BACKGROUND: Emotion dysregulation is a key feature of schizophrenia, a brain disorder strongly as... more BACKGROUND: Emotion dysregulation is a key feature of schizophrenia, a brain disorder strongly associated with genetic risk and aberrant dopamine signalling. Dopamine is inactivated by catechol-O-methyltransferase (COMT), whose gene contains a functional polymorphism (COMT Val158Met) associated with differential activity of the enzyme and with brain physiology of emotion processing. The aim of the present study was to investigate whether genetic risk for schizophrenia and COMT Val158Met genotype interact on brain activity during implicit and explicit emotion processing.MethodA total of 25 patients with schizophrenia, 23 healthy siblings of patients and 24 comparison subjects genotyped for COMT Val158Met underwent functional magnetic resonance imaging during implicit and explicit processing of facial stimuli with negative emotional valence. RESULTS: We found a main effect of diagnosis in the right amygdala, with decreased activity in patients and siblings compared with control subjects. Furthermore, a genotype×diagnosis interaction was found in the left middle frontal gyrus, such that the effect of genetic risk for schizophrenia was evident in the context of the Val/Val genotype only, i.e. the phenotype of reduced activity was present especially in Val/Val patients and siblings. Finally, a complete inversion of the COMT effect between patients and healthy subjects was found in the left striatum during explicit processing. CONCLUSIONS: Overall, these results suggest complex interactions between genetically determined dopamine signalling and risk for schizophrenia on brain activity in the prefrontal cortex during emotion processing. On the other hand, the effects in the striatum may represent state-related epiphenomena of the disorder itself.
CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental dela... more CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental delay; intellectual disability; behavioral disturbances; movement disorders; visual defects; and subtle facial features caused by de novo loss-of-function variants in the CTNNB1 gene. Due to paucity of data, this study intends to describe feeding issues and oral-motor dyspraxia in an unselected cohort of 10 patients with a confirmed molecular diagnosis. Pathogenic variants along with key information regarding oral-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children’s Hospital Feeding Scale (I-MCH-FS). Mild-to-severe coordination difficulties in single or in a sequence of movements involving the endo-oral and peri-oral muscles were noticed across the entire cohort. Mild-to-profuse drooling was a commonly complained-about issue by 30% of parents. The mean total I-MCH-FS t-scor...
Purpose: Describing the clinical and genetic features of an ethnically heterogeneous group of (in... more Purpose: Describing the clinical and genetic features of an ethnically heterogeneous group of (inherited retinal diseases) IRD patients from different underrepresented countries, referring to specialized Italian Hospitals, and expanding the epidemiological spectrum of the IRD in understudied populations.Methods: The patients’ phenotypes underwent were characterized by exhaustive ophthalmological examinations, including morpho-functional testing. Genetic testing was performed using next-generation sequencing (NGS) and gene sequencing panels targeting a specific set of genes, Sanger sequencing and—when necessary—multiplex ligation-dependent probe amplification (MLPA) to better identify the genotype. When possible, segregation analysis was performed in order to confirm unsolved cases.Results: The article reports the results of the phenotypes and genotypes of 123 IRD probands, 69 males and 54 females, mean age 41 (IQR, 54–30) years, disease onset at 13 (IQR, 27.25–5) years. Thirty-three...
Congenital heart defects (CHDs) are known to occur in 9%–25% of patients with KBG syndrome. In th... more Congenital heart defects (CHDs) are known to occur in 9%–25% of patients with KBG syndrome. In this study we analyzed the prevalence and anatomic types of CHDs in 46 personal patients with KBG syndrome, carrying pathogenetic variants in ANKRD11 or 16q24.3 deletion, and reviewed CHDs in patients with molecular diagnosis of KBG syndrome from the literature. CHD was diagnosed in 15/40 (38%) patients with ANKRD11 variant, and in one patient with 16q24.3 deletion. Left ventricular outflow tract obstructions have been diagnosed in 9/15 (60%), subaortic or muscular ventricular septal defect in 5/15 (33%), dextrocardia in 1/15 (8%). The single patient with 16q24.3 deletion and CHD had complete atrioventricular septal defect (AVSD) with aortic coarctation. Review of KBG patients from the literature and present series showed that septal defects have been diagnosed in 44% (27/61) of the cases, left ventricular tract obstructions in 31% (19/61), AVSD in 18% (11/61). Septal defects have been diagnosed in 78% of total patients with 16q24.3 deletion. Valvar anomalies are frequently diagnosed, prevalently involving the left side of the heart. A distinctive association with AVSD is identifiable and could represent a marker to suggest the diagnosis in younger patients. In conclusion, after precise molecular diagnosis and systematic cardiological screening the prevalence of CHD in KBG syndrome seems to be higher than previously reported in clinical articles. In addition to septal defects, left‐sided anomalies and AVSD should be considered. Clinical management of KBG syndrome should include accurate and detailed echocardiogram at time of diagnosis.
Pathophysiology of Haemostasis and Thrombosis, 1984
A case of factor VII deficiency in a 52-year-old woman who developed central nervous system hemor... more A case of factor VII deficiency in a 52-year-old woman who developed central nervous system hemorrhage is here reported. Screening coagulation tests were all normal except for prothrombin time, normotest and thrombotest. Specific assays of vitamin Independent factors revealed that factor VII activity was reduced (11 U/dl). The studies of the family demonstrated that 2 sisters out of 4 were heterozygous for the defect. The activity of factor VII in the offspring, classified as obligatory carriers, ranged between 62 and 78 U/dl, the antigen between 55 and 75 U/dl. The wide variability of factor VII in normal people and the possible compensative effect of normal alleles in carriers do not allow to define the variant, namely if the patient is a CRMR homozygote or a CRMR/CRM- double heterozygote.
ABSTRACT The amygdala plays an important role in the regulation of motivational states, especiall... more ABSTRACT The amygdala plays an important role in the regulation of motivational states, especially those associated with addiction. The amygdala also expresses high levels of brain-derived neurotrophic factor (BDNF), an activity-dependent neurotrophin that can influence the reinforcing and locomotor activating properties of psychostimulants. In the present study, we examined the effects of acute and repeated amphetamine administration on the expression and production of this factor in the forebrain of rats. Animals given a single, acute injection (5 mg/kg, i.p.) of D-amphetamine developed hyperactivity followed by stereotypical behavior but showed no change in the basal expression of BDNF mRNA or its immunocytochemical profile in any region except the piriform cortex. Repeated injections (5 days) of 5 mg/kg amphetamine were accompanied by an enhanced onset of stereotypical behavior and elevated BDNF mRNA in the basolateral amygdala, rostral piriform cortex and paraventricular nucleus of the hypothalamus. Repeated treatment also increased BDNF immunoreactivity in perikarya of these same regions. In addition, increased BDNF immunoreactivity was found in fibers of many projection targets of the basolateral amygdala--the central extended amygdala, olfactory tubercle, medial nucleus accumbens, and in small zones resembling striosomes in the dorsal medial striatum. These results suggest that the upregulation of BDNF expression and protein in the basolateral nucleus of the amygdala and its targets could be an important part of the neuroadaptive response to psychostimulants.
CTNNB1 [OMIM *116806] encodes β‐catenin, an integral part of the cadherin/catenin complex, which ... more CTNNB1 [OMIM *116806] encodes β‐catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previousl...
BACKGROUND: Emotion dysregulation is a key feature of schizophrenia, a brain disorder strongly as... more BACKGROUND: Emotion dysregulation is a key feature of schizophrenia, a brain disorder strongly associated with genetic risk and aberrant dopamine signalling. Dopamine is inactivated by catechol-O-methyltransferase (COMT), whose gene contains a functional polymorphism (COMT Val158Met) associated with differential activity of the enzyme and with brain physiology of emotion processing. The aim of the present study was to investigate whether genetic risk for schizophrenia and COMT Val158Met genotype interact on brain activity during implicit and explicit emotion processing.MethodA total of 25 patients with schizophrenia, 23 healthy siblings of patients and 24 comparison subjects genotyped for COMT Val158Met underwent functional magnetic resonance imaging during implicit and explicit processing of facial stimuli with negative emotional valence. RESULTS: We found a main effect of diagnosis in the right amygdala, with decreased activity in patients and siblings compared with control subjects. Furthermore, a genotype×diagnosis interaction was found in the left middle frontal gyrus, such that the effect of genetic risk for schizophrenia was evident in the context of the Val/Val genotype only, i.e. the phenotype of reduced activity was present especially in Val/Val patients and siblings. Finally, a complete inversion of the COMT effect between patients and healthy subjects was found in the left striatum during explicit processing. CONCLUSIONS: Overall, these results suggest complex interactions between genetically determined dopamine signalling and risk for schizophrenia on brain activity in the prefrontal cortex during emotion processing. On the other hand, the effects in the striatum may represent state-related epiphenomena of the disorder itself.
CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental dela... more CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental delay; intellectual disability; behavioral disturbances; movement disorders; visual defects; and subtle facial features caused by de novo loss-of-function variants in the CTNNB1 gene. Due to paucity of data, this study intends to describe feeding issues and oral-motor dyspraxia in an unselected cohort of 10 patients with a confirmed molecular diagnosis. Pathogenic variants along with key information regarding oral-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children’s Hospital Feeding Scale (I-MCH-FS). Mild-to-severe coordination difficulties in single or in a sequence of movements involving the endo-oral and peri-oral muscles were noticed across the entire cohort. Mild-to-profuse drooling was a commonly complained-about issue by 30% of parents. The mean total I-MCH-FS t-scor...
Purpose: Describing the clinical and genetic features of an ethnically heterogeneous group of (in... more Purpose: Describing the clinical and genetic features of an ethnically heterogeneous group of (inherited retinal diseases) IRD patients from different underrepresented countries, referring to specialized Italian Hospitals, and expanding the epidemiological spectrum of the IRD in understudied populations.Methods: The patients’ phenotypes underwent were characterized by exhaustive ophthalmological examinations, including morpho-functional testing. Genetic testing was performed using next-generation sequencing (NGS) and gene sequencing panels targeting a specific set of genes, Sanger sequencing and—when necessary—multiplex ligation-dependent probe amplification (MLPA) to better identify the genotype. When possible, segregation analysis was performed in order to confirm unsolved cases.Results: The article reports the results of the phenotypes and genotypes of 123 IRD probands, 69 males and 54 females, mean age 41 (IQR, 54–30) years, disease onset at 13 (IQR, 27.25–5) years. Thirty-three...
Congenital heart defects (CHDs) are known to occur in 9%–25% of patients with KBG syndrome. In th... more Congenital heart defects (CHDs) are known to occur in 9%–25% of patients with KBG syndrome. In this study we analyzed the prevalence and anatomic types of CHDs in 46 personal patients with KBG syndrome, carrying pathogenetic variants in ANKRD11 or 16q24.3 deletion, and reviewed CHDs in patients with molecular diagnosis of KBG syndrome from the literature. CHD was diagnosed in 15/40 (38%) patients with ANKRD11 variant, and in one patient with 16q24.3 deletion. Left ventricular outflow tract obstructions have been diagnosed in 9/15 (60%), subaortic or muscular ventricular septal defect in 5/15 (33%), dextrocardia in 1/15 (8%). The single patient with 16q24.3 deletion and CHD had complete atrioventricular septal defect (AVSD) with aortic coarctation. Review of KBG patients from the literature and present series showed that septal defects have been diagnosed in 44% (27/61) of the cases, left ventricular tract obstructions in 31% (19/61), AVSD in 18% (11/61). Septal defects have been diagnosed in 78% of total patients with 16q24.3 deletion. Valvar anomalies are frequently diagnosed, prevalently involving the left side of the heart. A distinctive association with AVSD is identifiable and could represent a marker to suggest the diagnosis in younger patients. In conclusion, after precise molecular diagnosis and systematic cardiological screening the prevalence of CHD in KBG syndrome seems to be higher than previously reported in clinical articles. In addition to septal defects, left‐sided anomalies and AVSD should be considered. Clinical management of KBG syndrome should include accurate and detailed echocardiogram at time of diagnosis.
Pathophysiology of Haemostasis and Thrombosis, 1984
A case of factor VII deficiency in a 52-year-old woman who developed central nervous system hemor... more A case of factor VII deficiency in a 52-year-old woman who developed central nervous system hemorrhage is here reported. Screening coagulation tests were all normal except for prothrombin time, normotest and thrombotest. Specific assays of vitamin Independent factors revealed that factor VII activity was reduced (11 U/dl). The studies of the family demonstrated that 2 sisters out of 4 were heterozygous for the defect. The activity of factor VII in the offspring, classified as obligatory carriers, ranged between 62 and 78 U/dl, the antigen between 55 and 75 U/dl. The wide variability of factor VII in normal people and the possible compensative effect of normal alleles in carriers do not allow to define the variant, namely if the patient is a CRMR homozygote or a CRMR/CRM- double heterozygote.
ABSTRACT The amygdala plays an important role in the regulation of motivational states, especiall... more ABSTRACT The amygdala plays an important role in the regulation of motivational states, especially those associated with addiction. The amygdala also expresses high levels of brain-derived neurotrophic factor (BDNF), an activity-dependent neurotrophin that can influence the reinforcing and locomotor activating properties of psychostimulants. In the present study, we examined the effects of acute and repeated amphetamine administration on the expression and production of this factor in the forebrain of rats. Animals given a single, acute injection (5 mg/kg, i.p.) of D-amphetamine developed hyperactivity followed by stereotypical behavior but showed no change in the basal expression of BDNF mRNA or its immunocytochemical profile in any region except the piriform cortex. Repeated injections (5 days) of 5 mg/kg amphetamine were accompanied by an enhanced onset of stereotypical behavior and elevated BDNF mRNA in the basolateral amygdala, rostral piriform cortex and paraventricular nucleus of the hypothalamus. Repeated treatment also increased BDNF immunoreactivity in perikarya of these same regions. In addition, increased BDNF immunoreactivity was found in fibers of many projection targets of the basolateral amygdala--the central extended amygdala, olfactory tubercle, medial nucleus accumbens, and in small zones resembling striosomes in the dorsal medial striatum. These results suggest that the upregulation of BDNF expression and protein in the basolateral nucleus of the amygdala and its targets could be an important part of the neuroadaptive response to psychostimulants.
CTNNB1 [OMIM *116806] encodes β‐catenin, an integral part of the cadherin/catenin complex, which ... more CTNNB1 [OMIM *116806] encodes β‐catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previousl...
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