Case report: Complex arterial findings in vascular ehlers-danlos syndrome with a novel COL3A1 variant and death at young age

Vascular Ehlers-Danlos syndrome (vEDS) is a genetic disease caused by a pathogenic mutation in the COL3A1 gene. Despite its severe course, the rarity and extreme clinical variability of the disease can pose significant obstacles to a timely diagnosis. Early and accurate diagnosis may lead to improved patient outcomes by providing access to targeted pharmacological treatments like celiprolol and enhancing the management of vEDS-related complications. Herein, we report a patient harboring a novel de novo COL3A1 missense variant, in which the diagnosis was only possible belatedly due to delayed referral for genetic evaluation. The patient developed pulmonary complications, aneurysms, and vascular malformations, and died at the age of 26 years due to massive pulmonary bleeding

MCM5: a new actor in the link between DNA replication and Meier-Gorlin syndrome

Meier-Gorlin syndrome (MGORS) is a rare disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recessive mutations in ORC1, ORC4, ORC6, CDT1, CDC6, and CDC45, encoding members of the pre-replication (pre-RC) and pre-initiation (pre-IC) complexes, and heterozygous mutations in GMNN, a regulator of cell-cycle progression and DNA replication, have already been associated with this condition. We performed whole-exome sequencing (WES) in a patient with a clinical diagnosis of MGORS and identified biallelic variants in MCM5. This gene encodes a subunit of the replicative helicase complex, which represents a component of the pre-RC. Both variants, a missense substitution within a conserved domain critical for the helicase activity, and a single base deletion causing a frameshift and a premature stop codon, were predicted to be detrimental for the MCM5 function. Although variants of MCM5 have never been reported in specific human diseases, defect of this gene in zebrafish causes a phenotype of growth restriction overlapping the one associated with orc1 depletion. Complementation experiments in yeast showed that the plasmid carrying the missense variant was unable to rescue the lethal phenotype caused by mcm5 deletion. Moreover cell-cycle progression was delayed in patient's cells, as already shown for mutations in the ORC1 gene. Altogether our findings support the role of MCM5 as a novel gene involved in MGORS, further emphasizing that this condition is caused by impaired DNA replication

Long-term prognosis of patients with Ehlers-Danlos syndrome and epilepsy

15noreservedObjective: Epilepsy in Ehlers-Danlos syndrome (EDS) has been reported in the literature, but there are no studies that have investigated in detail clinical and electroencephalography (EEG) features in patients with EDS, and that have compared the outcome of epilepsy in subjects with or without brain lesions. We report a series of 42 patients with EDS and epilepsy, including data that concern clinical characteristics, EEG abnormalities, brain malformations at magnetic resonance imaging (MRI) and long-term outcome. Methods: EEG, clinical information, and neuroimaging characteristics in 42 patients with EDS were analyzed at the onset of epilepsy and after long-term follow-up (at least 5 years). We subdivided the patients into two groups: group A, 26 patients without brain abnormalities; group B, 16 patients with brain lesions, often with periventricular heterotopia (PH). Results: Group A patients: Most cases (19 of 26) presented focal epilepsy, whereas 7 of 26 were affected by generalized epilepsy; interictal EEG showed temporal or temporoparietal spikes in most cases. Twenty-three patients received antiepileptic drug (AED) monotherapy; three patients were treated with polytherapy. During follow-up, all patients were seizure-free for at least 2 years, and only one continued to receive AEDs. Group B patients: the majority presented focal epilepsy (9 of 16), but many patients had generalized epilepsy (7 of 16); interictal EEG showed usually frontal or frontotemporal spikes and waves. Many patients (12 of 16) received AED polytherapy. During follow-up, 12 patients were seizure-free, and all patients continued pharmacologic treatment. Significance: All patients without brain lesions showed a favorable response to AED monotherapy and were seizure-free after a few years of treatment. Patients with central nervous system abnormalities had a worse outcome, suggesting that the presence of brain lesions could influence the long-term evolution in these patients.mixedVerrotti, A.; Spartà, M.V.; Monacelli, D.; Porto, R.; Castagnino, M.; Russo Raucci, A.; Compagno, F.; Viglio, S.; Foiadelli, T.; Nicita, F.; Grosso, S.; Spalice, A.; Chiarelli, F.; Marseglia, G.; Savasta, S.Verrotti, A.; Spartà, M. V.; Monacelli, D.; Porto, R.; Castagnino, M.; Russo Raucci, A.; Compagno, F.; Viglio, S.; Foiadelli, T.; Nicita, F.; Grosso, S.; Spalice, A.; Chiarelli, F.; Marseglia, G.; Savasta, S

Oral and Fecal Microbiota in Lynch Syndrome

The role of microbiota in Lynch syndrome (LS) is still under debate. We compared oral and fecal microbiota of LS saliva and stool samples with normal healthy controls (NHC)