Clinical, neuroradiological and genetic findings in a cohort of patients with multiple Cerebral Cavernous Malformations.

Cerebral cavernous malformations (CCM) consist of clusters of irregular dilated capillaries and represent the second most common type of vascular malformation affecting the central nervous system. CCM might be asymptomatic or cause cerebral hemorrhage, seizures, recurrent headaches and focal neurologic deficits. Causative mutations underlining CCM have been reported in three genes: KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3. Therapeutic avenues are limited to surgery. Here we present clinical, neuroradiological and molecular findings in a cohort of familial and sporadic CCM patients. Thirty subjects underwent full clinical and radiological assessment. Molecular analysis was performed by direct sequencing and MLPA analysis. Twenty-eight of 30 subjects (93%) experienced one or more typical CCM disturbances with cerebral/spinal hemorrhage being the most common (43%) presenting symptom. A molecular diagnosis was achieved in 87% of cases, with three novel mutations identified. KRIT1/CCM1 patients displayed higher risk of de novo CCMs appearance and bleedings. Magnetic Resonance Imaging (MRI) showed that infratentorial region was more frequently affected in mutated subjects while brainstem was often spared in patients with negative genetic testing.

Hereditary hemorrhagic telangiectasia associated with cortical development malformation due to a start loss mutation in ENG.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare disorder characterized by recurrent epistaxis, telangiectasias and systemic arteriovenous malformations (AVMs). HHT is associated with mutations in genes encoding for proteins involved in endothelial homeostasis such as ENG (endoglin) and ACVRL1 (activin receptor-like kinase-1). CASE PRESENTATION: Here we describe a 22-year-old male presenting with a transient episode of slurred speech and left arm paresis. Brain MRI displayed polymicrogyria. A right-to-left shunt in absence of an atrial septum defect was noted. Chest CT revealed multiple pulmonary AVMs, likely causing paradoxical embolism manifesting as a transient ischemic attack. The heterozygous ENG variant, c.3G > A (p.Met1lle), was detected in the patient. This variant was also found in patient's mother and in his younger brother who displayed cortical dysplasia type 2. CONCLUSIONS: The detection of cortical development malformations in multiple subjects from the same pedigree may expand the phenotypic features of ENG-related HHT patients. We suggest considering HHT in young patients presenting with acute cerebral ischemic events of unknown origin.

Violence against Women and Stress-Related Disorders: Seeking for Associated Epigenetic Signatures, a Pilot Study.

BACKGROUND: Violence against women is a relevant health and social problem with negative consequences on women's health. The interaction between genome and environmental factors, such as violence, represents one of the major challenges in molecular medicine. The Epigenetics for WomEn (EpiWE) project is a multidisciplinary pilot study that intends to investigate the epigenetic signatures associated with intimate partner and sexual violence-induced stress-related disorders. MATERIALS AND METHODS: In 2020, 62 women exposed to violence (13 women suffering from sexual violence and 49 from Intimate Partner Violence, IPV) and 50 women with no history of violence were recruited at the Service for Sexual and Domestic Violence. All women aged 18-65 were monitored for their physical and psychological conditions. Blood samples were collected, and DNAs were extracted and underwent the epigenetic analysis of 10 stress-related genes. RESULTS: PTSD prevalence in victims was assessed at 8.1%. Quantitative methylation evaluation of the ten selected trauma/stress-related genes revealed the differential iper-methylation of brain-derived neurotrophic factor, dopamine receptor D2 and insulin-like growth factor 2 genes. These genes are among those related to brain plasticity, learning, and memory pathways. CONCLUSIONS: The association of early detection of posttraumatic distress and epigenetic marker identification could represent a new avenue for addressing women survivors toward resilience. This innovative approach in gender-based violence studies could identify new molecular pathways associated with the long-term effects of violence and implement innovative protocols of precision medicine.

Charcot-Marie-Tooth disease type 2F associated with biallelic HSPB1 mutations.

OBJECTIVE: This work aims to expand knowledge regarding the genetic spectrum of HSPB1-related diseases. HSPB1 is a gene encoding heat shock protein 27, and mutations in HSPB1 have been identified as the cause of axonal Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy (dHMN). METHODS: Two patients with axonal sensorimotor neuropathy underwent detailed clinical examinations, neurophysiological studies, and next-generation sequencing with subsequent bioinformatic prioritization of genetic variants and in silico analysis of the likely causal mutation. RESULTS: The HSPB1 p.S135F and p.R136L mutations were identified in homozygosis in the two affected individuals. Both mutations affect the highly conserved alpha-crystallin domain and have been previously described as the cause of severe CMT2F/dHMN, showing a strictly dominant inheritance pattern. INTERPRETATION: Thus, we report for the first time two cases of biallelic HSPB1 p.S135F and p.R136L mutations in two families.

TYMP Variants Result in Late-Onset Mitochondrial Myopathy With Altered Muscle Mitochondrial DNA Homeostasis.

Biallelic TYMP variants result in the mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a juvenile-onset disorder with progressive course and fatal outcome. Milder late-onset (>40 years) form has been rarely described. Gene panel sequencing in a cohort of 60 patients featuring muscle accumulation of mitochondrial DNA (mtDNA) deletions detected TYMP defects in three subjects (5%), two of them with symptom onset in the fifth decade. One of the patients only displayed ptosis and ophthalmoparesis. Biochemical and molecular studies supported the diagnosis. Screening of TYMP is recommended in adult patients with muscle mtDNA instability, even in the absence of cardinal MNGIE features.