It has been proposed that impairments of the predictive function exerted by the cerebellum may ac... more It has been proposed that impairments of the predictive function exerted by the cerebellum may account for social cognition deficits. Here, we integrated cerebellar functions in a predictive coding framework to elucidate how cerebellar alterations could affect the predictive processing of others’ behavior. Experiment 1 demonstrated that cerebellar patients were impaired in relying on contextual information during action prediction, and this impairment was significantly associated with social cognition abilities. Experiment 2 indicated that patients with cerebellar malformation showed a domain-general deficit in using contextual information to predict both social and physical events. Experiment 3 provided first evidence that a social-prediction training in virtual reality could boost the ability to use context-based predictions to understand others’ intentions. These findings shed new light on the predictive role of the cerebellum and its contribution to social cognition, paving the ...
BackgroundPontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorde... more BackgroundPontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes.MethodsWe performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for CASK rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters.ResultsA genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was CASK, which account...
ObjectiveAiming to detect associations between neuroradiologic and EEG evaluations and long-term ... more ObjectiveAiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed.MethodsOnly patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed.ResultsPatients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% ...
Background It has been known for more than 30 years that balanced translocations, especially if d... more Background It has been known for more than 30 years that balanced translocations, especially if de novo, can associate with congenital malformations and / or neurodevelopmental disorders, following the disruption of a disease gene or its cis-regulatory elements at one or both breakpoints. Case presentation We describe a 10-year-old girl with a non-specific neurodevelopmental disorder characterized by moderate intellectual disability (ID), gross motor clumsiness, social and communication deficits. She carries a de novo reciprocal translocation between chromosomes 1q43 and 22q13.3, the latter suggesting the involvement of SHANK3. Indeed, its haploinsufficiency associates with Phelan-McDermid Syndrome, whose main symptoms are characterized by global developmental delay and absent or severely delayed expressive speech. A deep molecular approach, including next-generation sequencing of SHANK3 locus, allowed demonstrating the breakage of RYR2 and SHANK3 on the derivative chromosomes 1 and...
Background Patients with cerebellar malformations exhibit not only movement problems, but also im... more Background Patients with cerebellar malformations exhibit not only movement problems, but also important deficits in social cognition. Thus, rehabilitation approaches should not only involve the recovery of motor function but also of higher-order abilities such as processing of social stimuli. In keeping with the general role of the cerebellum in anticipating and predicting events, we used a VR-based rehabilitation system to implement a social cognition intensive training specifically tailored to improve predictive abilities in social scenarios (VR-Spirit). Methods/design The study is an interventional randomised controlled trial that aims to recruit 42 children, adolescents and young adults with congenital cerebellar malformations, randomly allocated to the experimental group or the active control group. The experimental group is administered the VR-Spirit, requiring the participants to compete with different avatars in the reaching of recreational equipment and implicitly promptin...
ObjectiveTo estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descr... more ObjectiveTo estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort.MethodsWe enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available.ResultsWe identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41–0.53), 0.41 (95% CI 0.32–0.49), and 0.53 (95% CI 0.45–0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49–1.97), 1.62 (95% CI 1.31–1.9...
Background: Patients with cerebellar malformations exhibit not only movement problems, but also i... more Background: Patients with cerebellar malformations exhibit not only movement problems, but also important deficits in social cognition. Thus, rehabilitation approaches should not only involve the recovery of motor function but also of higher-order abilities, such as processing of social stimuli. In keeping with the general role of the cerebellum in anticipating and predicting events, we used a VR-based rehabilitation system to implement a social cognition intensive training specifically tailored to improve predictive abilities in social scenarios (VR-Spirit). Methods: The study is an interventional randomized controlled trial that aims to recruit 42 children, adolescents and young adults with congenital cerebellar malformations, randomly allocated to the experimental or active control group. The experimental group is administered the VR-Spirit, requiring the participants to compete with different avatars in the reaching of recreational equipment and implicitly prompting them to form...
Mutations in tubulin genes are responsible for a large spectrum of brain malformations secondary ... more Mutations in tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation and axon guidance and maintenance. Motor impairment, intellectual disability and epilepsy are the main clinical symptoms. In the present study 15 patients from a personal cohort and 75 from 21 published studies carrying mutations in TUBA1A, TUBB2B and TUBB3 tubulin genes were evaluated with the aim to define a clinical and electrophysiological associated pattern. Epilepsy shows a wide range of severity without a specific pattern. Mutations in TUBA1A (60%) and TUBB2B (74%) and TUBB3 (25%) genes are associated with epilepsy. The accurate analysis of the Electroencephalogram (EEG) pattern in wakefulness and sleep in our series allows us to detect significant abnormalities of the background activity in 100% of patients. The involvement of white matter and of the inter-hemispheric connection structures typically observed in tubulin...
Background Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain–h... more Background Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain–hindbrain malformation and multiorgan involvement. Renal disease, mainly juvenile nephronophthisis (NPH), was reported in 25–30% patients although only ∼18% had a confirmed diagnosis of chronic kidney disease (CKD). NPH often remains asymptomatic for many years, resulting in delayed diagnosis. The aim of the study was to identify a biomarker able to quantify the risk of progressive CKD in young children with JS. Methods Renal features were investigated in 93 Italian patients, including biochemical tests, ultrasound and 1-deamino-8D-arginine vasopressin test in children with reduced basal urine osmolality. A subset of patients was followed-up over time. Results At last examination, 27 of 93 subjects (29%) presented with CKD, ranging from isolated urinary concentration defect (UCD) to end-stage renal disease. Both normal and pathological urine osmolality levels remained stable over time, ev...
European journal of medical genetics, Jan 17, 2018
A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each... more A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each is subject to specific spatial and temporal expression patterns. However, most are highly expressed in post-mitotic neurons during stages of neuronal migration and differentiation. The major tubulin subclasses (alpha- and beta-tubulin) share high sequence and structural homology. These globular proteins form heterodimers and subsequently co-assemble into microtubules. Microtubules are dynamic, cytoskeletal polymers which play key roles in cellular processes crucial for cortical development, including neuronal proliferation, migration and cortical laminar organisation. Mutations in seven genes encoding alpha-tubulin (TUBA1A), beta-tubulin (TUBB2A, TUBB2B, TUBB3, TUBB4A, TUBB) and gamma-tubulin (TUBG1) isoforms have been associated with a wide and overlapping range of brain malformations or "Tubulinopathies". The majority of cortical phenotypes include lissencephaly, polymicrogy...
Pediatric brain damage is associated with various cognitive deficits. Cognitive rehabilitation ma... more Pediatric brain damage is associated with various cognitive deficits. Cognitive rehabilitation may prevent and reduce cognitive impairment. In recent years, home-based computerized cognitive training (CCT) has been introduced in clinical practice to increase treatment opportunities for patients (telerehabilitation). However, limited research has been conducted thus far on investigating the effects of remote CCT for the juvenile population in contexts other than English-speaking countries. The aim of the present study was to investigate the feasibility of a home-based CCT in a group of Italian adolescents with brain damage. A commercially available CCT (Lumosity) developed in the English language was used due to the lack of telerehabilitation programs in the Italian language that allow stimulation of multiple cognitive domains and, at the same time, remote automatic collection of data. Thus, this investigation provides information on the possibility of introducing CCT programs availa...
It has been proposed that impairments of the predictive function exerted by the cerebellum may ac... more It has been proposed that impairments of the predictive function exerted by the cerebellum may account for social cognition deficits. Here, we integrated cerebellar functions in a predictive coding framework to elucidate how cerebellar alterations could affect the predictive processing of others’ behavior. Experiment 1 demonstrated that cerebellar patients were impaired in relying on contextual information during action prediction, and this impairment was significantly associated with social cognition abilities. Experiment 2 indicated that patients with cerebellar malformation showed a domain-general deficit in using contextual information to predict both social and physical events. Experiment 3 provided first evidence that a social-prediction training in virtual reality could boost the ability to use context-based predictions to understand others’ intentions. These findings shed new light on the predictive role of the cerebellum and its contribution to social cognition, paving the ...
BackgroundPontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorde... more BackgroundPontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes.MethodsWe performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for CASK rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters.ResultsA genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was CASK, which account...
ObjectiveAiming to detect associations between neuroradiologic and EEG evaluations and long-term ... more ObjectiveAiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed.MethodsOnly patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed.ResultsPatients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% ...
Background It has been known for more than 30 years that balanced translocations, especially if d... more Background It has been known for more than 30 years that balanced translocations, especially if de novo, can associate with congenital malformations and / or neurodevelopmental disorders, following the disruption of a disease gene or its cis-regulatory elements at one or both breakpoints. Case presentation We describe a 10-year-old girl with a non-specific neurodevelopmental disorder characterized by moderate intellectual disability (ID), gross motor clumsiness, social and communication deficits. She carries a de novo reciprocal translocation between chromosomes 1q43 and 22q13.3, the latter suggesting the involvement of SHANK3. Indeed, its haploinsufficiency associates with Phelan-McDermid Syndrome, whose main symptoms are characterized by global developmental delay and absent or severely delayed expressive speech. A deep molecular approach, including next-generation sequencing of SHANK3 locus, allowed demonstrating the breakage of RYR2 and SHANK3 on the derivative chromosomes 1 and...
Background Patients with cerebellar malformations exhibit not only movement problems, but also im... more Background Patients with cerebellar malformations exhibit not only movement problems, but also important deficits in social cognition. Thus, rehabilitation approaches should not only involve the recovery of motor function but also of higher-order abilities such as processing of social stimuli. In keeping with the general role of the cerebellum in anticipating and predicting events, we used a VR-based rehabilitation system to implement a social cognition intensive training specifically tailored to improve predictive abilities in social scenarios (VR-Spirit). Methods/design The study is an interventional randomised controlled trial that aims to recruit 42 children, adolescents and young adults with congenital cerebellar malformations, randomly allocated to the experimental group or the active control group. The experimental group is administered the VR-Spirit, requiring the participants to compete with different avatars in the reaching of recreational equipment and implicitly promptin...
ObjectiveTo estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descr... more ObjectiveTo estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort.MethodsWe enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available.ResultsWe identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41–0.53), 0.41 (95% CI 0.32–0.49), and 0.53 (95% CI 0.45–0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49–1.97), 1.62 (95% CI 1.31–1.9...
Background: Patients with cerebellar malformations exhibit not only movement problems, but also i... more Background: Patients with cerebellar malformations exhibit not only movement problems, but also important deficits in social cognition. Thus, rehabilitation approaches should not only involve the recovery of motor function but also of higher-order abilities, such as processing of social stimuli. In keeping with the general role of the cerebellum in anticipating and predicting events, we used a VR-based rehabilitation system to implement a social cognition intensive training specifically tailored to improve predictive abilities in social scenarios (VR-Spirit). Methods: The study is an interventional randomized controlled trial that aims to recruit 42 children, adolescents and young adults with congenital cerebellar malformations, randomly allocated to the experimental or active control group. The experimental group is administered the VR-Spirit, requiring the participants to compete with different avatars in the reaching of recreational equipment and implicitly prompting them to form...
Mutations in tubulin genes are responsible for a large spectrum of brain malformations secondary ... more Mutations in tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation and axon guidance and maintenance. Motor impairment, intellectual disability and epilepsy are the main clinical symptoms. In the present study 15 patients from a personal cohort and 75 from 21 published studies carrying mutations in TUBA1A, TUBB2B and TUBB3 tubulin genes were evaluated with the aim to define a clinical and electrophysiological associated pattern. Epilepsy shows a wide range of severity without a specific pattern. Mutations in TUBA1A (60%) and TUBB2B (74%) and TUBB3 (25%) genes are associated with epilepsy. The accurate analysis of the Electroencephalogram (EEG) pattern in wakefulness and sleep in our series allows us to detect significant abnormalities of the background activity in 100% of patients. The involvement of white matter and of the inter-hemispheric connection structures typically observed in tubulin...
Background Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain–h... more Background Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain–hindbrain malformation and multiorgan involvement. Renal disease, mainly juvenile nephronophthisis (NPH), was reported in 25–30% patients although only ∼18% had a confirmed diagnosis of chronic kidney disease (CKD). NPH often remains asymptomatic for many years, resulting in delayed diagnosis. The aim of the study was to identify a biomarker able to quantify the risk of progressive CKD in young children with JS. Methods Renal features were investigated in 93 Italian patients, including biochemical tests, ultrasound and 1-deamino-8D-arginine vasopressin test in children with reduced basal urine osmolality. A subset of patients was followed-up over time. Results At last examination, 27 of 93 subjects (29%) presented with CKD, ranging from isolated urinary concentration defect (UCD) to end-stage renal disease. Both normal and pathological urine osmolality levels remained stable over time, ev...
European journal of medical genetics, Jan 17, 2018
A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each... more A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each is subject to specific spatial and temporal expression patterns. However, most are highly expressed in post-mitotic neurons during stages of neuronal migration and differentiation. The major tubulin subclasses (alpha- and beta-tubulin) share high sequence and structural homology. These globular proteins form heterodimers and subsequently co-assemble into microtubules. Microtubules are dynamic, cytoskeletal polymers which play key roles in cellular processes crucial for cortical development, including neuronal proliferation, migration and cortical laminar organisation. Mutations in seven genes encoding alpha-tubulin (TUBA1A), beta-tubulin (TUBB2A, TUBB2B, TUBB3, TUBB4A, TUBB) and gamma-tubulin (TUBG1) isoforms have been associated with a wide and overlapping range of brain malformations or "Tubulinopathies". The majority of cortical phenotypes include lissencephaly, polymicrogy...
Pediatric brain damage is associated with various cognitive deficits. Cognitive rehabilitation ma... more Pediatric brain damage is associated with various cognitive deficits. Cognitive rehabilitation may prevent and reduce cognitive impairment. In recent years, home-based computerized cognitive training (CCT) has been introduced in clinical practice to increase treatment opportunities for patients (telerehabilitation). However, limited research has been conducted thus far on investigating the effects of remote CCT for the juvenile population in contexts other than English-speaking countries. The aim of the present study was to investigate the feasibility of a home-based CCT in a group of Italian adolescents with brain damage. A commercially available CCT (Lumosity) developed in the English language was used due to the lack of telerehabilitation programs in the Italian language that allow stimulation of multiple cognitive domains and, at the same time, remote automatic collection of data. Thus, this investigation provides information on the possibility of introducing CCT programs availa...
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