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BACKGROUND: Guselkumab is a monoclonal antibody approved for treating moderate-to-severe plaque psoriasis. Long-term data on the effectiveness and safety of guselkumab in a real-world setting are still limited. MATERIALS AND METHODS: We conducted a 104-week monocentric retrospective study on 102 psoriasis patients, all treated with guselkumab for at least 16 weeks. At each visit, we used the Psoriasis Area and Severity Index (PASI): effectiveness endpoints were the percentages of patients achieving 75%/90%/100% (PASI 75/90/100) improvement in PASI compared with baseline. The Kaplan-Meier curve was used to assess the drug survival. RESULTS: At week 16, PASI 90 and PASI 100 were achieved by 49.02% and 32.35% of patients. At week 52, PASI 90 and PASI 100 were achieved by 71.58% and 55.79% of patients. After 2 years, PASI 90 and PASI 100 were achieved by 79.63% and 61.11% of patients. Obese and overweight patients had comparable PASI 90 and PASI 100 responses throughout the study. At week 104, no significant differences were observed between bio-naïve and bio-experienced patients regarding all effectiveness endpoints. No significant safety signals were reported in our study. After 24 months, 91.57% of our cohort was still on treatment with guselkumab. CONCLUSION: Our findings, although limited by the study's retrospective nature, confirm that guselkumab is a safe and effective therapeutic option for a "real-life" cohort of patients with psoriasis. J Drugs Dermatol. 2024;23(8):632-639. doi:10.36849/JDD.7486R1.
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Anticuerpos Monoclonales Humanizados , Psoriasis , Índice de Severidad de la Enfermedad , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/diagnóstico , Estudios Retrospectivos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto , AncianoRESUMEN
Rarely, the gram-negative bacteria Klebsiella pneumoniae causes skin infections that are frequently challenging to identify. We present a case of an atypical presentation of this specific disease in terms of its site, lack of risk factors, and length of illness.
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Biallelic expansions of the AAGGG repeat in the replication factor C subunit 1 (RFC1) have recently been described to be responsible for cerebellar ataxia, peripheral neuropathy and vestibular areflexia syndrome. This genetic alteration has also allowed genetic classification in up to one-third of cases with idiopathic sensory neuropathy. Here, we screened a well-characterized cohort of inflammatory neuropathy patients for RFC1 repeat expansions to explore whether RFC1 was increased from background rates and possibly involved in the pathogenesis of inflammatory neuropathy. A total of 259 individuals with inflammatory neuropathy and 243 healthy controls were screened for the AAGGG repeat expansion using short-range flanking PCR and repeat-primed PCR. Cases without amplifiable PCR product on flanking PCR and positive repeat-primed PCR were also tested for the mostly non-pathogenic expansions of the AAAGG and AAAAG repeat units. None of the patients showed biallelic AAGGG expansion of RFC1, and their carrier frequency for AAGGG was comparable with controls [n = 27 (5.2%) and n = 23 (4.7%), respectively; P > 0.5]. Data suggest that the pathologic expansions of AAGGG repeats do not contribute to the development of inflammatory neuropathies nor lead to misdiagnosed cases. Accordingly, routine genetic screening for RFC1 repeat expansion is not indicated in this patient population.
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Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG ⢠CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG ⢠CCG repeat motif and a specific pattern of muscle weakness.
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Músculo Esquelético , Expansión de Repetición de Trinucleótido , Población Blanca , Humanos , Masculino , Femenino , Adulto , Expansión de Repetición de Trinucleótido/genética , Persona de Mediana Edad , Población Blanca/genética , Músculo Esquelético/patología , Transportadoras de Casetes de Unión a ATP/genética , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Linaje , Anciano , Adulto Joven , Fibroblastos/metabolismo , Fibroblastos/patología , Debilidad Muscular/genética , Debilidad Muscular/patología , Adolescente , Distrofias MuscularesRESUMEN
Nucleotide repeat expansions in the human genome are a well-known cause of neurological disease. In the past decade, advances in DNA sequencing technologies have led to a better understanding of the role of non-coding DNA, that is, the DNA that is not transcribed into proteins. These techniques have also enabled the identification of pathogenic non-coding repeat expansions that cause neurological disorders. Mounting evidence shows that adult patients with familial or sporadic presentations of epilepsy, cognitive dysfunction, myopathy, neuropathy, ataxia, or movement disorders can be carriers of non-coding repeat expansions. The description of the clinical, epidemiological, and molecular features of these recently identified non-coding repeat expansion disorders should guide clinicians in the diagnosis and management of these patients, and help in the genetic counselling for patients and their families.
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Enfermedades del Sistema Nervioso , Humanos , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/diagnóstico , Diagnóstico Diferencial , Expansión de las Repeticiones de ADN/genéticaRESUMEN
BACKGROUND: Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. OBJECTIVE: Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies. METHODS: We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases. RESULTS: In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment. CONCLUSION: Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies.
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Progresión de la Enfermedad , Humanos , Persona de Mediana Edad , Italia/epidemiología , Masculino , Femenino , Anciano , Estudios de Cohortes , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/epidemiología , Adulto , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/epidemiología , Ataxia Cerebelosa/diagnóstico por imagen , Ataxia Cerebelosa/fisiopatología , Edad de Inicio , Factores de Crecimiento de Fibroblastos , Degeneraciones EspinocerebelosasRESUMEN
BACKGROUND: Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects. METHODS: We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics. RESULTS: We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies. INTERPRETATION: Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.
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Enfermedad de Charcot-Marie-Tooth , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Humanos , Adulto , Masculino , Femenino , Persona de Mediana Edad , Adolescente , Adulto Joven , Índice de Severidad de la Enfermedad , Niño , Proteínas de la Mielina/genética , Selección de Paciente , Fenotipo , Anciano , Genes Modificadores , PreescolarRESUMEN
Charcot-Marie-Tooth disease (CMT) is one of the most common and genetically heterogeneous inherited neurological diseases, with more than 130 disease-causing genes. Whole genome sequencing (WGS) has improved diagnosis across genetic diseases, but the diagnostic impact in CMT is yet to be fully reported. We present the diagnostic results from a single specialist inherited neuropathy centre, including the impact of WGS diagnostic testing. Patients were assessed at our specialist inherited neuropathy centre from 2009-2023. Genetic testing was performed using single gene testing, next-generation sequencing targeted panels, research whole exome and whole genome sequencing (WGS), and latterly WGS through the UK National Health Service. Variants were assessed using the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science criteria. Excluding patients with hereditary ATTR amyloidosis, 1515 patients with a clinical diagnosis of CMT and related disorders were recruited. 621 patients had CMT1 (41.0%), 294 CMT2 (19.4%), 205 intermediate CMT (CMTi, 13.5%), 139 hereditary motor neuropathy (HMN, 9.2%), 93 hereditary sensory neuropathy (HSN, 6.1%), 38 sensory ataxic neuropathy (2.5%), 72 hereditary neuropathy with liability to pressure palsies (HNPP, 4.8%) and 53 'complex' neuropathy (3.5%). Overall, a genetic diagnosis was reached in 76.9% (1165/1515). A diagnosis was most likely in CMT1 (96.8%, 601/621), followed by CMTi (81.0%, 166/205) and then HSN (69.9%, 65/93). Diagnostic rates remained less than 50% in CMT2, HMN and complex neuropathies. The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%), then GJB1 (CMTX1; 151/1165, 13.0%), PMP22 deletion (HNPP; 72/1165, 6.2%) and MFN2 (CMT2A; 46/1165, 3.9%). We recruited 233 cases to the UK 100,000 Genomes Project (100KGP), of which 74 (31.8%) achieved a diagnosis; 28 had been otherwise diagnosed since recruitment leaving a true diagnostic rate of WGS through the 100KGP of 19.7% (46/233). However, almost half of the solved cases (35/74) received a negative report from the study, and the diagnosis was made through our research access to the WGS data. The overall diagnostic uplift of WGS for the entire cohort was 3.5%. Our diagnostic rate is the highest reported from a single centre, and has benefitted from the use of WGS, particularly access to the raw data. However, almost one quarter of all cases remain unsolved, and a new reference genome and novel technologies will be important to narrow the 'diagnostic gap'.
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We describe here a 73-year-old patient presenting with atypical MSA-P-like phenotype carrying a monoallelic p. W279X mutation in the APTX gene, which causes ataxia with oculomotor apraxia type 1 (AOA1) when in homozygous state. We hypothesize that rare monoallelic APTX variants could modulate MSA risk and phenotype.
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Atrofia de Múltiples Sistemas , Fenotipo , Anciano , Humanos , Masculino , Apraxias/genética , Apraxias/congénito , Síndrome de Cogan/genética , Proteínas de Unión al ADN/genética , Heterocigoto , Atrofia de Múltiples Sistemas/genética , MutaciónRESUMEN
Biological drugs have dramatically changed the approach to treating moderate-to-severe plaque psoriasis, achieving excellent skin clearance and safety outcomes. However, the management of difficult-to-treat areas (e.g., scalp, palms/soles, nails, and genitalia) still represents a challenge in psoriasis treatment. Data in the literature on difficult-to-treat sites are limited and, frequently, no specific analysis is performed during clinical trials. We conducted a 52-week, retrospective study to evaluate the effectiveness of ixekizumab in 120 patients with moderate-to-severe plaque psoriasis of at least one difficult-to-treat area (scalp, palmoplantar surfaces, nails, and genitalia). Ninety-nine patients had scalp psoriasis, 35 had involvement of the palms or soles, 27 were affected by genital psoriasis, and 22 patients reported involvement of the nails. After 1 year of treatment, 96% of patients with scalp involvement, 95.6% of patients with palmoplantar psoriasis, 95.2% of patients with genital psoriasis, and 85% of patients with nail involvement achieved a site-specific Physician's Global Assessment of 0 or 1 (clear or almost clear). No serious adverse events were observed during the study. Our study supports the effectiveness of ixekizumab in plaque psoriasis involving difficult-to-treat sites.
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Anticuerpos Monoclonales Humanizados , Fármacos Dermatológicos , Psoriasis , Índice de Severidad de la Enfermedad , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/diagnóstico , Psoriasis/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Fármacos Dermatológicos/uso terapéutico , Fármacos Dermatológicos/administración & dosificación , Resultado del Tratamiento , AncianoRESUMEN
INTRODUCTION: Hereditary ataxias (HAs) encompass a diverse and genetically intricate group of rare neurodegenerative disorders, presenting diagnostic challenges. Whole-exome sequencing (WES) has significantly improved diagnostic success. This study aimed to elucidate genetic causes of cerebellar ataxia within a diverse Brazilian cohort. METHODS: Biological samples were collected from individuals with sporadic or familial cerebellar ataxia, spanning various ages and phenotypes, excluding common SCAs and Friedreich ataxia. RFC1 biallelic AAGGG repeat expansion was screened in all patients. For AAGGG-negative cases, WES targeting 441 ataxia-related genes was performed, followed by ExpansionHunter analysis for repeat expansions, including the recently described GGC-ZFHX3. Variant classification adhered to ClinGen guidelines, yielding definitive or probable diagnoses. RESULTS: The study involved 76 diverse Brazilian families. 16 % received definitive diagnoses, and another 16 % received probable ones. RFC1-related ataxia was predominant, with two definitive cases, followed by KIF1A (one definitive and one probable) and SYNE-1 (two probable). Early-onset cases exhibited higher diagnostic rates. ExpansionHunter improved diagnosis by 4 %.We did not detected GGC-ZFHX3 repeat expansion in this cohort. CONCLUSION: This study highlights diagnostic complexities in cerebellar ataxia, even with advanced genetic methods. RFC1, KIF1A, and SYNE1 emerged as prevalent mutations. ZFHX3 repeat expansion seem to be rare in Brazilian population. Early-onset cases showed higher diagnostic success. WES coupled with ExpansionHunter holds promise as a primary diagnostic tool, emphasizing the need for broader NGS accessibility in Brazil.
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Ataxia Cerebelosa , Degeneraciones Espinocerebelosas , Humanos , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Brasil , Ataxia/genética , Fenotipo , Mutación/genética , Degeneraciones Espinocerebelosas/complicaciones , Cinesinas/genéticaRESUMEN
BACKGROUND AND PURPOSE: Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB. METHODS: Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot-Marie-Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features. RESULTS: The pathogenic CRYAB variant c.358A>G;p.Arg120Gly was segregated in all affected patients from two unrelated families. The disease presented as late onset CMT2 (onset over 40 years) with distal sensory and motor impairment and congenital cataracts. Muscle involvement was probably associated in cases showing mild axial and diaphragmatic weakness. In all cases, nerve conduction studies demonstrated the presence of an axonal sensorimotor neuropathy along with chronic neurogenic changes on needle examination. DISCUSSION: In cases with late onset autosomal dominant CMT2 and congenital cataracts, it is recommended that CRYAB is considered for genetic testing. The identification of CRYAB mutations causing CMT2 further supports a continuous spectrum of expressivity, from myopathic to neuropathic and mixed forms, of a growing number of genes involved in protein degradation and chaperone-assisted autophagy.
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Catarata , Enfermedad de Charcot-Marie-Tooth , Cristalinas , Humanos , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Mutación/genética , Pruebas Genéticas , Fenotipo , Cristalinas/genética , Catarata/genética , LinajeRESUMEN
Only few cases of rhino-orbital mucormycosis in patients with liver cirrhosis are described in the literature and most of these patients showed an associated diabetes mellitus. We describe a case of rhino-orbital mucormycosis in a patient with liver cirrhosis without other risk factors.