Publications by authors named "Angela Peron"

45 Publications

Ring Chromosome 20 Syndrome: Genetics, Clinical Characteristics, and Overlapping Phenotypes.

Front Neurol 2020 8;11:613035. Epub 2020 Dec 8.

Child Neuropsychiatry Unit - Epilepsy Center, Department of Health Sciences, ASST Santi Paolo e Carlo, San Paolo Hospital, Università Degli Studi di Milano, Milan, Italy.

Ring chromosome 20 [r(20)] syndrome is a rare condition characterized by a non-supernumerary ring chromosome 20 replacing a normal chromosome 20. It is commonly seen in a mosaic state and is diagnosed by means of karyotyping. r(20) syndrome is characterized by a recognizable epileptic phenotype with typical EEG pattern, intellectual disability manifesting after seizure onset in otherwise normally developing children, and behavioral changes. Despite the distinctive phenotype, many patients still lack a diagnosis-especially in the genomic era-and the pathomechanisms of ring formation are poorly understood. In this review we address the genetic and clinical aspects of r(20) syndrome, and discuss differential diagnoses and overlapping phenotypes, providing the reader with useful tools for clinical and laboratory practice. We also discuss the current issues in understanding the mechanisms through which ring 20 chromosome causes the typical manifestations, and present unpublished data about methylation studies. Ultimately, we explore future perspectives of r(20) research. Our intended audience is clinical and laboratory geneticists, child and adult neurologists, and genetic counselors.
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http://dx.doi.org/10.3389/fneur.2020.613035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753021PMC
December 2020

Phenotypes in adult patients with Rett syndrome: results of a 13-year experience and insights into healthcare transition.

J Med Genet 2020 Oct 26. Epub 2020 Oct 26.

Department of Health Sciences, Università degli Studi di Milano, Milano, Lombardia, Italy.

Background: Rett syndrome is a complex genetic disorder with age-specific manifestations and over half of the patients surviving into middle age. However, little information about the phenotype of adult individuals with Rett syndrome is available, and mainly relies on questionnaires completed by caregivers. Here, we assess the clinical manifestations and management of adult patients with Rett syndrome and present our experience in transitioning from the paediatric to the adult clinic.

Methods: We analysed the medical records and molecular data of women aged ≥18 years with a diagnosis of classic Rett syndrome and/or pathogenic variants in , and , who were in charge of our clinic.

Results: Of the 50 women with classic Rett syndrome, 94% had epilepsy (26% drug-resistant), 20% showed extrapyramidal signs, 40% sleep problems and 36% behavioural disorders. Eighty-six % patients exhibited gastrointestinal problems; 70% had scoliosis and 90% low bone density. Breathing irregularities were diagnosed in 60%. None of the patients had cardiac issues. CDKL5 patients experienced fewer breathing abnormalities than women with classic Rett syndrome.

Conclusion: The delineation of an adult phenotype in Rett syndrome demonstrates the importance of a transitional programme and the need of a dedicated multidisciplinary team to optimise the clinical management of these patients.
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http://dx.doi.org/10.1136/jmedgenet-2020-107333DOI Listing
October 2020

De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females.

Neurogenetics 2020 Sep 17. Epub 2020 Sep 17.

Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Individuals harboring pathogenic variants in ARHGEF9, encoding an essential submembrane protein for gamma-aminobutyric acid (GABA)-ergic synapses named collybistin, show intellectual disability (ID), facial dysmorphism, behavioral disorders, and epilepsy. Only few affected females carrying large chromosomal rearrangements involving ARHGEF9 have been reported so far. Through next-generation sequencing (NGS)-based panels, we identified two single nucleotide variants (SNVs) in ARHGEF9 in two females with neurodevelopmental features. Sanger sequencing revealed that these variants were de novo. The X-inactivation pattern in peripheral blood cells was random. We report the first affected females harboring de novo SNVs in ARHGEF9, expanding the genotypic and phenotypic spectrum of ARHGEF9-related neurodevelopmental disorder in females.
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http://dx.doi.org/10.1007/s10048-020-00622-5DOI Listing
September 2020

The TAND checklist: a useful screening tool in children with tuberous sclerosis and neurofibromatosis type 1.

Orphanet J Rare Dis 2020 09 7;15(1):237. Epub 2020 Sep 7.

Epilepsy Center- Child Neuropsychiatry Unit, ASST Santi Paolo Carlo, Department of Health Sciences, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.

Background: Tuberous Sclerosis Complex (TSC) and Neurofibromatosis type 1 (NF1) are neurocutaneous disorders commonly characterized by neuropsychiatric comorbidities. The TAND (Tuberous Sclerosis Associated Neuropsychiatric Disorders) Checklist is currently used to quickly screen for behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations in patients with TSC. We administered the authorized Italian version of the TAND Checklist to the parents of 42 TSC patients and 42 age- and sex-matched NF1 patients, for a total of 84 individuals, aged 4-20 years. Aims of this study: - to test the overall usability of the TAND Checklist in NF1, -to compare the results between children and adolescents with TSC and NF1, and -to examine the association between neuropsychiatric manifestations and severity of the phenotype in terms of epilepsy severity in the TSC cohort and disease severity according to the modified version of the Riccardi severity scale in the NF1 cohort.

Results: TSC cohort: 35.6% had Intellectual Disability (ID), 11.9% Specific Learning Disorders (SLD), 50.0% Attention Deficit Hyperactivity Disorder (ADHD) and 16.6% anxious/mood disorder. 33.3% had a formal diagnosis of Autism Spectrum Disorder (ASD). Paying attention and concentrating (61.9%), impulsivity (54.8%), temper tantrums (54.8%), anxiety (45.2%), overactivity/hyperactivity (40.5%), aggressive outburst (40.5%), absent or delayed onset of language (40.5%), repetitive behaviors (35.7%), academic difficulties (> 40%), deficits in attention (61.9%) and executive skills (50.0%) were the most commonly reported problems. NF1 cohort: 9.5% had ID, 21.4% SLD, 46.6% ADHD, and 33.3% anxious/mood disorder. No one had a diagnosis of ASD. Commonly reported issues were paying attention and concentrating (59.5%), impulsivity (52.4%), anxiety (50.0%), overactivity/hyperactivity (38.1%), temper tantrums (38.1%), academic difficulties (> 40%), deficits in attention (59.5%), and executive skills (38.1%). Neuropsychiatric features in TSC vs NF1: Aggressive outburst and ASD features were reported significantly more frequently in TSC than in NF1. Neuropsychiatric manifestations and phenotype severity: Depressed mood, absent or delayed onset of language, repetitive language, difficulties in relationship with peers, repetitive behaviors, spelling, mathematics, dual-tasking, visuo-spatial tasks, executive skills, and getting disoriented were significantly different among TSC patients with different epilepsy severity. No statistically significant differences in the NF1 subgroups were noted for any of the items in the checklist.

Conclusion: The TAND Checklist used for TSC is acceptable and feasible to complete in a clinical setting, and is able to detect the complexity of neuropsychiatric involvement in NF1 as well. NF1 is mainly characterized by an ADHD profile, anxiety problems and SLD, while ASD features are strongly associated with TSC. In conclusion, the TAND Checklist is a useful and feasible screening tool, in both TSC and NF1.
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http://dx.doi.org/10.1186/s13023-020-01488-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487732PMC
September 2020

Tuberous sclerosis complex (TSC), lymphangioleiomyomatosis, and COVID-19: The experience of a TSC clinic in Italy.

Am J Med Genet A 2020 11 17;182(11):2479-2485. Epub 2020 Aug 17.

Child Neuropsychiatry Unit - Epilepsy Center, ASST Santi Paolo e Carlo, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

Individuals with comorbidities are at higher risk of coronavirus disease 2019 (COVID-19) and worse outcome, but little information has been available about patients with genetic diseases and COVID-19. This study aims at evaluating the presence and outcome of COVID-19 in a cohort of Italian patients with tuberous sclerosis complex (TSC) and/or lymphangioleiomyomatosis (LAM), and at reviewing the possible effects of mTOR inhibitors on SARS-CoV-2 infection. We included 102 unselected individuals with a diagnosis of TSC and/or LAM assessed between January 1, 2020 and April 24, 2020 (29% children, 71% adults). Twenty-six patients were on mTOR inhibitors. Demographic data, TSC manifestations, presence, and outcomes in individuals with confirmed or suspected SARS-CoV-2 infection were evaluated. Health status and outcomes of all patients on mTOR inhibitors were assessed. One patient with severe TSC had polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection, was admitted to ICU, and died. Nine additional patients either met the definition of suspect case or presented with at least two of the most common symptoms of SARS-CoV-2 infection. All recovered fully. None of the patients treated with mTOR inhibitors for their underlying comorbidities was diagnosed with COVID-19, and those who showed suspicious respiratory symptoms recovered fully. This cohort study provides preliminary information on COVID-19 in people with TSC in Italy and suggests feasibility to systematically evaluate the role of mTOR inhibitors in SARS-CoV-2 infection.
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http://dx.doi.org/10.1002/ajmg.a.61810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461282PMC
November 2020

Aortic dilation in Sotos syndrome: An underestimated feature?

Am J Med Genet A 2020 07 14;182(7):1819-1823. Epub 2020 Apr 14.

Unità di Pediatria ad Alta Intensità di Cura, Fondazione IRCCS Ca' Granda, Milan, Italy.

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http://dx.doi.org/10.1002/ajmg.a.61591DOI Listing
July 2020

PIGW-related glycosylphosphatidylinositol deficiency: Description of a new patient and review of the literature.

Am J Med Genet A 2020 06 21;182(6):1477-1482. Epub 2020 Mar 21.

Child Neuropsychiatry Unit-Epilepsy Center, ASST Santi Paolo e Carlo, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

Inherited glycosylphosphatidylinositol (GPI) deficiencies are a group of clinically and genetically heterogeneous conditions belonging to the congenital disorders of glycosylation. PIGW is involved in GPI biosynthesis and modification, and biallelic pathogenic variants in this gene cause autosomal recessive GPI biosynthesis defect 11. Only five patients and two fetuses have been reported in the literature thus far. Here we describe a new patient with a novel homozygous missense variant in PIGW, who presented with hypotonia, severe intellectual disability, early-onset epileptic seizures, brain abnormalities, nystagmus, hand stereotypies, recurrent respiratory infections, distinctive facial features, and hyperphosphatasia. Our report expands the phenotype of GPI biosynthesis defect 11 to include stereotypies and recurrent respiratory infections. A detailed and long-term analysis of the electroclinical characteristics and review of the literature suggest that early-onset epileptic seizures are a key manifestation of GPI biosynthesis defect 11. West syndrome and focal-onset epileptic seizures are the most common seizure types, and the fronto-temporal regions may be the most frequently involved areas in these patients.
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http://dx.doi.org/10.1002/ajmg.a.61555DOI Listing
June 2020

Missense variants in the Arg206 residue of HNRNPH2: Further evidence of causality and expansion of the phenotype.

Am J Med Genet A 2020 04 14;182(4):823-828. Epub 2020 Jan 14.

Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Milan, Italy.

Missense variants in HNRNPH2 cause Bain type syndromic X-linked intellectual disability (XLID). To date, only six affected females and three affected males have been reported in the literature, and the phenotype has yet to be delineated in detail. Here, we report on a 35-year-old female with a novel de novo variant in HNRNPH2, providing further evidence that missense changes in the nuclear localization sequence cause Bain type XLID and that aminoacid 206 likely represents a mutational hotspot. We expand the phenotype of Bain type XLID to include breathing, sleep and movement disorders, cerebellar vermis hypoplasia, stereotypies, and hypersensitivity to noise. Our data indicate that the phenotype may be broader and more variable than initially reported, and suggest Rett syndrome as a possible differential diagnosis.
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http://dx.doi.org/10.1002/ajmg.a.61486DOI Listing
April 2020

Pathogenic Variants in and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes.

Int J Mol Sci 2019 Jul 24;20(15). Epub 2019 Jul 24.

Istituto Auxologico Italiano, IRCCS, Cytogenetics and Molecular Genetics Laboratory, 20145 Milan, Italy.

Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a pathogenic variant in 95% of cases, from atypical girls, 40-73% carrying variants, and rarely and alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants-one in and, for first time, one in -were disclosed in classic and atypical RTT patients. Interestingly, the variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in defective and models.
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http://dx.doi.org/10.3390/ijms20153621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696386PMC
July 2019

Characterization of intellectual disability and autism comorbidity through gene panel sequencing.

Hum Mutat 2019 09 2;40(9):1346-1363. Epub 2019 Aug 2.

Molecular Genetics of Neurodevelopment, Department of Woman and Child Health, University of Padova, C.so Stati Uniti, 4, Padova, Italy.

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next-generation sequencing gene panel that has been transferred into clinical practice, replacing single disease-gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease-causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.
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http://dx.doi.org/10.1002/humu.23822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428836PMC
September 2019

Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy.

Am J Med Genet A 2019 08 17;179(8):1543-1546. Epub 2019 Jun 17.

Stanford University, Stanford, California.

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.
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http://dx.doi.org/10.1002/ajmg.a.61266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254578PMC
August 2019

Hot water epilepsy and SYN1 variants.

Epilepsia 2018 11;59(11):2162-2163

Child Neuropsychiatric Unit, Epilepsy Center, San Paolo Hospital, Department of Health Sciences, University of Milan, Milan, Italy.

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http://dx.doi.org/10.1111/epi.14572DOI Listing
November 2018

Tuberous sclerosis complex.

Am J Med Genet C Semin Med Genet 2018 09 16;178(3):274-277. Epub 2018 Oct 16.

Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.

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http://dx.doi.org/10.1002/ajmg.c.31657DOI Listing
September 2018

Genetics, genomics, and genotype-phenotype correlations of TSC: Insights for clinical practice.

Am J Med Genet C Semin Med Genet 2018 09 26;178(3):281-290. Epub 2018 Sep 26.

Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.

Tuberous Sclerosis Complex (TSC) is a multisystem autosomal dominant condition caused by inactivating pathogenic variants in either the TSC1 or the TSC2 gene, leading to hyperactivation of the mTOR pathway. Here, we present an update on the genetic and genomic aspects of TSC, with a focus on clinical and laboratory practice. We briefly summarize the structure of TSC1 and TSC2 as well as their protein products, and discuss current diagnostic testing, addressing mosaicism. We consider genotype-phenotype correlations as an example of precision medicine, and discuss genetic counseling in TSC, with the aim of providing geneticists and health care practitioners involved in the care of TSC individuals with useful tools for their practice.
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http://dx.doi.org/10.1002/ajmg.c.31651DOI Listing
September 2018

Current concepts on epilepsy management in tuberous sclerosis complex.

Am J Med Genet C Semin Med Genet 2018 09 26;178(3):299-308. Epub 2018 Sep 26.

Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting approximately 1 in 6,000 people, and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first 12 months of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique opportunity to monitor EEG before the onset of clinical seizures, thus enabling early intervention in the process of epileptogenesis. In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and present recommendations of American and European experts in the field of epilepsy.
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http://dx.doi.org/10.1002/ajmg.c.31652DOI Listing
September 2018

Healthcare transition from childhood to adulthood in Tuberous Sclerosis Complex.

Am J Med Genet C Semin Med Genet 2018 09 25;178(3):355-364. Epub 2018 Sep 25.

Department of Health Sciences, Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Università degli Studi di Milano, Milan, Italy.

Healthcare transition from childhood to adulthood is required to ensure continuity of care of an increasing number of individuals with chronic conditions surviving into adulthood. The transition for patients with tuberous sclerosis complex (TSC) is complicated by the multisystemic nature of this condition, age-dependent manifestations, and high clinical variability and by the presence of intellectual disability in at least half of the individuals. In this article, we address the medical needs regarding each TSC-related manifestation in adulthood, and the services and support required. We review existing models of transition in different chronic conditions, discuss our experience in transitioning from the pediatric to the adult TSC Clinic at our Institution, and propose general rules to follow when establishing a transition program for TSC. Although a generalizable transition model for TSC is likely not feasible for all Institutions, a multidisciplinary TSC clinic is probably the best model, developed in accordance with the resources available and country-specific healthcare systems. Coordination of care and education of the adult team should be always sought regardless of the transition model.
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http://dx.doi.org/10.1002/ajmg.c.31653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635672PMC
September 2018

Rhinencephalon changes in tuberous sclerosis complex.

Neuroradiology 2018 Aug 17;60(8):813-820. Epub 2018 Jun 17.

Pediatric Neurology and Neurophysiology Unit, Department of Woman and Child Health, University Hospital of Padova, Padova, PD, Italy.

Purpose: Despite complex olfactory bulb embryogenesis, its development abnormalities in tuberous sclerosis complex (TSC) have been poorly investigated.

Methods: Brain MRIs of 110 TSC patients (mean age 11.5 years; age range 0.5-38 years; 52 female; 26 TSC1, 68 TSC2, 8 without mutation identified in TSC1 or TSC2, 8 not tested) were retrospectively evaluated. Signal and morphological abnormalities consistent with olfactory bulb hypo/aplasia or with olfactory bulb hamartomas were recorded. Cortical tuber number was visually assessed and a neurological severity score was obtained. Patients with and without rhinencephalon abnormalities were compared using appropriate parametric and non-parametric tests.

Results: Eight of110 (7.2%) TSC patients presented rhinencephalon MRI changes encompassing olfactory bulb bilateral aplasia (2/110), bilateral hypoplasia (2/110), unilateral hypoplasia (1/110), unilateral hamartoma (2/110), and bilateral hamartomas (1/110); olfactory bulb hypo/aplasia always displayed ipsilateral olfactory sulcus hypoplasia, while no TSC patient harboring rhinencephalon hamartomas had concomitant forebrain sulcation abnormalities. None of the patients showed overt olfactory deficits or hypogonadism, though young age and poor compliance hampered a proper evaluation in most cases. TSC patients with rhinencephalon changes had more cortical tubers (47 ± 29.1 vs 26.2 ± 19.6; p = 0.006) but did not differ for clinical severity (p = 0.45) compared to the other patients of the sample.

Conclusions: Olfactory bulb and/or forebrain changes are not rare among TSC subjects. Future studies investigating clinical consequences in older subjects (anosmia, gonadic development etc.) will define whether rhinencephalon changes are simply an imaging feature among the constellation of TSC-related brain changes or a feature to be searched for possible implications in the management of TSC subjects.
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http://dx.doi.org/10.1007/s00234-018-2045-xDOI Listing
August 2018

Ictal signs in tuberous sclerosis complex: Clinical and video-EEG features in a large series of recorded seizures.

Epilepsy Behav 2018 08 12;85:14-20. Epub 2018 Jun 12.

Epilepsy Center-Child Neuropsychiatric Unit, ASST Santi Paolo e Carlo, Milan, Italy; Department of Health Sciences, University of Milan, Italy.

Epilepsy is the most common neurological symptom in tuberous sclerosis complex (TSC), occurring in 72-85% of affected individuals. Despite the large number of patients reported, their electroclinical phenotype has been rarely described. We analyzed seizure semiology through ictal video-electroencephalography (V-EEG) recordings in a large series of patients. In this multicenter study, we reviewed V-EEGs of 51 patients: ictal recordings were analyzed in correlation with their clinical variables. The median age of epilepsy onset was six months (one day-16 years), with onset in the first year of life in 71% patients (36/51), in 10 of them during the neonatal period. Sixty-five percent of patients (33/51) experienced epileptic spasms in their life, with late-onset (>two years) in five; 42% of the epileptic spasms persisted after age two years, despite the onset in the first year of life. We identified four different electroclinical subsets: focal epilepsy (35%, 18/51), Lennox-Gastaut Syndrome evolution (27%, 14/51), focal seizures with persisting spasms (33%, 17/51), and spasms only (4%, 2/51). We reviewed 45 focal seizures, 13 clusters of epileptic spasms, and seven generalized seizures. In 12 patients, we recorded different seizure types. In 71% of the focal seizures (32/45), the ictal pattern was focal without diffusion. In 38% of the patients (5/13) epileptic spasms were related to typical diffuse slow wave pattern associated with superimposed fast activity, with focal predominance. Focal seizures and focal spasms resulted as the most frequent seizure types in TSC. Seizure onset was variable but showing a predominant involvement of the frontocentral regions (40%). Discrete clinical signs characterized the seizures, and behavioral arrest was the predominant first clinical objective sign. Epileptic spasms were a typical presentation at all ages, frequently asymmetrical and associated with lateralizing features, especially in older patients.
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http://dx.doi.org/10.1016/j.yebeh.2018.05.027DOI Listing
August 2018

Prenatal upper-limb mesomelia and 2q31.1 microdeletions affecting the regulatory genome.

Genet Med 2018 11;20(11):1483-1484

Medical Genetics Unit, Fondazione, Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1038/gim.2018.19DOI Listing
November 2018

Deep phenotyping of patients with Tuberous Sclerosis Complex and no mutation identified in TSC1 and TSC2.

Eur J Med Genet 2018 Jul 9;61(7):403-410. Epub 2018 Feb 9.

Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Milan, Italy; Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

Tuberous Sclerosis Complex (TSC) is a multisystemic condition caused by mutations in TSC1 or TSC2, but a pathogenic variant is not identified in up to 10% of the patients. The aim of this study was to delineate the phenotype of pediatric and adult patients with a definite clinical diagnosis of TSC and no mutation identified in TSC1 or TSC2. We collected molecular and clinical data of 240 patients with TSC, assessing over 50 variables. We compared the phenotype of the homogeneous group of individuals with No Mutation Identified (NMI) with that of TSC patients with a TSC1 and TSC2 pathogenic variant. 9.17% of individuals were classified as NMI. They were diagnosed at an older age (p = 0.001), had more frequent normal cognition (p < 0.001) and less frequent epilepsy (p = 0.010), subependymal nodules (p = 0.022) and giant cell astrocytomas (p = 0.008) than patients with TSC2 pathogenic variants. NMI individuals showed more frequent bilateral and larger renal angiomyolipomas (p = 0.001; p = 0.003) and pulmonary involvement (trend) than patients with TSC1 pathogenic variants. Only one NMI individual had intellectual disability. None presented with a subependymal giant cell astrocytoma. Other medical problems not typical of TSC were found in 42.86%, without a recurrent pattern of abnormalities. Other TSC-associated neuropsychiatric disorders and drug-resistance in epilepsy were equally frequent in the three groups. This study provides a systematic clinical characterization of patients with TSC and facilitates the delineation of a distinctive phenotype indicative of NMI patients, with important implications for surveillance.
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http://dx.doi.org/10.1016/j.ejmg.2018.02.005DOI Listing
July 2018

Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?

Orphanet J Rare Dis 2018 01 29;13(1):25. Epub 2018 Jan 29.

Department of Neurology and Epileptology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warszawa, Poland.

Background: Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence of 1:6000 live births and associated with the development of benign tumors in several organs. It is also characterized by high rates of neurological and neuropsychiatric abnormalities, including epilepsy affecting 70-90% of patients and being one of the major risk factors of intellectual disability. The first seizures in TSC patients appear usually between the 4th and the 6th months of life. Recent studies have shown the beneficial role of preventative antiepileptic treatment in TSC patients, with the possibility for improvement of cognitive outcome. Moreover, European recommendations suggest early introduction of Vigabatrin if ictal discharges occur on EEG recordings, with or without clinical manifestation. The aim of this study was to define the most useful approach to make the diagnosis of TSC before seizure onset (before age 4th months), in order to start early EEG monitoring with possible preventative treatment intervention.

Methods: We performed a retrospective review of children who were suspected of having TSC due to single or multiple cardiac tumors as the first sign of the disease. We analyzed the medical records in terms of conducted clinical tests and TSC signs, which were observed until the end of the 4th month of age. Subsequently, we described the different clinical scenarios and recommendations for early diagnosis.

Results: 82/100 children were diagnosed with TSC within the first 4 months of life. Apart from cardiac tumors, the most frequently observed early TSC signs were subependymal nodules (71/100, 71%), cortical dysplasia (66/100, 66%), and hypomelanotic macules (35/100, 35%). The most useful clinical studies for early TSC diagnosis were brain magnetic resonance imaging (MRI), skin examination and echocardiography. Genetic testing was performed in 49/100 of the patients, but the results were obtained within the first 4 months of life in only 3 children.

Conclusions: Early diagnosis of TSC, before seizure onset, is feasible and it is becoming pivotal for epilepsy management and improvement of cognitive outcome. Early TSC diagnosis is mostly based on clinical signs. Brain MRI, echocardiography, skin examination and genetic testing should be performed early in every patient suspected of having TSC.
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http://dx.doi.org/10.1186/s13023-018-0764-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789613PMC
January 2018

Lennox-Gastaut syndrome in adulthood: Long-term clinical follow-up of 38 patients and analysis of their recorded seizures.

Epilepsy Behav 2017 12 7;77:73-78. Epub 2017 Nov 7.

Epilepsy Center, San Paolo Hospital, Milan, Italy; Department of Health Sciences, Università degli Studi di Milano, Italy.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy with childhood onset that usually continues through adolescence and into adulthood. In the long term, patients with this condition still have intractable seizures, intellectual disability, behavioral problems, and physical comorbidities. The aim of this study was to describe the clinical and EEG characteristics of a group of adults with Lennox-Gastaut syndrome. We identified 38 (22 females, 16 males) patients with LGS older than age 18years at their last evaluation, with mean age of 43.3±10.6years. Median follow-up was 14.4years (range: 2-40). All of our patients had 3 or more seizure types during their clinical history. The most prevalent seizure types at follow-up were atypical absences (28/38), tonic (28/38), generalized tonic-clonic (17/38), focal (11/38), and myoclonic seizures (9/38). All patients had drug-resistant seizures. Besides epilepsy, intellectual disability and behavioral problems were prominent features. Surprisingly, paroxysmal nonepileptic seizures were reported in 3 patients. Our observations confirm the poor outcome of Lennox-Gastaut syndrome through adulthood, regardless of age at seizure onset, etiology, and history of previous West syndrome.
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http://dx.doi.org/10.1016/j.yebeh.2017.09.006DOI Listing
December 2017

Dramatic relapse of seizures after everolimus withdrawal.

Eur J Paediatr Neurol 2018 Jan 3;22(1):203-206. Epub 2017 Aug 3.

Child Neuropsychiatry Unit - Epilepsy Center, ASST Santi Paolo e Carlo Hospital, Department of Health Sciences, University of Milan, Italy.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystemic disorder caused by deregulation of the mTOR pathway, and represents one of the leading genetic causes of epilepsy. mTOR inhibitors (Sirolimus and Everolimus) are currently approved only for the treatment of growing subependymal giant cell astrocytomas, renal angiomyolipomas and lymphangioleiomyomatosis in TSC. However, preclinical and clinical evidence supports their potential role in effectively treating TSC-associated epilepsy, but no consensus on its use in seizures has been reached yet and there are few data on epilepsy outcome after the suspension of mTOR inhibitors treatment. We report for the first time on a patient in whom discontinuation of Everolimus (prescribed for growing subependymal giant cell astrocytomas) was associated with a relapse of seizures twice, and control of seizures was regained after reintroducing the medicine. This clinical report supports the promising potential of Everolimus in treating epilepsy in TSC, and specifically underlines the non-permanent effect on seizures after withdrawal.
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http://dx.doi.org/10.1016/j.ejpn.2017.07.018DOI Listing
January 2018

Lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia, and sarcoidosis: more pathological findings in the same chest CT, or a single pathological pathway?

BMC Pulm Med 2017 Jul 28;17(1):107. Epub 2017 Jul 28.

Respiratory Unit, Ospedale San Paolo, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

Background: Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome, lymphangioleiomyomatosis/tuberous sclerosis complex (LAM-TSC), and sarcoidosis are three rare diseases. Here we present, to the best of our knowledge, the first description of a patient with the coexistence of these three diseases.

Case Presentation: A 47-year-old woman affected by LAM-TSC and primary biliary cirrosis/autoimmune hepatitis overlap syndrome. During her follow up a high resolution chest CT scan (HRTC) confirmed the presence of both multiple cysts and micronodular opacities consistent with multifocal micronodular pneumocytes hyperlasia (MMPH), and revealed multiple hilar-mediastinal symmetrical lymphadenopathies suggestive of sarcoidosis. Simultaneously, subcutaneous nodules appeared on her forearm bilaterally. Cutaneous biopsy showed granulomatous dermatitis with sarcoid-like granulomas. A diagnosis of stage I pulmonary sarcoidosis was made. No treatment for sarcoidosis was initiated since the patient had neither systemic involvement, nor respiratory impairment.

Conclusions: The presence of more than one rare disease should challenge the concept of a potential common underlying mechanism, since the a priori probability of the concomitant presence of different conditions with different pathogenic mechanisms - especially if rare diseases - is low. We speculate that the dysregulation of the pathway involving mTOR and MAPK and their interaction might play a role in the pathogenesis of other diseases, including sarcoidosis.
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http://dx.doi.org/10.1186/s12890-017-0447-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534042PMC
July 2017

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.

Nat Genet 2017 Apr 13;49(4):537-549. Epub 2017 Feb 13.

Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.
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http://dx.doi.org/10.1038/ng.3790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450907PMC
April 2017

Effectiveness and tolerability of antiepileptic drugs in 104 girls with Rett syndrome.

Epilepsy Behav 2017 01 15;66:27-33. Epub 2016 Dec 15.

Epilepsy Center, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Italy.

Approximately 60-80% of girls with Rett Syndrome (RTT) have epilepsy, which represents one of the most severe problems clinicians have to deal with, especially when patients are 7-12years old. The aim of this study was to analyze the antiepileptic drugs (AEDs) prescribed in RTT, and to assess their effectiveness and tolerability in different age groups from early infancy to adulthood. We included in this study 104 girls, aged 2-42years (mean age 13.9years): 89 had a mutation in MECP2, 5 in CDKL5, 2 in FOXG1, and the mutational status was unknown in the remaining 8. Epilepsy was present in 82 patients (79%). Mean age at epilepsy onset was 4.1years. We divided the girls into 5 groups according to age: <5, 5-9, 10-14, 15-19, 20years and older. Valproic acid (VPA) was the most prescribed single therapy in young patients (<15years), whereas carbamazepine (CBZ) was preferred by clinicians in older patients. The most frequently adopted AED combination in the patients younger than 10years and older than 15 was VPA and lamotrigine (LTG). Seizures in the group aged 10-14years were the most difficult to treat, requiring a mean of three different AEDs, often used in combination and mostly including VPA. Seizures in fifteen patients (18%) were considered drug resistant. VPA was reported as the most effective AED in younger girls (in 40% of the patients aged <5years, in 19% of the girls aged 5-9years), and CBZ the most effective in the patients 15years or older. Adverse reactions did not differ from expected: agitation, drowsiness, and weight loss were the most frequently reported. In our sample, LTG was the least tolerated AED. We did not find correlations with MECP2 mutations in terms of effectiveness or adverse reactions.

Conclusion: in this study we observed different effectiveness of AEDs based on age, and suggest that clinicians consider age-dependency when prescribing appropriate AEDs in the RTT population.
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http://dx.doi.org/10.1016/j.yebeh.2016.10.006DOI Listing
January 2017

2q33.1q34 Deletion in a Girl with Brain Anomalies and Anorectal Malformation.

Cytogenet Genome Res 2016 3;150(1):23-28. Epub 2016 Dec 3.

Medical Genetics Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.

2q33 deletions are considered to constitute a distinct clinical entity (Glass syndrome or 2q33 microdeletion syndrome) with a characteristic phenotype. Most patients have moderate to severe developmental delay, speech delay, a particular behavioural phenotype, feeding problems, growth restriction, a typical facial appearance, thin and sparse hair, tooth abnormalities, and skeletal anomalies. Here, we report on a patient with a 2q33.1q34 deletion spanning 8.3 Mb of genomic DNA. Although her clinical features are very reminiscent of the 2q33 microdeletion syndrome, she also presented with brain and anorectal malformations. Based on the present and published patients with 2q33 deletions, we suggest that the critical region for the Glass syndrome may be larger than initially proposed. Moreover, we suggest that brain abnormalities might be an additional feature of the 2q33 microdeletion syndrome, but that anorectal malformation is likely not a key marker.
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http://dx.doi.org/10.1159/000452090DOI Listing
January 2017