Alice Bonuccelli

Pitt-Hopkins syndrome: report of a case with a TCF4 gene mutation

AimsWe will discuss the clinical and genetic diagnosis of a child with severe psychomotor delay, who at 3 years of age presented with paroxysms of hyperpnea-apnea and seizures unrelated to breathing anomalies.MethodsThe child underwent genetic (karyotype, FISH telomeres) and neuroradiological (cranial CT and MRI) tests, which proved to be normal. He came under our clinical observation at 3 years and 5 months of age. Due to severe psychomotor delay and facial dysmorphisms we completed the genetic investigations based on his clinical feature and analysis of the available literature.ResultsThe presence of severe mental retardation associated with anomalous breathing pattern may suggest the Joubert and Rett syndrome, however these were excluded on the basis of clinical and genetic examination. Angelman syndrome, suspected for facial dysmorphisms and absent language, was also excluded because of the presence of a normal pattern of methylation at SNRPN locus. Another possible diagnosis was the Pitt-Hopkins Syndrome (PHS), characterized by severe mental retardation, breathing anomalies (paroxisms of hyperpnea-apnea), dysmorphisms and sometimes epilepsy. Haploinsufficiency of TCF4 gene located at 18q21.2 region has been recently identified as causative of this syndrome. In our patient the research of TCF4 mutation by the Institute of Human Genetics, University Hospital Erlangen (Germany), showed a de novo mutation.ConclusionsThe diagnosis of Pitt-Hopkins syndrome, an underdiagnosed cause of mental retardation, was based on clinical and genetic findings. Searching for TCF4 mutations is highly recommended when others overlapping syndromes was excluded. At our knowledge our patient is the first italian case of PHS diagnosed at molecular level.

Molecular cytogenetic characterization of a de novo mosaic supernumerary ring chromosome 7: Report of a new patient†‡

Here, we report on a patient with a de novo, mosaic, supernumerary r(7) chromosome. The patient (Fig. 1a,b), a 10-year-old girl, was born at 41 weeks of gestation after an uneventful pregnancy. She was the first child of healthy and unrelated parents, age 30 (mother) and 31 (father); her younger brother (5-year-old)washealthy. Family historywas negative for congenital anomalies and/or psychomotor retardation excluding a father’s cousin with language developmental delay; unfortunately, he was not available for karyotype or clinical investigation. The birth weight was 4,030 g (>97th centile), length 51 cm (75th centile) and OCF 36 cm (50th centile). No clinical symptoms were reported in the neonatal period. Her motor development was slightly delayed: she was hypotonic at birth and was sitting at age of 9 months; walking abilities were in the normal range and since the age of 12 months, she could walk without support. However, speech was severely delayed: first words were not until 3 years of age, and her language skills were delayed with poor performances on the expressive side.Nohearing loss was detected. She was referred by the local pediatrician at age of 5 years because of language delay. At this time her weight was 24.8 kg (95th centile), height 114 cm (90th centile), and OCF 53 cm (97th centile). Physical examination showed a flat face, high and prominent forehead, deep-set eyes, short nose, prominent nasal root close to frontal bone, short philtrum, thick columella, thin lips, relative microstomia with downturned corners, and low set ears. Palmar creases and digits were normal but her fingers had wide nails; a partial cutaneous syndactyly was present between 2nd and 3rd toe. No signs of premature puberty were present, but she showed hirsutism on the dorsal side of her limbs and a café-au-lait macula on the abdomen.Ophthalmologyevaluation showedamild astigmatism. A soft cardiac murmur was present, but cardiac evaluation, EKG, and heart echocardiography were normal. Abdominal ultrasound revealed no visceral anomalies. A cerebral MRI showed dilatation of the ventricles and cisterna magna, whereas the results of an awake EEG were in the normal range. Hematologic and neuro-metabolic screenings were normal. Her slightly retarded psychomotor development improved with time. Recently, she demonstrated no learning difficulties at school and her cognitive development fell into normal lower limits (WISCR scale). Her performances were lowered by verbal difficulties (mostly in the phonologic, semantic and syntactic areas). Karyotype analysis of 100 metaphases showed the presence of a supernumerary marker chromosome (SMC) in about 50% of cells. The marker was shaped like a ring, C-band positive, DA-DAPI and AgNOR negative. Parental karyotypes were normal.

Generalized epilepsy and mild intellectual disability associated with 13q34 deletion: A potential role for SOX1 and ARHGEF7

Terminal deletions of long arm of chromosome 13 are rare and poorly characterized by cytogenetic studies, making for difficult genotype-phenotype correlations. We report two siblings presenting generalized epilepsy, intellectual disability, and genitourinary tract defects. Array CGH detected a 1.3 Mb deletion at 13q34; it contains two protein-coding genes, SOX1 and ARHGEF7, whose haploinsufficiency can contribute to the epileptic phenotype.

Mothers and fathers of children with epilepsy: gender differences in post-traumatic stress symptoms and correlations with mood spectrum symptoms

Background Post-traumatic stress disorder (PTSD) and post-traumatic stress spectrum have been recently applied to understand the impact of life-threatening disease or injury in one’s child; nevertheless, scant data are available on a particular chronic illness such as epilepsy whose phenotypic expression is seizures, which are acute, sudden, and unpredictable manifestations. Subjects with bipolar disorders or with mood spectrum symptoms demonstrated to be more vulnerable to develop PTSD in the aftermath of a trauma. Objectives The main aim of this study was to evaluate post-traumatic symptoms among 134 parents of children with a diagnosis of epilepsy, followed at the outpatient neurologic unit of Department of Pediatrics in Santa Chiara Hospital in Pisa, as well as gender differences. The second aim of this study was to estimate the impact of lifetime mood spectrum on post-traumatic stress symptoms in the same study sample after fulfillment of the Trauma and Loss Spectrum-Self Report (TALS-SR) and the Mood Spectrum-Self Report (MOODS-SR) lifetime version. Results Results showed 10.4% and 37.3% of PTSD full and partial, respectively. Demographic characteristics and clinical features of the study sample did not show any impact on stress symptomatology. Mothers presented higher rates at all Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 PTSD symptoms’ clusters except avoidance. Nevertheless, noteworthy correlations between post-traumatic symptomatology and mood spectrum symptoms detected with the self-report tools, emerged only in the subgroup of the fathers. Conclusion These findings corroborate the need to provide assistance to caregivers of pediatric patients and confirm the hypothesis that lifetime mood spectrum may have an impact on reaction to traumas.

A Case of 22q11 Deletion Syndrome (22q11DS) with a Panayiotopoulos Epileptic Pattern: Are Additional Copy-Number Variations a Possible Second Hit in Modulating the 22q11DS Phenotype?

“22q11 deletion syndrome” (22q11DS) is a rare genetic syndrome, in which most patients share the same deletion, but their clinical features may vary a great deal. The genetic mechanisms underlying the variable expressivity and reduced penetrance of 22q11DS still have to be fully elucidated. Epilepsy has been reported in about 15.2% of the patients; however, few studies have focused on this topic, and in most cases, a detailed epileptic profile is missing. Since only a minority of patients experience epileptic seizures, 22q11deletion can be considered a predisposing factor, which is not sufficient “per se” to cause epilepsy; to date, no candidate gene for epilepsy has been identified in the deleted region. We report on a 6-year-old girl with 22q11DS presenting a form of epilepsy that can be classified as “Panayiotopoulos syndrome.” Array CGH revealed an additional microduplication of 172 kb in 2q37, harboring three genes. One of these, DGKD (diacylglycerol kinase delta), is interrupted by the distal breakpoint of the duplication. DGKD encodes a cytoplasmic enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. This is an important second messenger in a pathway of lipid signaling that has been implicated in epilepsy and other neurological diseases. Disruption of DGKD by a t(X;2) has been previously reported in a patient with epilepsy. The 2q37 microduplication was inherited from her mother, who never experienced epileptic seizures, thus this imbalance is not “per se” sufficient to cause epilepsy. It can be hypothesized that the epileptic phenotype is provoked by the simultaneous presence of 22q11.2 deletion and 2q37 duplication. It has been shown that rare additional copy-number variations (CNVs) outside the 22q11.2 region may modulate the risk of congenital heart defects. It is possible that also for the epileptic phenotype, the additional CNVs may represent an important modifying factor underlying the variable expressivity and incomplete penetrance in the 22q11DS.

DSM-5 criteria for PTSD in parents of pediatric patients with epilepsy: What are the changes with respect to DSM-IV-TR?

Increasing literature suggests the need to explore for post-traumatic stress disorder (PTSD) and post-traumatic stress symptoms in parents and caregivers of children with acute and chronic illnesses but scant data are available on epilepsy. The aim of the present study was to estimate full and partial PTSD rates among parents of children with epilepsy comparing DSM-5 and DSM-IV-TR criteria. Further, the aim of the present study was to examine possible gender differences between mothers and fathers. Results showed 9.1% and 12.1% PTSD rates in the total sample, according to DSM-5 or DSM-IV-TR criteria, respectively, with an overall consistency of 92.9% (Kohens K=0.628, p=.453). Significant gender differences emerged for Avoidance/Numbing and Hyperarousal symptoms diagnosed by means of DSM-IV-TR criteria, as well as for Negative alterations in cognitions/mood and Hyperarousal symptoms, when adopting DSM-5 criteria. This study underscores the relevance of detecting PTSD in parents of children with a chronic illness such as epilepsy.

Maternally derived 15q11.2‐q13.1 duplication in a child with Lennox–Gastaut‐type epilepsy and dysmorphic features: Clinical‐genetic characterization of the family and review of the literature

Maternally Derived 15q11.2-q13.1 Duplication in a Child with Lennox–Gastaut-Type Epilepsy and Dysmorphic Features: Clinical-Genetic Characterization of the Family and Review of the Literature Alice Bonuccelli, Angelo Valetto,* Alessandro Orsini, Angela Michelucci, Anna Rita Ferrari, Maurizio Elia, and Veronica Bertini Section of Pediatric Neurology, Department of Pediatrics, University of Pisa, Italy Section of Clinical Genetics, AOUP, Pisa, Italy Department of Pediatric Neurology, Oxford Children’s Hospital, Oxford, United Kingdom Epilepsy Unit, Institute of Child Neurology and Psychiatry, IRCCS Stella Maris Foundation, Calambrone, Pisa, Italy Unit of Neurology and Clinical Neurophysiopathology, IRCCS “Associazione Oasi Maria SS”, Troina (EN), Italy

Molecular cytogenetic characterization of a translocation t(13;22)(q22.3;q11.23) in a patient with idiopathic partial epilepsy.

PURPOSE We report on a balanced de novo translocation t(13;22)(q22.3;q11.23) in a patient with a form of focal idiopathic epilepsy. Since candidate genes for FPEVF (familial partial epilepsy with variable foci) have been mapped by linkage studies in the same cytogenetic band of chromosome 22 involved in the translocation, this case can be helpful to identify genes involved in this form of epilepsy. METHODS Molecular cytogenetics analyses (FISH and array-CGH) were performed. RESULTS AND CONCLUSIONS Neither DNA duplications nor deletions were detected by array-CGH, thus it can be inferred that the translocation is balanced. The breakpoint on chromosome 22 was precisely mapped by FISH on the RP11-432I9 clone, which is located in the interval defined by the linkage studies for FPEVF. The role of the known or hypothetical genes next to the 22q breakpoint is discussed.

Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and headache in children: a retrospective study from a tertiary level outpatient service

BackgroundIn adult studies the MTHFR C677T polymorphism has been associated with an increased risk of migraine, but little research has been done in this area in children.MethodsA retrospective study of children referred with headache to a tertiary level Paediatric Neurology Service between 2008 and 2012. This study included only patients who had been genotyped for the MTHFR C677T polymorphism. An evaluation of homocysteine serum levels was necessary to exclude other types of migraine.ConclusionCompared with the wild-type genotype, the T/T genotype was associated with an increased risk of any type of migraine, though the statistical significance was greatest in migraine with aura. The homocysteine serum levels were significantly higher in migraine with aura compared to migraine without aura. In a pediatric population MTHFR T/T homozygosity influences susceptibility to migraine.

Adult Autism Subthreshold Spectrum (AdAS Spectrum) in parents of pediatric patients with epilepsy: Correlations with post-traumatic stress symptoms

Increasing literature has shown the usefulness of a dimensional approach to mental disorders, particularly when exploring subjects exposed to traumatic experiences such as a severe illness in ones child. Recent evidence suggests an increased vulnerability in subjects with autism spectrum symptoms to develop post-traumatic stress symptoms. The aim of the present study was to evaluate the presence of adult autism subthreshold spectrum in a sample of parents of children with epilepsy and its impact on post-traumatic stress spectrum symptoms in the same study sample. Results revealed noteworthy correlations between post-traumatic stress symptoms and adult autism subthreshold spectrum (AdAS Spectrum) only in the subgroup of the fathers. In particular, were evidenced correlations between AdAS Spectrum domain of rumination and narrow interests and some TALS-SR nuclear domains: reaction to traumatic events, reexperiencing and arousal. These findings corroborate the hypothesis that subthreshold autistic features may influence the possible psychopathological reaction to trauma.