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BACKGROUND AND OBJECTIVE: Early-onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next-generation sequencing (NGS) of PD-associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far. METHODS: We retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD-related genes, as well as PD-multiplex ligation-dependent probe amplification in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report, and final interpretation (positive/negative/inconclusive). Patients were further stratified based on age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD-associated GBA1 variants were considered diagnostic. RESULTS: In 186 of 648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18 of 186 (10%) patients, with 5 shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive. CONCLUSIONS: This study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS-multigene panels, with relevant implications for counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Humanos , Persona de Mediana Edad , Adulto , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , Estudios Retrospectivos , Mutación , Pruebas Genéticas , Edad de InicioRESUMEN
Cooperative H-bonding interactions are a feature of supramolecular networks involving alcohols. A family of phenol oligomers, in which the hydroxyl groups form intramolecular H-bonds, was used to investigate this phenomenon. Chains of intramolecular H-bonds were characterized using nuclear magnetic resonance (NMR) spectroscopy in solution and X-ray crystallography in the solid state. The phenol oligomers were used to make quantitative measurements of the effects of the intramolecular interactions on the strengths of intermolecular H-bonding interactions between the H-bond donor on the end of the chain and a series of H-bond acceptors. Intramolecular H-bonding interactions in the chain increase the strength of a single intermolecular H-bond between the terminal phenol and quinuclidine by up to 14 kJ mol-1 in the n-octane solution. Although the magnitude of the effect increases with the length of the H-bonded chain, the first intramolecular H-bond has a much larger effect than subsequent interactions. H-bond cooperativity is dominated by pairwise interactions between nearest neighbors, and longer range effects are negligible. The results were used to develop a simple model for cooperativity in H-bond networks using an empirical parameter κ to quantify the sensitivity of the H-bond properties of a functional group to polarization. The value of κ measured in these systems was 0.33, which means that formation of the first H-bond increases the polarity of the next H-bond donor in the chain by 33%. The cumulative cooperative effect in longer H-bonded chains reaches an asymptotic value, which corresponds to a maximum increase in the polarity of the terminal H-bond donor of 50%.
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Alcoholes , Fenoles , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , QuinuclidinasRESUMEN
INTRODUCTION/AIMS: Currently, there are no straightforward guidelines for the clinical and diagnostic management of hyperCKemia, a frequent and nonspecific presentation in muscle diseases. Therefore, we aimed to describe our diagnostic workflow for evaluating patients with this condition. METHODS: We selected 83 asymptomatic or minimally symptomatic patients with persistent hyperCKemia for participation in this Italian multicenter study. Patients with facial involvement and distal or congenital myopathies were excluded, as were patients with suspected inflammatory myopathies or predominant respiratory or cardiac involvement. All patients underwent a neurological examination and nerve conduction and electromyography studies. The first step of the investigation included a screening for Pompe disease. We then evaluated the patients for myotonic dystrophy type II-related CCTG expansion and excluded patients with copy number variations in the DMD gene. Subsequently, the undiagnosed patients were investigated using a target gene panel that included 20 genes associated with isolated hyperCKemia. RESULTS: Using this approach, we established a definitive diagnosis in one third of the patients. The detection rate was higher in patients with severe hyperCKemia and abnormal electromyographic findings. DISCUSSION: We have described our diagnostic workflow for isolated hyperCKemia, which is based on electrodiagnostic data, biochemical screening, and first-line genetic investigations, followed by successive targeted sequencing panels. Both clinical signs and electromyographic abnormalities are associated with increased diagnostic yields.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Enfermedades Musculares , Creatina Quinasa , Variaciones en el Número de Copia de ADN , Electromiografía , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , HumanosRESUMEN
Vanishing White Matter Disease (VWMD) is a rare autosomal recessive leukoencephalopathy . The classical presentation is characterized by a severe cerebellar ataxia, spasticity, neurological deterioration with a chronic progressive course and episodes of acute neurological deterioration after stress conditions.We report a 52-year-old man with VWMD and atypical features who manifested two major events of transient aphasia eleven years apart with complete recovery in 48 hours. No cognitive decline was present. Brain MRI revealed typical aspects of VWMD including diffuse leukoencephalopathy with relative sparing of U-fibers. We identified the presence of c.592G>A (p.Glu198Lys) and c.1360 C>T (p.Pro454Ser) mutations in EIF2B5.
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Leucoencefalopatías , Sustancia Blanca , Adulto , Factor 2B Eucariótico de Iniciación/genética , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Sustancia Blanca/diagnóstico por imagenRESUMEN
Perrault syndrome is a rare disorder characterized by ovarian dysgenesis, bilateral sensorineural hearing loss and associated with mutations in six mitochondrial proteins. Additional neurological features were also described. Herein, we report on a 27-year-old woman with Perrault syndrome (PS), moderate ataxia and axonal sensory-motor peripheral neuropathy in whom we identified compound heterozygous mutations in the TWNK gene (p.Val507Ile and the novel p.Phe248Ser variant). Fewer than 30 patients with PS have been reported worldwide. Neurological involvement is more frequently associated with mutations in TWNK and indicates possible genotype-phenotype correlations. TWNK mutations should be searched in patients with sensory ataxia, early onset bilateral sensorineural hearing loss, and ovarian dysfunction in women.
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ADN Helicasas/genética , Disgenesia Gonadal 46 XX/genética , Pérdida Auditiva Sensorineural/genética , Proteínas Mitocondriales/genética , Adulto , Secuencia de Aminoácidos , Análisis Mutacional de ADN , Femenino , Humanos , Mutación , Mutación Missense , LinajeRESUMEN
Peripheral myelin protein 2 (PMP2) is a small protein located on the cytoplasmic side of compact myelin, involved in the lipids transport and in the myelination process. In the last years few families affected with demyelinating Charcot-Marie-Tooth neuropathy (CMT1), caused by PMP2 mutations, have been identified. In this study we describe the first case of a PMP2 in-frame deletion. PMP2 was analyzed by direct sequencing after exclusion of the most frequent CMT-associated genes by using a next generation sequencing (NGS) genes panel. Sanger sequencing was used for family's segregation analysis. Molecular modeling analysis was used to evaluate the mutation impact on the protein structure. A novel PMP2: p.I50del has been identified in a child with early onset CMT1 and in three affected family members. All family members show an early onset demyelinating neuropathy without other distinguish features. Molecular modeling analysis and in silico evaluations do not suggest a strong impact on the overall protein structure, but a most likely altered protein function. This study suggests the importance to add PMP2 in CMT NGS genes panels or, at most, to test it after major CMT1 genes exclusion, due to the lack of diagnostic-addressing additional features.
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Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Proteína P2 de Mielina/genética , Adulto , Edad de Inicio , Femenino , Humanos , Lactante , Masculino , Linaje , Adulto JovenRESUMEN
The aim of our study was to evaluate the role of mutations in the MAPT gene in patients with pure amyotrophic lateral sclerosis (ALS). A cohort of 120 ALS patients, both sporadic and familial, without cognitive impairment was analyzed by next-generation sequencing with a multiple-gene panel comprising 23 genes, including MAPT, known to be associated with ALS and frontotemporal dementia. The presence of the C9orf72 expansion was also investigated. Twelve patients had mutations in the SOD1, TARDBP, MATR3, and FUS genes, while 10 patients carried the C9orf72 expansion. One female patient was found to carry the D348G mutation in MAPT, previously reported in an Italian family with lower motor neuron disease. Our patient presented both upper and lower motor neuron signs, early development of dyspnea, resting and kinetic tremor, and a slow disease course (> 11 years). The present case further broadens the clinical phenotype associated with MAPT mutations and suggests that, although rarely, MAPT mutations can cause ALS and, therefore, should be analyzed in ALS patients, especially in those with early breathing difficulties and long-lasting disease.
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Esclerosis Amiotrófica Lateral/genética , Enfermedad de la Neurona Motora/genética , Mutación/genética , Proteínas tau/genética , Anciano , Expansión de las Repeticiones de ADN/genética , Femenino , Demencia Frontotemporal/genética , Estudios de Asociación Genética , Humanos , Italia , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited peripheral neuropathies. Although the typical disease onset is reported in the second decade, earlier onsets are not uncommon. To date, few studies on pediatric populations have been conducted and the achievement of molecular diagnosis remains challenging. METHODS: During the last 24 years we recruited 223 patients with early-onset hereditary peripheral neuropathies (EOHPN), negative for PMP22 duplication, 72 of them referred by a specialized pediatric hospital. Genetic testing for CMT-associated genes has been carried out with a range of different techniques. RESULTS: Of the 223 EOHPN cases, 43% were classified as CMT1 (demyelinating), 49% as CMT2 (axonal), and 8% as CMTi (intermediate). Genetic diagnosis was reached in 51% of patients, but the diagnostic yield increased to 67% when focusing only on cases from the specialized pediatric neuromuscular centers. Excluding PMP22 rearrangements, no significant difference in diagnostic rate between demyelinating and axonal forms was identified. De novo mutations account for 38% of cases. CONCLUSIONS: This study describes an exhaustive picture of EOHPN in an Italian referral genetic center and analyzes the molecular diagnostic rate of a heterogeneous cohort compared with one referred by a specialized pediatric center. Our data identify MPZ, MFN2, GDAP1, and SH3TC2 genes as the most frequent players in EOHPN. Our study underlines the relevance of a specific neurological pediatric expertise to address the genetic testing and highlights its importance to clarify possible unexpected results when neuropathy is only a secondary clinical sign of a more complex phenotype.
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Enfermedad de Charcot-Marie-Tooth , Humanos , Niño , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Pruebas Genéticas , Fenotipo , MutaciónRESUMEN
Approximately 10% to 15% of breast cancer cases in young women are diagnosed in patients harbouring germline (g) pathogenic or likely pathogenic variants (PVs) in the BReast CAncer 1 (BRCA1) or BReast CAncer 2 (BRCA2) genes. Preclinical and clinical studies showed a potential negative effect of germline BRCA1/2 (gBRCA1/2) PVs on ovarian reserve and reproductive potential, even before starting anticancer therapies. The aim of this article is to summarize the current literature on the fertility potential of young gBRCA1/2 PVs carriers with breast cancer and the risk of gonadotoxicity associated with anticancer treatments. Moreover, we describe the available evidence on the efficacy of fertility preservation techniques in young gBRCA1/2 PVs carriers and the safety data on having a pregnancy after breast cancer treatment.
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BACKGROUND: Universal screening of colorectal cancer (CRC) patients for Lynch syndrome (LS) through MisMatch Repair (MMR) testing is recommended. BRAF V600E mutation and/or MLH1 promoter methylation (Reflex Testing, RefT)generally rule out LS in MLH1-deficient (dMLH1) patients. We estimated the impact of RefTon genetic counseling (GC) and on the diagnostic yield of genetic testing (GT). METHODS: Overall, 3199 CRC patients were referred to our center between 2011 and 2021. Patients referred until January 2019 (n=2536) underwent universal MMR testing and were termed 'Cohort A'; among patients after February 2019 (n=663), 'Cohort B', RefT was also performed in dMLH1 patients. RESULTS: Overall, 401/3199 patients (12.5%) were MMR-deficient (dMMR); 312 (77.8%) in cohort A and 89 (22.2%) inB; 346/401 were dMLH1 (86.3%), 262/312 (83.9%) in cohort A and 84/89 (94.3%) in B. In Cohort A, 91/312 (29.1%) dMMR patients were referred to GC, 69/91 (75.8%) were in the dMLH1 group; 57/69 (82.6%) dMLH1 patients underwent GT and 1/57 (1.7%) had LS. In Cohort B, 3/84 dMLH1 patients did not undergo BRAF testing. Three BRAF wt and not hypermethylated of the remaining 81 dMLH1 patients were referred to GC and GT, and one had LS. This diagnostic pathway reduced GC referrals by 96% (78/81) in Cohort B and increased the diagnostic yield of GT by about 20 times. CONCLUSION: Our findings support RefT in dMLH1 CRC patients within the LS diagnostic pathway, as it reduces the number of GC sessions needed and increases the diagnostic yield of GT.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Reparación de la Incompatibilidad de ADN , Pruebas Genéticas , Homólogo 1 de la Proteína MutL , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Femenino , Masculino , Persona de Mediana Edad , Italia/epidemiología , Pruebas Genéticas/métodos , Reparación de la Incompatibilidad de ADN/genética , Anciano , Homólogo 1 de la Proteína MutL/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/epidemiología , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Metilación de ADN , Asesoramiento Genético , Mutación , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos , Estudios Retrospectivos , Estudios de SeguimientoRESUMEN
Multiple primary colorectal carcinomas (CRCs) synchronous, when detected approximately at the same time, or metachronous, when a significant amount of time has elapsed between diagnoses can show both mismatch repair (MMR) status concordance and discordance between primary tumors. The aim was to evaluate the MMR status of a monoinstitutional, retrospective cohort of synchronous and metachronous CRCs, with a focus on the frequency of cases with discordant MMR status, and explore the MMR status of metastatic nodal deposits. All synchronous and metachronous CRCs diagnosed in our institution between 2011 and 2023 were collected. Clinicopathologic characteristics were evaluated, including MMR status of all CRCs, BRAF mutation, and MLH1 promoter methylation analyses. MMR status discordant cases were further analyzed, and MMR testing was performed on nodal metastases. Of 3671 patients, 107 (2.9%) had multiple CRCs (94 synchronous and 13 metachronous; total number of CRCs 220). Sixty CRCs were MMR deficient (dMMR) (27.3%), and most were right-sided and high-grade and showed special histologic features (P < .00001). Ninety-three patients showed intertumoral MMR concordance: 70 (65.4%) with MMR-proficient (pMMR) CRCs, and 23 (21.5%) were dMMR. Fourteen patients (13.1%) showed intertumoral MMR discordance (at least one dMMR and one pMMR), and in 5 patients, nodal metastases were present: 2 patients harbored metastases only from their pMMR cancer, 2 only from their dMMR cancer, and in 1 patient both pMMR and dMMR metastases were present. In conclusion, all multiple primary CRCs should be analyzed for MMR status as discordant MMR is possible as well as discordant metastatic nodal deposits, and this may be important for patient management.
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Neoplasias Colorrectales , Neoplasias Primarias Múltiples , Humanos , Reparación de la Incompatibilidad de ADN , Estudios Retrospectivos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Inestabilidad de MicrosatélitesRESUMEN
Healthy carriers of BRCA1/2 pathogenic variants (PVs) may benefit from risk-reducing measures of proven efficacy. The main approach to identify these individuals is cascade testing, and strategies to support this complex process are under investigation. In Italy, cascade testing has received little attention; therefore, we analyzed the uptake and characteristics of BRCA1/2 cascade testing in families diagnosed with HBOC between 2017 and 2019 at two Italian genetics centers. All blood relatives aged 18 years or older at September 2022 and who could be involved in the first step of cascade testing (i.e., all the living relatives closest to the proband) were included. In addition to first-degree relatives, individuals who were second-, third- or fourth-degree relatives were included if the closest relative(s) was/were deceased. Overall, 213 families were included (103, Genoa; 110, Bologna). Most probands were women affected by breast and/or ovarian cancer (86.4%, Genoa; 84.5%, Bologna), and the branch segregating the PV was known/suspected in 62% of families (62.1%, Genoa; 60.9%, Bologna). Overall, the uptake of cascade testing was 22.8% (25.8%, Genoa; 19.9%, Bologna; OR = 0.59: 95%CI 0.43-0.82). It was strongly associated with female gender (OR = 3.31, 95%CI 2.38-4.59), age ≤ 70 years (< 30 years OR = 3.48, 95%CI 1.85-6.56; 30-70 years OR = 3.08, 95%CI 2.01-4.71), first-degree relationship with the proband (OR = 16.61, 95%CI 10.50-26.28) and segregation of the PV in both the maternal (OR = 2.54, 95%CI 1.72-3.75) and the paternal branch (OR = 4.62, 95%CI 3.09-6.91). These real-world data may be important to inform the design and implementation of strategies aimed at improving the uptake of HBOC cascade testing in Italy.
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INTRODUCTION: We recently demonstrated specific spectral signatures associated with updating of memory information, working memory (WM) maintenance and readout, with relatively high spatial resolution by means of high-density electroencephalography (hdEEG). WM is impaired already in early symptomatic HD (early-HD) and in pre-manifest HD (pre-HD). The aim of this study was to test whether hdEEG coupled to source localization allows for the identification of neuronal oscillations in specific frequency bands in 16 pre-HD and early-HD during different phases of a WM task. METHODS: We examined modulation of neural oscillations by event-related synchronization and desynchronization (ERS/ERD) of θ, ß, gamma low, γLOW and γHIGH EEG bands in a-priori selected large fronto-parietal network, including the insula and the cerebellum. RESULTS: We found: (i) Reduced θ oscillations in HD with respect to controls in almost all the areas of the WM network during the update and readout phases; (ii) Modulation of ß oscillations, which increased during the maintenance phase of the WM task in both groups; (iii) correlation of γHIGH oscillations during WM task with disease burden score in HD patients. CONCLUSIONS: Our data show reduced phase-specific modulation of oscillations in pre-HD and early-HD, even in the presence of preserved dynamic of modulation. Particularly, reduced synchronization in the θ band in the areas of the WM network, consistent with abnormal long-range coordination of neuronal activity within this network, was found in update and readout phases in HD groups.
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Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention.
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Neoplasias de la Mama , Síndrome de Li-Fraumeni , Proteína p53 Supresora de Tumor , Niño , Femenino , Humanos , Neoplasias de la Mama/patología , Predisposición Genética a la Enfermedad , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patología , Mastectomía , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Hereditary myopathies represent a clinically and genetically heterogeneous group of neuromuscular disorders, characterized by highly variable clinical presentations and frequently overlapping phenotypes with other neuromuscular disorders, likely influenced by genetic and environmental modifiers. Genetic testing is often challenging due to ambiguous clinical diagnosis. Here, we present the case of a family with clinical and Electromyography (EMG) features resembling a myotonia-like disorder in which Whole Exome Sequencing (WES) analysis revealed the co-segregation of two rare missense variants in UBR4 and HSPG2, genes previously associated with episodic ataxia 8 (EA8). A review of the literature highlighted a striking overlap between the clinical and the molecular features of our family and the previously described episodic ataxias (EAs), which raises concerns about the genotype-phenotype correlation, clinical variability, and the confounding overlap in these groups of disorders. This emphasizes the importance of thoroughly framing the patient's phenotype. The more clear-cut the diagnosis, the easier the identification of a genetic determinant, and the better the prognosis and the treatment of patients.
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Endometrial cancer (EC) is the most frequent gynecological cancer. The ESGO/ESTRO/ESP 2020 guidelines identify prognostic groups based on morpho-molecular characteristics. This study aims to evaluate the clinical applicability of NGS analysis to define an appropriate risk class and to improve the diagnostic and prognostic stratification of ECs. Cases of serous carcinoma (OHEC) and high- (HGEC) and low-grade (LGEC) endometrioid carcinoma diagnosed with the morphological and immunohistochemical (IHC) protocols were considered. After a standardized pre-analytical phase, tumor DNA was semi-automatically extracted and analyzed using NGS with a panel of 14 genes. A total of 63 cases were considered. NGS analysis was successful in 60 cases; all of these were classified according to the new diagnostic algorithm. The molecular risk classification showed a good correlation with the morphological (k = 0.8). The study showed that the protocols of the pre-analytical and analytical phases used are robust and can lead to molecular results that fall within the standards required, which can be used in clinical practice for more precise diagnostic-therapeutic management of patients. The implementation of the classification is particularly relevant for better prognostic stratification of HGECs. In addition, the identification of a suspicious VUS in POLE questions the classification of truncating variants.
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Chorea, cognitive decline, and psychiatric symptoms are shared by Huntington's disease (HD) and similar conditions called HD phenocopies. We describe the first case reported in Italy of Huntington disease-like 2 (HDL2), clinically and radiologically indistinguishable from HD, showing the importance of considering African ancestry in the diagnostic process.
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Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a "strictly length-dependent" phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation.
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Transmission of chemical signals across lipid bilayer membranes can be achieved using membrane-anchored molecules, where molecular motion across the bilayer is controlled by switching the polarity of two different head groups. An external redox signal delivered by ascorbic acid was used to trigger membrane translocation in a synthetic transduction system.
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Técnicas Electroquímicas/métodos , Membrana Dobles de Lípidos/química , Compuestos Organometálicos/química , Ácido Ascórbico/química , Cobre/química , Membranas Artificiales , Oxidación-ReducciónRESUMEN
BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a heritable connective tissue disorder caused by defects in the type III collagen protein. It is generally considered the most severe form of Ehlers-Danlos syndrome (EDS) due to an increased risk of spontaneous artery or organ rupture. vEDS has an extremely heterogeneous presentation and muscle rupture is considered a minor diagnostic criterium. METHODS: A patient with a long history of inconclusive examinations and investigations was referred to our unit. The clinical picture was mainly characterized by muscle ruptures, whereas the cardiovascular involvement was limited to mitral regurgitation. We performed a panel analysis of genes associated with inheritable heart diseases using the TruSight Cardio kit (Illumina). A skin biopsy was then performed for functional studies to analyze the different forms of collagen molecules produced in vitro by cutaneous fibroblasts. RESULTS: The patient presented the novel variant c.3478A>G (p.Ile1160Val) in COL3A1 (NM_000090.3), whose pathogenicity was supported by biochemical analysis of type III collagen. CONCLUSION: In this report, we describe a case of vEDS with predominant and severe musculoskeletal involvement. Our findings provide insight into genetic variants and clinical expression of vEDS, broadening the clinical scenario of the syndrome.