Publications by authors named "Elisa De Grandis"

39 Publications

Alternating Hemiplegia of Childhood in a Child Harboring a Novel TBC1D24 Mutation: Case Report and Literature Review.

Neuropediatrics 2021 Dec 1. Epub 2021 Dec 1.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.

Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease characterized by early-onset recurrent paroxysmal events and persistent neurological deficits. gene variants have been associated with a phenotypic spectrum having epilepsy as the main clinical manifestation. Herein, we report the case of a child affected by developmental delay, polymorphic seizures, and nonepileptic episodes characterized by hemiplegia or bilateral plegia, pallor, hypotonia, and dystonic postures without loss of consciousness that resolved with sleep. Noteworthy, the patient fulfills all the diagnostic criteria for AHC. An epilepsy gene panel revealed a novel mutation. This variant may be considered a PM5, according to the American College of Medical Genetics and Genomics guidelines. gene variants are associated with various clinical features, and increasing data confirms the association with permanent and paroxysmal movement disorders. Our report suggests that the molecular analysis could be considered in the diagnostic workup of AHC patients.
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http://dx.doi.org/10.1055/s-0041-1739132DOI Listing
December 2021

A nationwide study on Sydenham's chorea: Clinical features, treatment and prognostic factors.

Eur J Paediatr Neurol 2021 Nov 6;36:1-6. Epub 2021 Nov 6.

Pediatric Rheumatology, Pediatric University Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.

Objectives: Sydenham's Chorea (SC) is a neuropsychiatric disorder and a major manifestation of acute rheumatic fever. The erroneous assumption that SC is a benign and self-limiting disease, has led to a lack of high-quality scientific evidence of the therapeutical and prognostic features of SC.

Study Design: We retrospectively analyzed the medical records of patients <18-years old with SC in 17 Italian pediatric centers. Recorded data included clinical, instrumental and laboratory parameters. Prognostic risk factors including treatment regimens were assessed with univariate and multivariate sub-analysis.

Results: We included 171 patients with SC. 66% had generalized chorea, and 34% hemichorea. 81% had carditis (subclinical in 65%). Additional neurological symptoms were reported in 60% of the patients, mainly dysarthria and dysgraphia. 51% had neuropsychiatric symptoms at onset, which persisted after 12 months in 10%. Among psychiatric manifestations, the most common was anxiety disorder/depression (77%). Neurological remission was reached by 93% of the patients at 6 months; 9% relapsed. Patients were treated as follows: 11% penicillin alone, 37% immunomodulatory therapy, 16% symptomatic drugs (i.e. anti-seizure medication, dopamine antagonists) and 37% both symptomatic and immunomodulatory treatment. Neurological outcome did not differ between groups. Patients receiving symptomatic drugs had a higher risk of relapse on multivariate analysis (p = 0.045).

Conclusions: Treatment of SC was largely heterogeneous. Based on our results, immunomodulatory therapy did not show higher efficacy at medium term, although it was associated to a slightly lower risk of relapse compared to symptomatic therapy. Longitudinal studies are needed to assess specific risk factors and best treatment options.
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http://dx.doi.org/10.1016/j.ejpn.2021.11.002DOI Listing
November 2021

Stress symptoms and Coronavirus disease 2019 (COVID-19): a comparative study between Attention Deficit Hyperactivity Disorder and typically developing children and adolescents.

Minerva Pediatr (Torino) 2021 Oct 14. Epub 2021 Oct 14.

Department of Developmental and Social Psychology, Sapienza University, Rome, Italy.

Background: Coronavirus disease 2019 (COVID-19) related confinement severely impacted people wellbeing. Many studies focused on general population, although it is reasonable to expect that patients with neurodevelopmental disorders might have been at higher risk. Children/adolescents with Attention Deficit/Hyperactivity Disorder (ADHD) might be potentially more vulnerable, due to their intolerance to forced restrictions that limit stimulating experiences, to obligation to follow instructions and to acceptation of imposed rules We aimed to compare stress-related behavioral changes of the first COVD-19 related confinement among 6-18 years old ADHD and typically developing subjects.

Methods: Two parent-proxy online surveys have been employed, shared via social media. Symptoms of acute stress related to the pandemic and a question about family members/households' COVID-19 positivity have been listed in 8 yes/no items. Chi-squared tests were applied.

Results: Final sample consisted of 1078 typically developing subjects and 979 ADHD. Exaggerated startle response, difficulties in waking-up, angry mood as well as COVID-19 related fears were more prevalent among ADHD vs. typically developing subjects. typically developing subjects showed higher prevalence of research for information about COVID-19 and worries about death.

Conclusions: In conclusion, the COVID-19 experience significantly impacted children and adolescents with ADHD to a great extent, similarly to typically developing subjects. ADHD showed more anxious-phobic responses, while typically developing subjects demonstrate more depressive attitudes. Differences in stress symptoms profiles between ADHD and T typically developing subjects warrant to develop distinct strategies of therapeutic interviews.
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http://dx.doi.org/10.23736/S2724-5276.21.06477-6DOI Listing
October 2021

Alternating hemiplegia of childhood: evolution over time and mouse model corroboration.

Brain Commun 2021 4;3(3):fcab128. Epub 2021 Jun 4.

Division of Pediatric Neurology and Developmental Medicine, Department of Pediatrics, Duke University, Durham, NC 27710, USA.

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder caused by mutations. Some evidence for disease progression exists, but there are few systematic analyses. Here, we evaluate alternating hemiplegia of childhood progression in humans and in the D801N knock-in alternating hemiplegia of childhood mouse, Mashlool, model. This study performed an ambidirectional (prospective and retrospective data) analysis of an alternating hemiplegia of childhood patient cohort ( = 42, age 10.24 ± 1.48 years) seen at one US centre. To investigate potential disease progression, we used linear mixed effects models incorporating early and subsequent visits, and Wilcoxon Signed Rank test comparing first and last visits. Potential early-life clinical predictors were determined via multivariable regression. We also compared EEG background at first encounter and at last follow-up. We then performed a retrospective confirmation study on a multicentre cohort of alternating hemiplegia of childhood patients from France ( = 52). To investigate disease progression in the Mashlool mouse, we performed behavioural testing on a cohort of Mashlool mice at prepubescent and adult ages ( = 11). Results: US patients, over time, demonstrated mild worsening of non-paroxysmal disability index scores, but not of paroxysmal disability index scores. Increasing age was a predictor of worse scores:  < 0.0001 for the non-paroxysmal disability index, intellectual disability scale and gross motor scores. Earliest non-paroxysmal disability index score was a predictor of last visit non-paroxysmal disability index score ( = 0.022), and earliest intellectual disability score was a predictor of last intellectual disability score ( = 0.035). More patients with EEG background slowing were noted at last follow-up as compared to initial ( = 0.015). Similar worsening of disease with age was also noted in the French cohort: age was a significant predictor of non-paroxysmal disability index score ( = 0.001) and first and last non-paroxysmal disability index score scores significantly differed ( = 0.002). In animal studies, adult Mashlool mice had, as compared to younger Mashlool mice, (i) worse balance beam performance; (ii) wider base of support; (iii) higher severity of seizures and resultant mortality; and (iv) no increased predisposition to hemiplegic or dystonic spells. In conclusion, (i) non-paroxysmal alternating hemiplegia of childhood manifestations show, on average over time, progression associated with severity of early-life non-paroxysmal disability and age. (ii) Progression also occurs in Mashlool mice, confirming that disease can lead to age-related worsening. (iii) Clinical findings provide a basis for counselling patients and for designing therapeutic trials. Animal findings confirm a mouse model for investigation of underlying mechanisms of disease progression, and are also consistent with known mechanisms of -related neurodegeneration.
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http://dx.doi.org/10.1093/braincomms/fcab128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361420PMC
June 2021

Alternating Hemiplegia of Childhood: Genotype-Phenotype Correlations in a Cohort of 39 Italian Patients.

Front Neurol 2021 8;12:658451. Epub 2021 Apr 8.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.

Alternating hemiplegia of childhood is a rare neurological disease characterized by paroxysmal movement disorders and chronic neurological disturbances, with onset before 18 months of age. Mutations in the gene have been identified in up to 80% of patients. Thirty-nine patients [20 females, 19 males, mean age 25.32 years (7.52-49.34)] have been recruited through the Italian Biobank and Clinical Registry for Alternating Hemiplegia of Childhood. Demographic data, genotype, paroxysmal movement disorders, chronic neurological features, and response to flunarizine have been analyzed. gene mutations have been detected in 92.3% of patients. Patients have been divided into three groups-p.Asp801Asn mutation patients (26%), p.Glu815Lys cases (23%), and patients with other mutations-and statistically compared. The Italian cohort has a higher percentage of gene mutation than reported in literature (92.3%). Our data confirm a more severe phenotype in patients with p.Glu815Lys mutation, with an earlier age of onset of plegic ( = 0.02 in the correlation with other mutations) and tonic attacks. P.Glu815Lys patients most frequently present altered muscle tone, inability to walk ( = 0.01 comparing p.Glu815Lys and p.Asp801Asn mutations), epilepsy, and a more severe grade of dystonia ( < 0.05 comparing p.Glu815Lys and p.Asp801Asn mutations). They have moderate/severe intellectual disability and severe language impairment ( < 0.05). Interestingly, flunarizine seems to be more efficacious in patients with p.Glu815Lys mutation than p.Asp801Asn. In conclusion, our research suggests a genotype-phenotype correlation and provides information on this disorder's features, clinical course, and treatment.
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http://dx.doi.org/10.3389/fneur.2021.658451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060701PMC
April 2021

CASK related disorder: Epilepsy and developmental outcome.

Eur J Paediatr Neurol 2021 Mar 19;31:61-69. Epub 2021 Feb 19.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genova, Italy; Unit of Child Neuropsychiatry, ASST Fatebenefratelli Sacco, Milano, Italy.

Objective: CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay.

Methods: this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature.

Results: we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy.

Conclusions: epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory.
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http://dx.doi.org/10.1016/j.ejpn.2021.02.006DOI Listing
March 2021

Photoparoxysmal response in ADCK3 autosomal recessive ataxia: a case report and literature review.

Epileptic Disord 2021 Feb;23(1):153-160

Unit of Child Neuropsychiatry, Epilepsy Centre, Department of Medical and Surgical Neuroscience and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Mutations in AarF domain-containing kinase 3 (ADCK3) are responsible for the most frequent form of hereditary coenzyme Q10 (CoQ10) deficiency (Q10 deficiency-4), which is mainly associated with autosomal recessive cerebellar ataxia type 2 (ARCA2). Clinical presentation is characterized by a variable degree of cerebellar atrophy and a broad spectrum of associated symptoms, including muscular involvement, movement disorders, neurosensory loss, cognitive impairment, psychiatric symptoms and epilepsy. In this report, we describe, for the first time, a case of photoparoxysmal response in a female patient with a mutation in ADCK3. Disease onset occurred in early childhood with gait ataxia, and mild-to-moderate degeneration. Seizures appeared at eight years and six months, occurring only during sleep. Photoparoxysmal response was observed at 14 years, almost concomitant with the genetic diagnosis (c.901C>T;c.589-3C>G) and the start of CoQ10 oral supplementation. A year later, disease progression slowed down, and photosensitivity was attenuated. A review of the literature is provided focusing on epileptic features of ADCK3-related disease as well as the physiopathology of photoparoxysmal response and supposed cerebellar involvement in photosensitivity. Moreover, the potential role of CoQ10 oral supplementation is discussed. Prospective studies on larger populations are needed to further understand these data.
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http://dx.doi.org/10.1684/epd.2021.1243DOI Listing
February 2021

Impact of the COVID-19 Outbreak on the Behavior of Families in Italy: A Focus on Children and Adolescents.

Front Public Health 2021;9:608358. Epub 2021 Feb 5.

Child Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

The COVID-19 pandemic has changed individuals' lifestyles to a great extent, particularly in Italy. Although many concerns about it have been highlighted, its impact on children and adolescents has scarcely been examined. The purpose of this study was to explore behavioral consequences and coping strategies related to the pandemic among families in Italy, by focusing on developmental ages from the caregivers' perspective, 3 weeks into quarantine. An exploratory cross-sectional online survey was conducted over 14 days. Google Forms was employed to conduct the survey. Demographic variables and pre-existing Psychological Weaknesses (PsW) were asked. Adults' sleep difficulties (SleepScore) and coping strategies during quarantine were assessed. Behavioral changes related to quarantine of both subjects completing the form (COVIDStress) and their children (when present) were questioned. Of the 6,871 respondents, we selected 6,800 valid questionnaires; 3,245 declared children aged under 18 years of age (caregivers). PsWs were recognizable in 64.9% among non-caregivers and in 61.5% of caregivers, with a mean PsW score of 1.42 ± 1.26 and 1.30 ± 1.25 over 3 points, respectively. The 95.5% of the non-caregivers and the 96.5% of caregivers presented behavioral changes with a mean COVIDStress of 3.85 ± 1.82 and 4.09 ± 1.79 over 8, respectively (<0.001). Sleep difficulties were present in the 61.6% of the non-caregivers and in the 64.4% of the caregivers ( < 0.001), who showed higher SleepScores (2.41 ± 1.26 against 2.57 ± 1.38 points over 6, < 0.001). COVIDStress (and SleepScore) strongly correlated with PsW ( < 0.001). Caregivers observed behavioral changes in their children in the 64.3% of the <6 years old and in 72.5% of 6-18 years old. Caregivers' discomfort related to quarantine (COVIDStress, SleepScore) was strongly associated to behavioral changes in both age groups of <6 and 6-18 ( < 0.001). Presence of caregivers' coping strategies was less associated to behavioral changes in the <6 sample ( = 0.001) but not in the 6-18 ( = 0.06). The COVID-19 pandemic has adversely impacted families in Italy with regard to behavioral changes, especially in high-risk categories with PsWs and caregivers, especially the ones with children aged <6 years. While coping strategies functioned as protective factors, a wide array of stress symptoms had implications for children's and adolescents' behaviors. It is recommended that public children welfare strategies be implemented, especially for higher-psychosocial-risk categories.
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http://dx.doi.org/10.3389/fpubh.2021.608358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893111PMC
March 2021

Cardiac phenotype in -related syndromes: A multicenter cohort study.

Neurology 2020 11 10;95(21):e2866-e2879. Epub 2020 Sep 10.

From the Department of Clinical and Experimental Epilepsy (S.B., S.M.S.), UCL Queen Square Institute of Neurology, London; Chalfont Centre for Epilepsy (S.B., S.M.S.), Bucks, UK; Division of Pediatric Neurology (M.A.M., A.S.H., B.K., M.M., L.P.), Department of Neurobiology, and Division of Cardiology (M.C.), Department of Pediatrics, Duke University, School of Medicine, Durham, NC; Centre for Inherited Cardiovascular Diseases (R.A.G.-R., J.P.K.), Great Ormond Street Hospital for Children NHS Foundation Trust; Institute of Cardiovascular Science(R.A.G.-R., J.P.K.), University College London, London, UK; Child Neuropsychiatry Unit (E.D.G., A.G., L.P., M.S., E.V.), IRCCs Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, DINOG-MI, University of Genoa; Department of Pediatric Neuroscience (A.G., T.G., N.N., F.R.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Unit of Child Neuropsychiatry (L.P.), ASST Fatebenefratelli Sacco, Milan, Italy; Paediatric Neurology Department (J.C., C.F., L.P.-P., A.A.), Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona University, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Barcelona, Spain; Department of Neurology (A.B., C.M.), Wake Forest School of Medicine, Winston-Salem, NC; Neurology Department (R.S.), Centro Hospitalar e Universitario do Porto-Hospital de Santo António, Porto, Portugal; Clinic for Child Neurology and Psychiatry (V.B., A.P.), Department of Child Neurology, Medical Faculty University of Belgrade, Serbia; Department of Human Genetics (Q.S.P.), Graduate School of Public Health, University of Pittsburgh, PA; Department of Pediatric Neurology (J.P.), Medical University of Silesia, Katowice, Poland; Clinical Neurosciences (K.V., J.H.C.), Developmental Neuroscience Programme, UCL Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, London, UK; Sydney Children's Hospital (A.M.E.B.), Randwick; Department of Cardiology (A.M.D.), The Royal Children's Hospital, Melbourne, University of Melbourne; Department of Neurology (M.M.R.), Royal Children's Hospital, Melbourne; Agnes Ginges Centre for Molecular Cardiology (C.S.), Centenary Institute, University of Sydney; Epilepsy Research Centre (G.H., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC; Department of Paediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Australia; Department of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children (A.A., E.P.), University Hospitals of Lyon (HCL), Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Lyon, France; Paediatric Neurology Unit (I.C.), CMIN, Centro Hospitalar e Universitario Porto, Porto, Portugal; Clinical Neurophysiology Unit (C.Z.), IRCCS "E. Medea," Bosisio Parini (LC), Italy; Department of Neurology (J.N.), CHUV and Université de Lausanne, Switzerland; Second Department of Neurology (K.D.), Institute Psychiatry and Neurology, Warsaw, Poland; Association AHC18+ e. V. (Germany) and Polish Association for People Affected by AHC, ahc-pl (M.P.); Department of Developmental Neurology (M.M.B.), Medical University of Gdańsk, Poland; Neurology Department (S.W.), University Hospital Antwerp; Neurogenetics Group (S.W.), University Antwerp, Belgium; First Department of Pediatrics (R.P.), "Agia Sofia" Children Hospital, National & Kapodistrian University of Athens, Greece; Department of Neurology (S.G.), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Ion Channel Research Unit (D.S.S.), Department of Medicine/Cardiology and Pharmacology, Duke University Medical Center, Durham, NC; Cardiovascular Research Institute (G.S.P.), Weill Cornell Medical College, New York, NY; The Heart Centre (A.T.), Queen Mary University of London; Department of Pathology (M.A.), Great Ormond Street Hospital for Children NHS Foundation Trust; Department of Neuropathology (Z.M., M.T.), Institute of Neurology, University College London, UK; and ICT and Data Analysis Section (R.V.), Euro-Mediterranean Institute of Science and Technology (I.E.ME.S.T.), Palermo, Italy.

Objective: To define the risks and consequences of cardiac abnormalities in -related syndromes.

Methods: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an knock-in mouse (Mashl) to determine the sequence of events in seizure-related cardiac death.

Results: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.

Conclusions: We found increased prevalence of ECG dynamic abnormalities in all -related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine -related disease. -related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
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http://dx.doi.org/10.1212/WNL.0000000000010794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734736PMC
November 2020

Safety and pharmacokinetics of medical cannabis preparation in a monocentric series of young patients with drug resistant epilepsy.

Complement Ther Med 2020 Jun 28;51:102402. Epub 2020 Apr 28.

DINOGMI Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, University of Genoa, Genoa, Italy; Child Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. Electronic address:

Objectives: To evaluate safety and pharmacokinetic parameters (PK) of medical cannabis in add-on for children and young adults with drug-resistant epilepsy.

Design, Setting: Ten patients (4 females, 6 males, age 2.5-23.2 years) were enrolled in a prospective open trial with a galenic preparation (decoction) of Italian cannabis (FM2, ratio THC:CBD = 3:5, range THC 5.2-7.2 %; CBD 8.2-11.1 %). Patients received the first dose in Hospital, progressively augmented by CBD dose titration (from 1 to 4 mg/kg/day).

Outcome Measures: In order to assess safety, blood parameters, heart rates and electrocardiograms (ECGs) were evaluated before the enrollment and during the follow up. The PK study was performed measuring THC and CBD concentrations by UHPLC-MS/MS in plasma samples collected during the first administration and at each follow-up visit.

Results: Two out of ten patients stopped the treatment for adverse events (detected in 6/10: gastroenteric, sleep or behavioral disorders) and difficulties in drug supply. We observed minor ECG alterations in two patients and asymptomatic transient reductions of fibrinogen after 6 months of therapy. The PK study during follow-up revealed statistically significant correlations between THC-CBD blood concentrations and: volumes of decoction, FM2 and THC-CBD daily dosages.

Conclusions: The present study, although with some limitations, shows a good safety profile of medical cannabis in children and young patients with drug-resistant epilepsy and encourages the possibility of further studies with oral cannabis-based drugs. The correlations between THC-CBD plasma concentrations and their administered dosages underline the need of a therapeutic drug monitoring for cannabinoids therapy.
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http://dx.doi.org/10.1016/j.ctim.2020.102402DOI Listing
June 2020

Optic Atrophy and Generalized Chorea in a Patient Harboring an OPA10/RTN4IP1 Pathogenic Variant.

Neuropediatrics 2020 12 11;51(6):425-429. Epub 2020 May 11.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal, and Child Health, University of Genoa, Genoa, Italy.

pathogenic variants (OPA10 syndrome) have been described in patients with early-onset recessive optic neuropathy and recently associated with a broader clinical spectrum, from isolated optic neuropathy to severe encephalopathies with epilepsy. Here we present a case of a patient with a complex clinical picture characterized by bilateral optic nerve atrophy, horizontal nystagmus, myopia, mild intellectual disability, generalized chorea, isolated small subependymal heterotopia, and asynchronous self-resolving midbrain MRI (magnetic resonance imaging) lesions. By using massive gene sequencing, we identified in this patient the c.308G > A (p.Arg103His) homozygous pathogenic variant in the gene. Complex movement disorders and relapsing-remitting neuroradiological lesions have not been previously reported in this condition. Our case expands the clinical spectrum of OPA10 syndrome and opens new opportunities for the molecular diagnosis.
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http://dx.doi.org/10.1055/s-0040-1708539DOI Listing
December 2020

Schimke immuno-osseous dysplasia, two new cases with peculiar EEG pattern.

Brain Dev 2020 May 27;42(5):408-413. Epub 2020 Feb 27.

Unit of Child Neuropsychiatry, Epilepsy Centre, Department of Medical and Surgical Neuroscience and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genoa, Italy. Electronic address:

Introduction: Schimke Immuno-Osseous Dysplasia (SIOD) is an autosomal recessive multisystem disorder caused by pathogenic variants in the gene SMARCAL1. The clinical picture is characterized by spondyloepiphyseal dysplasia resulting in growth failure, nephropathy and T-cell deficiency. Neurologic manifestations include microcephaly, cognitive impairment, migraine-like headaches and cerebrovascular manifestations such as cerebral atherosclerotic vascular disease and reversible cerebral vasoconstriction. The role of SMARCAL1 deficiency in non-vascular neurological complications is still under debate. Epilepsy has been reported in a few patients, even in the absence of brain abnormalities. Data regarding electroencephalographic (EEG) patterns in SIOD are scarce METHODS: We describe the clinical, neuroradiological and EEG findings in two unrelated patients with SIOD showing a peculiar pseudo-periodic EEG pattern apparently not related to the cerebrovascular complications, since it was recognized both before and after cerebrovascular events CONCLUSION: Our observations support the hypothesis that SMARCAL1plays an important role in neurodevelopment and brain function and expand the spectrum of neurological abnormalities related to SIOD.
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http://dx.doi.org/10.1016/j.braindev.2020.01.008DOI Listing
May 2020

White matter and cerebellar involvement in alternating hemiplegia of childhood.

J Neurol 2020 May 16;267(5):1300-1311. Epub 2020 Jan 16.

Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, via G. Gaslini 5, 16147, Genova, Italy.

Objective: To determine whether brain volumetric and white matter microstructural changes are present and correlate with neurological impairment in subjects with alternating hemiplegia of childhood (AHC).

Methods: In this prospective single-center study, 12 AHC subjects (mean age 22.9 years) and 24 controls were studied with 3DT1-weighted MR imaging and high angular resolution diffusion imaging at 3T. Data obtained with voxel-based morphometry and tract-based spatial statistics were correlated with motor impairment using the International Cooperative Ataxia Rating Scale (ICARS) and Movement and Disability sub-scales of Burke-Fahn-Marsden Dystonia Rating Scale (BFMMS and BFMDS).

Results: Compared to healthy controls, AHC subjects showed lower total brain volume (P < 0.001) and white matter volume (P = 0.002), with reduced clusters of white matter in frontal and parietal regions (P < 0.001). No significant regional differences were found in cortical or subcortical grey matter volumes. Lower cerebellar subvolumes correlated with worse ataxic symptoms and global motor impairment in AHC group (P < 0.001). Increased mean and radial diffusivity values were found in the corpus callosum, corticospinal tracts, superior and inferior longitudinal fasciculi, subcortical frontotemporal white matter, internal and external capsules, and optic radiations (P < 0.001). These diffusion scalar changes correlated with higher ICARS and BFMDS scores (P < 0.001).

Interpretation: AHC subjects showed prevalent white matter involvement, with reduced volume in several cerebral and cerebellar regions associated with widespread microstructural changes reflecting secondary myelin injury rather than axonal loss. Conversely, no specific pattern of grey matter atrophy emerged. Lower cerebellar volumes, correlating with severity of neurological manifestations, seems related to disrupted developmental rather than neurodegenerative processes.
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http://dx.doi.org/10.1007/s00415-020-09698-3DOI Listing
May 2020

Pediatric optic neuritis and anti MOG antibodies: a cohort of Italian patients.

Mult Scler Relat Disord 2019 Dec 24;39:101917. Epub 2019 Dec 24.

Unit of Child Neuropsychiatry, Clinical and Surgical Neurosciences Department, IRCCS Istituto Giannina Gaslini, Genova, Italy. Electronic address:

Background: recent studies reported that anti myelin oligodendrocyte glycoprotein (MOG) antibody (ab) related optic neuritis (ON) tend to have characteristics that differ from seronegative ones. The aim of our study was to investigate the clinical characteristics of pediatric anti-MOG ON by comparing anti MOG-ab-seropositive and seronegative patients with ON.

Methods: in this retrospective Italian multicentre study, participants were identified by chart review of patients evaluated for acquired demyelinating syndromes of the central nervous system (over the period 2009-2019). We selected patients presenting with ON as their first demyelinating event. Inclusion criteria were age < 18 years at symptoms onset; presentation consistent with ON; negativity of anti-aquaporin 4 antibodies (AQP4). Only patients who were tested for MOG-IgG1-ab with a live cell-based assay were included.

Results: 22 patients (10 MOG-ab-positive and 12 MOG-ab-negative) were included. Fundus oculi examination at onset showed disc swelling in 9/10 in the MOG-ab-positive cohort and 2/10 in the seronegative group (P = 0.002). Retinal Fiber Nerve Layer (RFNL) thickness measured by Spectral Domain Optical Coherence Tomography (S-OCT) was increased in the 5/5 MOG-ab-positive patients tested and was normal or reduced in the seronegative patients tested (4/4 patients) (P = 0.024). Visual acuity impairment at onset did not differ significantly between the two groups, but the MOG-ab-positive cohort showed better recovery at follow-up both regarding visual acuity (P = 0.025) and expanded disability status scale (EDSS) (P = 0.013). A final diagnosis of MS was frequent among seronegative patients (6/12, 50%), whereas none of the MOG-ab-positive group received a diagnosis of MS (P = 0.015). Clinical relapse frequency was low in both groups: 2/10 MOG-ab-positive and 2/12 seronegative cases relapsed, with a median follow up of 25 months.

Conclusion: optic disc swelling and increased RFNL at baseline are strongly associated with MOG-ab positivity. MOG-ab-positive patients with ON showed better recovery compared to the seronegative ones. The relapse rate was low and did not differ among the two groups.
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http://dx.doi.org/10.1016/j.msard.2019.101917DOI Listing
December 2019

Severe early-onset developmental and epileptic encephalopathy (DEE) associated with novel compound heterozygous pathogenic variants in SLC25A22: Case report and literature review.

Seizure 2019 Aug 27;70:56-58. Epub 2019 Jun 27.

Unit of Child Neuropsychiatry, Epilepsy Centre, Department of Medical and Surgical Neuroscience and Rehabilitation, IRCSS Istituto Giannina Gaslini, Genoa, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2019.06.029DOI Listing
August 2019

Personality profile and health-related quality of life in adults with previous continuous spike-waves during slow sleep syndrome.

Brain Dev 2019 Jun 20;41(6):522-530. Epub 2019 Feb 20.

Unit of Child Neuropsychiatry, Dept of Clinical and Surgical Neurosciences and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genoa 16147, Italy; Dept. of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy.

Introduction: Epilepsy with continuous spike-waves during slow sleep syndrome (CSWSS) is characterized by various seizure types, a characteristic EEG pattern and neuropsychological disorders. The main purpose of this study was to evaluate the long-term outcome of CSWSS occurred in childhood and to evaluate the variables that could influence the quality of social adaptation and the personality profile.

Material And Methods: This is a prospective study on 24 young adults with previous CSWSS (median age 24.5 yrs) who were enrolled between January and July 2011 at the G. Gaslini Children's Hospital, Genoa, Italy. Patients were divided into two groups: twelve with previous spike-wave index (SWI > 85%) defined as typical CSWSS (T-CSWSS) and twelve with previous SWI = 50-85% defined as atypical CSWSS (A-CSWSS). All the subjects were submitted to Minnesota Multiphasic Personality Inventory-2 (MMPI-2), Psychological General Well-Being Index (PGWBI), and to a structured interview.

Results: A correlation was observed with the severity of EEG abnormalities expressed by the SWI and outcome. The T-CSWSS group showed a significantly lower perceived well-being. Similarly in the T-CSWSS group the percentage of MMPI-2 clinical scales with T-scores ≥65 was higher than in the A-CSWSS group. Finally, a significant lower schooling in the T-CSWSS group was observed.

Conclusion: There seem to be two forms of the same disease, with similar onset and clinical evolution but a different outcome regarding the social and psychological conditions. The outcome of the social adaptation and of the personality consciousness was related with the severity of the EEG abnormalities: more favorable in patients with less intense SWI activity (A-CSWSS) compared those with a more severe EEG impairment (T-CSWSS).
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http://dx.doi.org/10.1016/j.braindev.2019.02.004DOI Listing
June 2019

PANDAS and PANS: Clinical, Neuropsychological, and Biological Characterization of a Monocentric Series of Patients and Proposal for a Diagnostic Protocol.

J Child Adolesc Psychopharmacol 2019 05 6;29(4):305-312. Epub 2019 Feb 6.

1 Child Neuropsychiatry Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, Istituto Giannina Gaslini, University of Genoa, Genoa, Italy.

Whether PANS (pediatric acute-onset neuropsychiatric syndrome) and PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) represent true clinical entities is debated and data for a characteristic phenotype are still controversial. In this study, we aim to characterize clinical, neuropsychological, and biochemical aspects in a sample of PANS and PANDAS patients. Patients fulfilling a clinical diagnosis of PANS or PANDAS from 2014 to 2017 were enrolled. Neurological and psychiatric examination and biochemical and instrumental assessment results were collected. A neuropsychological battery was administered. For comparison purposes, a control group of patients with Sydenham's chorea (SC) was evaluated. Descriptive and comparative statistical analyses were performed. Seven subjects received a diagnosis of PANS, 12 of PANDAS, and 11 of SC. Clinical presentation of PANS children showed statistically significant differences compared with both PANDAS and SC, in particular, with the presence of obsessive symptoms, behavioral regression, and somatic symptoms in the first group. Moreover, all PANS patients showed some neuropsychological deficits in visual-motor abilities, short- and long-term memory, and processing speed. Our experience confirms that patients with PANS had a complex clinical presentation and a compromised neuropsychological profile with respect to patients with PANDAS or SC. However, the absence of biological markers or instrumental alterations made the diagnosis of the two entities, PANS and PANDAS, a matter of exclusion. For these reasons, we propose a pilot diagnostic protocol that (when applied in a prospective manner) will allow comparison with similar childhood-onset neuropsychiatric disorders, such as obsessive-compulsive or tic disorders, and efficacy evaluation of different therapeutic approaches.
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http://dx.doi.org/10.1089/cap.2018.0087DOI Listing
May 2019

A UHPLC-MS/MS method for the quantification of Δ9-tetrahydrocannabinol and cannabidiol in decoctions and in plasma samples for therapeutic monitoring of medical cannabis.

Bioanalysis 2018 Dec 6;10(24):2003-2014. Epub 2018 Nov 6.

Department of Services and Diagnostic Laboratories, Central Laboratory of Analyses Unit, IRCCS Istituto Giannina Gaslini, 16143 Genoa, Italy.

Monitoring of blood levels of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is necessary for optimization of administration of medical cannabis. We describe the validation of a ultra-HPLC-MS/MS method for quantifying THC and CBD from plasma and decoctions and its application for therapeutic drug monitoring. Analyses were performed by using a TSQ Quantiva™ Triple Quadrupole coupled to a Ultimate 3000 UHPLC system with atmospheric pressure chemical ionization after sample preparation with a straightforward method with deuterated internal standards.  The method has been validated following EMA guidelines and is linear in plasma from 0.16 to 10 ng/ml for both THC and CBD and in decoctions from 4.7 to 600 ng/ml. Given the unpredictable pharmacokinetic behavior of THC and CBD in patients, monitoring of plasma concentrations is strongly recommended for patients under treatment with medical cannabis.
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http://dx.doi.org/10.4155/bio-2018-0184DOI Listing
December 2018

Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.

Am J Hum Genet 2018 09 9;103(3):431-439. Epub 2018 Aug 9.

Pediatric Neurology, Department of Pediatric Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 15731, Iran.

ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.
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http://dx.doi.org/10.1016/j.ajhg.2018.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128219PMC
September 2018

ATP1A3 spectrum disorders: A video-documented history of 7 genetically confirmed early onset cases.

Eur J Paediatr Neurol 2018 Mar 31;22(2):264-271. Epub 2018 Jan 31.

Child Neuropsychiatry Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, Giannina Gaslini Institute, University of Genoa, Genoa, Italy. Electronic address:

Mutations in the ATP1A3 gene, which encodes the alpha-subunit of sodium-potassium ATPase, are related to a spectrum of neurological diseases including Rapid onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome. Moreover, an increasing number of patients with intermediate and non classical phenotypes have been reported. Herein we describe 7 patients with 6 different de novo ATP1A3 mutations, and we focus on paroxysmal and chronic movement disorders with the help of video documentation. Our cases confirm that ATP1A3-related neurological disorders make up a phenotypic continuum rather than overlapping syndromes, in which early onset dystonia, ataxia and paroxysmal episodes with triggering or worsening factors are key diagnostic clues. Moreover, our experience suggests that ATP1A3 gene analysis should be extended both to children with channelopathy-like spells and to patients with early onset, fever-related encephalopathy.
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http://dx.doi.org/10.1016/j.ejpn.2018.01.010DOI Listing
March 2018

A novel pathogenic MYH3 mutation in a child with Sheldon-Hall syndrome and vertebral fusions.

Am J Med Genet A 2018 03 5;176(3):663-667. Epub 2018 Jan 5.

UOC Neurochirurgia, Istituto Giannina Gaslini, Genoa, Italy.

Sheldon-Hall syndrome (SHS) is the most common of the distal arthrogryposes (DAs), a group of disorders characterized by congenital non-progressive contractures. Patients with SHS present with contractures of the limbs and a distinctive triangular facies with prominent nasolabial folds. Calcaneovalgus deformity is frequent, as well as camptodactyly and ulnar deviation. Causative mutations in at least four different genes have been reported (MYH3, TNNI2, TPM2, and TNNT3). MYH3 plays a pivotal role in fetal muscle development and mutations in this gene are associated with Freeman-Sheldon syndrome, distal arthrogryposis 8 (DA8), and autosomal dominant spondylocarpotarsal synostosis. The last two disorders are characterized by skeletal abnormalities, in particular bony fusions. The observation that MYH3 may be mutated in these syndromes has suggested the involvement of this gene in bone development. We report the case of a boy with a novel pathogenic MYH3 mutation, presenting with the classical clinical features of SHS in association with unilateral carpal bone fusion and multiple vertebral fusions. This distinctive phenotype has never been reported in the literature so far and expands the phenotypic spectrum of SHS, endorsing the clinical variability of patients with MYH3-related disorders. Our findings also support a role for MYH3 in both muscle and bone development, suggesting a phenotypic continuum in MYH3-related disorders.
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http://dx.doi.org/10.1002/ajmg.a.38593DOI Listing
March 2018

Alternating Hemiplegia of Childhood: Pharmacological treatment of 30 Italian patients.

Brain Dev 2017 Jun 27;39(6):521-528. Epub 2017 Feb 27.

Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, University of Genoa, Genoa, Italy. Electronic address:

Background: Alternating Hemiplegia of Childhood (AHC) is a severe disorder. Several drugs have been administered as prophylaxis for paroxysmal attacks, however, no therapy is completely effective.

Methods: Our aim is to review the pharmacological data related to the prophylactic and acute treatment of a cohort of 30 patients (16M, 14F, age range 5-42years) and to correlate them with the clinical and genetic data collected through the Italian Biobank and Clinical Registry for AHC.

Results: Flunarizine was the most commonly used long-term treatment in the cohort; it reduced duration and frequency of attacks in 50% of patients and decreased intensity in 32.1%. In younger patients, flunarizine seemed significantly more effective in reducing intensity. We found no correlation between the effectiveness of flunarizine and genotype, or between developmental outcome and duration of treatment. In particular, 3 of our patients affected by E815K mutation presented rapid neurological deterioration despite ongoing treatment. Among the other administered prophylactic therapies, few proved to be effective (benzodiazepines, niaprazine, acetazolamide, melatonin, olanzapine, ketogenic diet). No clear rationale exists regarding their use, but these therapies may work by reducing the triggering factors.

Conclusions: The presented data are retrospective, but they are aimed at filling a gap given the rarity of the disease and the lack of randomized and controlled studies. Besides their usefulness in clarifying the pathophysiology of the disease, prospective studies involving larger cohorts of ATP1A3 mutated AHC patients are needed to provide a rationale for testing other molecules.
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http://dx.doi.org/10.1016/j.braindev.2017.02.001DOI Listing
June 2017

Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.

Orphanet J Rare Dis 2015 Sep 26;10:123. Epub 2015 Sep 26.

Division of Pediatric Neurology and Department of Neurobiology, Duke University, School of Medicine, Durham, NC, USA.

Background: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype.

Methods: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient.

Results: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations.

Conclusions: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials.
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http://dx.doi.org/10.1186/s13023-015-0335-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583741PMC
September 2015

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.

Brain 2015 Oct 21;138(Pt 10):2859-74. Epub 2015 Aug 21.

3 NIHR UCLH Biomedical Research Centre Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK 4 Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK.

Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.
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http://dx.doi.org/10.1093/brain/awv243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671482PMC
October 2015

Paroxysmal features responding to flunarizine in a child with rapid-onset dystonia-parkinsonism.

Neurology 2014 Jun 2;82(22):2037-8. Epub 2014 May 2.

From the Child Neuropsychiatry Unit (S.F., M.S., M.M.M., M.T., E.V., E.D.), Istituto Giannina Gaslini, University of Genoa; and the Istituto di Genetica Medica (M.R., D.T.), Università Cattolica S. Cuore, Rome, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000000473DOI Listing
June 2014

Epileptic encephalopathy with continuous spike and wave during sleep associated to periventricular leukomalacia.

J Child Neurol 2014 Nov 28;29(11):1479-85. Epub 2013 Nov 28.

Epilepsy Center, Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genoa, Italy.

Periventricular leukomalacia is the most common type of brain injury in premature infants. Our aim is to describe the frequency and the features of epilepsy in a single-center population of 137 children with periventricular leukomalacia. Forty-two of the 137 (31%) patients presented epilepsy. Twelve percent of these patients presented West syndrome, whereas 19% showed a pattern of continuous spike-waves during slow sleep syndrome. In the latter group, outcome was frequently unfavorable, with a greater number of seizures and more drug resistance. A significant association was found between epilepsy and neonatal seizures, spastic tetraplegia, and mental retardation. Although less common than in other forms of brain injury, epilepsy is nevertheless a significant complication in children with periventricular leukomalacia. The fairly frequent association with continuous spike-waves during slow sleep syndrome deserves particular attention: electroencephalographic sleep monitoring is important in order to provide early treatment and prevent further neurologic deterioration.
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http://dx.doi.org/10.1177/0883073813508223DOI Listing
November 2014

Lack of SLC2A1 (glucose transporter 1) mutations in 30 Italian patients with alternating hemiplegia of childhood.

J Child Neurol 2013 Jul 16;28(7):863-6. Epub 2012 Aug 16.

Child Neuropsychiatry Unit, Department of Neurosciences, Ophthalmology & Genetics, G. Gaslini Institute, University of Genoa, Genoa, Italy.

Alternating hemiplegia of childhood is a rare, predominantly sporadic disorder. Diagnosis is clinical, and little is known about genetics. Glucose transporter 1 deficiency syndrome shares with alternating hemiplegia of childhood paroxysmal and nonparoxysmal symptoms. The aim of the study was to investigate glucose transporter 1 mutations in 30 Italian patients. Genetic material was analyzed by DNA amplification and glucose transporter 1 region sequencing. Mutational analysis findings of the SLC2A1 gene were negative in all patients. The pattern of movement disorders was reviewed. Interictal dystonia and multiple paroxysmal events were typical of alternating hemiplegia of childhood. In conclusion, alternating hemiplegia of childhood is a heterogeneous clinical condition, and although glucose transporter 1 deficiency can represent an undiagnosed cause of this disorder, mutational analysis is not routinely recommended. Alternatively, a careful clinical analysis and the 3-O-methyl-D-glucose uptake test can allow prompt identification of a subgroup of patients with alternating hemiplegia of childhood treatable with a ketogenic diet.
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http://dx.doi.org/10.1177/0883073812452789DOI Listing
July 2013

Early-onset neurodegeneration with brain iron accumulation due to PANK2 mutation.

Brain Dev 2012 Jun 14;34(6):536-8. Epub 2011 Oct 14.

Child Neurology and Psychiatry Unit, G. Gaslini Institute, Genova, Italy.

Background: Pantothenate kinase-associated neurodegeneration (PKAN) is a neurodegenerative disorder caused by pantothenate kinase (PANK2) gene mutations. Brain magnetic resonance imaging (MRI) typically shows the "eye-of-the-tiger" sign, i.e. bilateral pallidal T2 hypointensity with a small central region of T2-hyperintensity.

Aims: To describe clinical and MRI findings of a boy with early-onset neurodegeneration with brain iron accumulation due to PANK2 mutation.

Methods: Clinical, neuroradiological and molecular investigations have been performed.

Results: At first observation (2years and 10months) the boy presented only with developmental delay and toe-walking and isolated T2 hyperintensity within globi pallidi on brain MRI. One year later, small rounded areas of markedly low signal within the globi pallidi on T2∗- weighted images appeared in association with mild dystonia. PANK2 gene homozygous mutation confirmed the diagnosis of PKAN.

Conclusions: In young children, PKAN should be suspected also before clinical and neuroradiological picture is fully indicative, to avoid delayed diagnosis of a genetic disease for which therapeutical options could be potentially useful if administered in paucisymptomatic subjects.
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http://dx.doi.org/10.1016/j.braindev.2011.09.010DOI Listing
June 2012

Movement lateralization and bimanual coordination in children with Tourette syndrome.

Mov Disord 2011 Sep 7;26(11):2114-8. Epub 2011 Jul 7.

Department of Neurosciences, Ophthalmology & Genetics and Istituto Nazionale di Neuroscienze, University of Genoa, Genoa, Italy.

Background: Gilles de la Tourette syndrome is a childhood-onset disorder characterized by persistent motor and vocal tics fluctuating in severity. Although structural changes observed in Gilles de la Tourette syndrome concern brain structures involved in voluntary motor control such as the basal ganglia, the frontoparietal cortex, and the corpus callosum, movement lateralization and bimanual coordination have been underinvestigated.

Methods: Using a sensor-engineered glove, we analyzed the performance of repetitive externally paced single-hand and bimanual finger movements in 11 children with Gilles de la Tourette syndrome.

Results: When requested to perform sequential single-hand finger movements, patients with Gilles de la Tourette syndrome showed longer touch duration, shorter movement time, and more errors than healthy subjects. When requested to execute the task bimanually, healthy subjects exhibited a slight loss in accuracy and an increase in touch duration compared with the single-hand task, whereas patients with Gilles de la Tourette syndrome did not. Further, healthy subjects presented great asymmetry in terms of movement accuracy between left and right hands during the bimanual task, whereas patients with Gilles de la Tourette syndrome did not.

Conclusions: These findings suggest that patients with Gilles de la Tourette syndrome may present an abnormal process of sensorimotor integration, movement lateralization, and bimanual coordination during sequential finger movements.
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http://dx.doi.org/10.1002/mds.23839DOI Listing
September 2011
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