67.9%) patients. The detection of CEACAM5mRNA-positive CTCs was performed using a real-time PCR assay. RESULTS: The patients' median age was 67 years and PS (EGOG 0-1) 92%; KRAS exon 2 and BRAFV600E mutated primary tumors were identified in 31.9% and 6.4% of the tested patients, respectively, whereas metastasectomy was performed in 17.7% of the patients. Circulating CEACAM5mRNA-positive CTCs were detected in 125 (28.7%) and 85 (28.7%) patients at baseline and on treatment assessment, respectively. The detection of CEACAM5mRNA-positive cells was revealed, in multivariate analysis, as an independent prognostic factor associated with decreased PFS (HR 1.6; 95% CI 1.1-2.5; p = 0.026) and OS (HR 2.2; 95% CI 1.3-3.2; p < 0.001). The detection of CEACAM5mRNA-positive CTCs in patients with KRAS and BRAFV600E mutations was correlated with shorter PFS (p = 0.041 and p = 0.022, respectively). Moreover, OS was significantly shorter in patients with CEACAM5+/KRAS mutations compared to those with CEACAM5+/KRAS wt tumors (p = 0.023). CONCLUSIONS: Detection of peripheral blood CEACAM5mRNA-positive CTCs is an adverse prognostic factor correlated with poor clinical outcome in patients with mCRC, especially in patients with KRAS and BRAF mutated tumors.
Assuntos
Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/sangue , Células Neoplásicas Circulantes/metabolismo , Idoso , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Células Neoplásicas Circulantes/patologia , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Estudos Prospectivos , RNA Mensageiro/sangue , RNA Mensageiro/genéticaAssuntos
Transtornos Musculares Atróficos/diagnóstico , Transtornos Musculares Atróficos/epidemiologia , Adulto , Feminino , Grécia/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Transtornos Musculares Atróficos/genética , Receptores Androgênicos/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto JovemRESUMO
An expanded hexanucleotide repeat in C9ORF72 has been identified as the most common genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia in many populations, including the Greek. Recently, C9ORF72 expansions were reported as the most common genetic cause of Huntington disease (HD) phenocopies in a UK population. In the present study, we screened a selected cohort of 40 Greek patients with HD phenocopies for C9ORF72 hexanucleotide repeat expansions using repeat-primed polymerase chain reaction. We identified 2 patients (5%) with pathologic expansions. The first patient had chorea, behavioral-psychiatric disturbance, cognitive impairment, and a positive family history, fulfilling the strictest criteria for HD phenocopy. The second patient was sporadic and had parkinsonism, behavioral-psychiatric disturbance, and cognitive impairment, corresponding to a broader definition of HD phenocopy. These findings identify C9ORF72 expansions as a frequent cause of HD phenocopies in the Greek population, confirming recent findings in other populations and supporting proposed diagnostic testing for C9ORF72 expansions in patients with HD-like syndromes.
Assuntos
Expansão das Repetições de DNA/genética , Doença de Huntington/genética , Fenótipo , Proteínas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72 , Criança , Pré-Escolar , Estudos de Coortes , Demência Frontotemporal/genética , Grécia , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family.
RESUMO
OBJECTIVE: To address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD). METHODS: We analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20-59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale. RESULTS: Late-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046). CONCLUSIONS: A positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD.
Assuntos
Doença de Huntington/diagnóstico , Doença de Huntington/epidemiologia , Índice de Gravidade de Doença , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Doença de Huntington/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
Limited data exist on the spectrum of heredoataxias in Greece, including the prevalence and phenotype of Friedreich's ataxia (FRDA) and the prevalence and subtypes of dominant spinocerebellar ataxias (SCAs). We analyzed clinically and investigated genetically for FRDA and triplet-repeat expansion SCAs a consecutive series of 186 patients with suspected heredoataxia referred to Athens over 18 years. For prevalence estimates we included patients with molecular diagnosis from Cyprus that were absent from the Athens cohort. The minimum prevalence of FRDA was ~0.9/100,000, with clusters of high prevalence in Aegean islands. FRDA was diagnosed in 73 probands. The genotypic and phenotypic spectrum of FRDA was similar to other populations, with one patient compound heterozygote for a known point mutation in FXN (Asn146Lys). Undiagnosed recessive ataxias included FRDA-like and spastic ataxias. The minimum prevalence of dominant SCAs was ~0.7/100,000. SCA1 (4), SCA7 (4), SCA2, SCA6, and SCA17 (1 each) probands were identified. A molecular diagnosis was reached in 31% of dominant cases. Undiagnosed dominant patients included a majority of type III autosomal dominant cerebellar ataxias. FRDA is the commonest heredoataxia in the Greek population with prevalence towards the lower end of other European populations. Dominant SCAs are almost as prevalent. SCA1, SCA2, SCA6, SCA7 and SCA17 patients complete the spectrum of cases with a specific molecular diagnosis.
Assuntos
Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/epidemiologia , Vigilância da População , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Ataxia de Friedreich/genética , Grécia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População/métodos , Prevalência , Degenerações Espinocerebelares/diagnóstico , Degenerações Espinocerebelares/epidemiologia , Degenerações Espinocerebelares/genética , Adulto JovemRESUMO
OBJECTIVE: In a cohort of patients with suspected juvenile-onset Huntington disease (HD), we compared HD expansion-positive and -negative cases in order to identify parameters that may allow differentiating between them and may act as a guide to clinicians contemplating genetic testing. METHODS: We analyzed the clinical and genetic characteristics of 76 juvenile-onset patients referred consecutively for HD genetic testing over a 16-year period. RESULTS: In total, 24 patients were positive for the HD expansion (7.8% of our HD cohort). Mean age at onset of expanded cases was similar to unexpanded cases. All expanded cases had a family history of genetically confirmed HD compared to only 13.5% of unexpanded cases (p = 0.000). Clinical symptoms at onset or at presentation could not differentiate between expanded and unexpanded patients. Although criteria suggested by previous reports allowed statistical differentiation between the 2 groups, they were not sufficiently sensitive and specific to be used in clinical context and performed less satisfactorily than presence of a family history of HD alone. CONCLUSIONS: A diagnosis of juvenile HD should be primarily contemplated in symptomatic children with a family history of HD, although a proportion of these will test negative. With no family history of HD, juvenile HD is very unlikely and genetic testing should never delay searching for other causes. The specific nature of symptoms at onset or at presentation is of limited value in guiding the decision to test or not to test.
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Testes Genéticos/métodos , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
The relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. No data exist at present on the frequency of different SCAs in the Greek population. In the present study we investigated the presence of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in a cohort of 83 Greek patients with slowly progressive cerebellar ataxia. Twenty patients came from autosomal dominant (AD) pedigrees, seven displayed recessive or unclear inheritance and 56 were sporadic. We found four patients with pathological SCA expansions, all from AD pedigrees. Two patients had SCA1, one SCA2 and one SCA7 (10.0, 5.0 and 5.0% of the AD group, respectively). The clinical features of these patients were within the expected spectrum. In total, a pathological expansion was detected in 20% of patients from AD pedigrees. Interestingly, no cases of SCA3 or SCA6 were detected in the AD group. No expansions were found in other familial cases or in sporadic patients. Overall, no cases of SCA3, SCA6, SCA12, SCA17 or DRPLA were identified in the Greek population. In conclusion, SCA1, SCA2 and SCA7 are present in Greek patients with AD cerebellar ataxia in frequencies similar to those observed in other populations. SCA3 and SCA6 appear however to be rare in Greece. The genetic cause for the majority of AD ataxias remains to be identified.
Assuntos
Predisposição Genética para Doença/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Estudos de Coortes , Feminino , Genótipo , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Ataxias Espinocerebelares/classificaçãoRESUMO
UNLABELLED: Interatrial block is a predictor of atrial arrhythmias. Aim of the present study was to estimate the prevalence of interatrial block (IAB) in Friedreich's Ataxia (FA) compared to controls and correlate it with echocardiographic and genetic features. METHODS: IAB, defined as an electrocardiographic (ECG) derived P-wave duration >120 ms, echocardiographic variables and genetic markers were evaluated in 23 FA patients with no manifestation of cardiac involvement and were compared to 23 sex- and age-matched controls. RESULTS: IAB was significantly more frequent among FA patients compared to controls (11/23 vs 1/23, p<0.005 respectively). However, no correlations with echocardiographic parameters or Guanine-Adenine-Adenine (GAA) trinucleotide repeat lengths could be established. CONCLUSION: Early recognition of IAB could allow the identification of asymptomatic FA patients who are prone to develop potentially life-threatening arrhythmias.
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Ataxia de Friedreich/complicações , Ataxia de Friedreich/epidemiologia , Bloqueio Sinoatrial/complicações , Bloqueio Sinoatrial/epidemiologia , Adulto , Ecocardiografia , Feminino , Ataxia de Friedreich/genética , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Bloqueio Sinoatrial/genéticaRESUMO
UNLABELLED: OBJECTIVES. To define the incidence and prevalence of familial amyloidotic polyneuropathy (FAP) TTRVal30Met on the island of Cyprus. To study the clinical phenotype and genetic features of FAP TTRVal30Met in the Cypriot population. METHODS: The clinical and neurogenetic databases were used to identify probands with FAP TTRVal30Met and detailed family trees were constructed. Potential carriers of the mutation were identified from the family trees and assessed clinically and genetically. Transthyretin was completely sequenced in patients and potential carriers. RESULTS: Thirty-six patients carrying the TTRVal30Met mutation (one homozygote) from 22 families were identified. On 1 December 2003 the prevalence of FAP was 3.72/100,000 while the incidence is estimated to be 0.69/100,000 per year. The phenotype observed was characteristic for a length dependent sensorimotor and autonomic neuropathy with neuropathic pain. Mean age of onset was 46 years. Penetrance is estimated to be 28% and positive anticipation in the age of onset is found. CONCLUSION: FAP is relatively prevalent in Cyprus which may be considered as another endemic focus of the disease in Europe. The mean age of onset and penetrance is different from the Portuguese and Swedish populations. Understanding the biological factors that determine these differences could potentially lead to therapeutic advances.
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Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/genética , Pré-Albumina/genética , Adolescente , Adulto , Idade de Início , Idoso , Chipre/epidemiologia , Feminino , Triagem de Portadores Genéticos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
There is strong evidence that the length of CAG repeats, in patients with Huntington's disease (HD), govern the age of onset and the rate of clinical progression of neurological symptoms. However, psychiatric manifestations of the disease have not been examined as comprehensively. Seventy two Greek patients with Huntington's disease had DNA testing and were clinically assessed by means of a semi-structured interview (SCID) and four self-rated questionnaires. Genotype-phenotype correlations were examined. The CAG repeat length had a significant negative association with the age of onset of psychiatric disorders, the total level of functioning and the MMSE. However, the probability of developing a psychiatric disorder and the severity of psychiatric symptoms were not determined by the trinucleotide expansion, after controlling for the duration of illness, sex, and age of the subjects. The factors that determine the development of psychiatric symptoms in HD patients seem not to be limited to a dose related toxicity of the expanded Huntington. It is hypothesized that alternative genetic or environmental factors underlie the pathogenesis of the psychiatric phenotype.
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Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Expansão das Repetições de DNA/genética , Doença de Huntington/epidemiologia , Doença de Huntington/genética , Transtornos do Humor/epidemiologia , Transtornos do Humor/genética , Repetições de Trinucleotídeos/genética , Transtornos de Ansiedade/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Genótipo , Humanos , Doença de Huntington/diagnóstico , Entrevista Psicológica , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/diagnóstico , Fenótipo , Prevalência , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Numerous retrospective studies have reported the presence of psychiatric disorders at the prodromal or early stages of Huntington's disease (HD). However, most of the studies comparing gene carriers with non-carriers before the clinical manifestation of the illness have failed to reveal differences in the psychiatric manifestation. The objective of the present study was to detect behavioral and psychological features that differentiate gene carriers from non-carriers. METHODS: Eighty-one Greek patients at 50% risk for HD were recruited prospectively and examined by means of a semi-structured interview and four self-rated questionnaires. The study focused predominantly on hostility/irritability and obsessional behavior. RESULTS: Gene carriers had significantly higher extroverted hostility than non-carriers (p = .005). The elevated level of hostility was unaffected by the proximity to the estimated age of onset. The remainder of the scales did not reveal significant differences. CONCLUSIONS: Extroverted hostility, in particular criticism of others and delusional hostility, is increased in gene carriers well before the onset of clinical HD. Hostility is regarded as a personality dimension rather than as a behavioral pattern.
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Hostilidade , Doença de Huntington/genética , Doença de Huntington/psicologia , Risco , Repetições de Trinucleotídeos/genética , Adulto , Sintomas Comportamentais/fisiopatologia , Feminino , Humanos , MMPI , Masculino , Pessoa de Meia-Idade , Inventário de Personalidade , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
It is well recognized that statins affect muscular tissue adversely and that their use is associated with clinically important myositis, rhabdomyolysis, mild elevation of serum creatine kinase (CK) levels, myalgias, muscle weakness, muscle cramps, and persistent myalgias or serum CK level elevations after statin treatment is discontinued. The association between statins and the disclosure of presymptomatic metabolic myopathy is another underrated phenomenon related to statin therapy that was recently recognized in rare cases. The purpose of this report is to provide additional support for this association and to report other neuromuscular disorders that have also been seen following statin intake. The present case series illustrates that statins may act as unmasking agents in asymptomatic patients with a latent neuromuscular disorder. Thus, it may be postulated that statin intake may be a sufficient insult to precipitate neuromuscular symptoms and substantially increase muscle enzymes in presymptomatic patients with an abnormal neuromuscular substrate. In conclusion, muscular symptoms or increased serum CK levels persisting after statin treatment discontinuation should alert the clinician to pursue further diagnostic evaluations for the detection of potential underlying neuromuscular diseases.