Luigina Spaccini

Ospedale dei Bambini Vittore Buzzi, Milano, Lombardy, Italy

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Publications (16)46.51 Total impact

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    ABSTRACT: Snyder-Robinson syndrome is a rare form of X-linked intellectual disability caused by mutations in the spermine synthase (SMS) gene, and characterized by intellectual disability, thin habitus with diminished muscle mass, osteoporosis, kyphoscoliosis, facial dysmorphism (asymmetry, full lower lip), long great toes, and nasal or dysarthric speech. Physical signs seem to evolve from childhood to adulthood. We describe the first Italian patient with Snyder-Robinson syndrome and a novel nonsense mutation in SMS (c.200G>A; p.G67X). Apart from the typical features of the syndrome, the index patient presented with an ectopic right kidney and epilepsy from the first year of age that was characterized by focal motor seizures and negative myoclonus. The clinical and molecular evaluation of this family and the review of the literature expand the phenotype of Snyder-Robinson syndrome to include myoclonic or myoclonic-like seizures (starting even in the first years of life) and renal abnormalities in affected males. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2013; · 2.30 Impact Factor
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    ABSTRACT: Early-onset epileptic encephalopathies (EOEEs) are characterised by epileptic seizures beginning in the first months of life, abnormal background EEG activity, and are associated with severe developmental delay and poor prognosis. Mutations and deletions in the STXBP1 gene are associated with Ohtahara syndrome, also known as "early infantile epileptic encephalopathy". We report an infant affected by EOEE with a 9q34.11 deletion that encompassed the genes STXBP1 and SPTAN1. The infant presented with neonatal encephalopathy without epileptic seizures and an EEG pattern varying from highly discontinuous to suppression-burst. This was followed by West syndrome at 2 months with atypical hypsarrhythmia and spasms, easily controlled by therapy. Our findings suggest that molecular analysis of STXBP1 should be considered for newborns affected by neonatal encephalopathy associated with a peculiar EEG pattern, even in the absence of neonatal epileptic seizures.
    Epileptic disorders: international epilepsy journal with videotape 03/2013; · 1.17 Impact Factor
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    ABSTRACT: PURPOSE: To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS). METHODS: Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method. KEY FINDINGS: A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation. SIGNIFICANCE: Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene.
    Epilepsia 01/2013; · 3.96 Impact Factor
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    ABSTRACT: Purpose:  Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients. Methods:  We studied 35 patients with PCDH19 gene-related epilepsy and analyzed clinical history and ictal video-EEG recordings obtained in 34 of them. Key Findings:  Clusters of focal febrile and afebrile seizures had occurred in 34 patients, at a mean age of 10 months. The predominant and more consistent ictal sign was fearful screaming, occurring in 24 patients (70.5%); it was present since epilepsy onset in 12 and appeared later on, during the course in the remaining 12 patients. In infancy, fearful screaming mainly appeared within the context of seizures with prominent hypomotor semiology, whereas during follow-up it was associated with prominent early motor manifestations. In 16 patients, seizures were video-EEG recorded both at onset and during follow-up: in five patients (31%) seizure semiology remained identical, in 7 (44%) semiology varied and in four patients it was unclear whether ictal semiology changed with age. Three patients (9%) had both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a prominent involvement of the frontotemporal regions (22 patients). About 45% of patients had an alternating EEG pattern, with the ictal discharge migrating from one hemisphere to the contralateral during the same ictal event. Status epilepticus occurred in 30% of patients. Cognitive impairment occurred in 70%, ranging from mild (42%) to moderate (54%) and severe (4%); autistic features occurred in 28.5%. Direct sequencing detected 33 different heterozygous candidate mutations, 8 of which were novel. Mutations were missense substitutions (48.5%), premature termination (10 frameshift, 4 nonsense, and 2 splice-site mutations; 48.5%), and one in-frame deletion. Thirty candidate mutations (91%) were de novo. No specific genotype-phenotype correlation could be established, as missense and truncating mutations were associated with phenotypes of comparable severity. Significance:  Most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Awareness of this distinctive phenotype will likely enhance recognition of this disorder.
    Epilepsia 09/2012; · 3.96 Impact Factor
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    ABSTRACT: Epilepsy and mental retardation limited to females (EFMR) is a genetic disorder that affects females but spares transmitting males. The condition is caused by protocadherin 19 mutations and is characterised by seizures beginning at around 1 year of age, frequently associated with cognitive regression at seizure onset or later. Seizures can be generalised or focal, exacerbated by febrile illnesses, and grouped in clusters. This report shows the first video-EEG recording of EFMR, in a 7-year-old female presenting peculiar ictal features. [Published with video sequences].
    Epileptic disorders: international epilepsy journal with videotape 08/2012; 14(3):304-9. · 1.17 Impact Factor
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    ABSTRACT: Rare intrachromosomal triplications producing partial tetrasomies have been reported for a number of chromosomes. A detailed molecular characterization, necessary to define the mechanism of their formation, has so far been lacking. We report on the detailed clinical, cytogenetic, and molecular characterization of two triplications, one de novo involving chromosome 18q, the other familial on chromosome Xp. The clinical phenotype of the patient with 18q triplication, very likely due to overexpression of one or more of the genes in the region, consists mainly of facial dysmorphisms and developmental delay. The familial Xp triplication does not cause an increase in the number of copies of any gene and is almost certainly a polymorphism. The rearrangements are actually complex duplications/triplications. In both patients, their proximal breakpoints are located within complex segmental duplications, one containing the VCX gene cluster on chromosome Xp, the other the TCEB3 genes on chromosome 18q. A proximal duplicated region is also present in both patients. All junctions we analyzed were formed by non-homologous end joining (NHEJ). The structural features shared between our patients suggest the involvement of a common mechanism in the genesis of interstitial intrachromosomal triplications.
    American Journal of Medical Genetics Part A 09/2011; 155A(11):2681-7. · 2.30 Impact Factor
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    ABSTRACT: Pyridoxine-dependent seizures (PDS) is a rare disorder characterized by seizures resistant to anticonvulsants but controlled by daily pharmacologic doses of pyridoxine. Mutations in the antiquitin (ALDH7A1) gene have recently reported to cause PDS in most of patients. We report the long-term follow-up in two PDS siblings carrying a novel ALDH7A1 mutation.
    European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 07/2011; 15(6):547-50. · 2.01 Impact Factor
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    ABSTRACT: Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.
    The American Journal of Human Genetics 10/2009; 85(3):394-400. · 11.20 Impact Factor
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    ABSTRACT: Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
    American Journal of Medical Genetics Part A 09/2009; 149A(10):2173-80. · 2.30 Impact Factor
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    ABSTRACT: The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.
    Human Mutation 01/2009; 30(2):E432-42. · 5.21 Impact Factor
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    ABSTRACT: This study reviews prenatal findings in two cases with a suspected diagnosis of Cornelia de Lange Syndrome, a multisystem disorder characterized by somatic defects and mental retardation, that were later confirmed by postmortem examination and molecular testing. Although the correlation between the Cornelia de Lange Syndrome genotype and phenotype is still unclear, preliminary data indicate several severe phenotypic features that are likely to be detected prenatally in NIPBL-mutated patients. We report on two prenatal/neonatal cases with unusual pathologic findings indicating Cornelia de Lange Syndrome. The first, with suspected Cornelia de Lange Syndrome after a set of typical dysmorphisms was noted by prenatal ultrasound, was confirmed by a physical examination after termination of the pregnancy. The second was diagnosed neonatally on the basis of typical clinical signs. Medical complications led to death within the first month of life. Molecular analysis of NIPBL, the gene that codes for delangin (a component of the cohesin complex), performed postnatally detected two de novo mutations: a missense change (P2056L) in a highly conserved residue and a nonsense alteration (S2490 replaced by a stop codon). We suggest that early diagnosis of Cornelia de Lange Syndrome would be made much easier by the assemblage of a set of prenatal diagnostic features and criteria in Cornelia de Lange Syndrome cases that have been confirmed by direct physical and molecular examinations. We also suggest that Cornelia de Lange Syndrome genotype-phenotype correlations need to be extended to prenatal cases.
    Genetics in Medicine 04/2007; 9(3):188-94. · 5.56 Impact Factor
  • Donald School Journal of Ultrasound in Obstetrics & Gynecology. 01/2007;
  • American Journal of Medical Genetics Part A 02/2005; 132A(3):329-30. · 2.30 Impact Factor
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    ABSTRACT: We describe a female affected by diaphragmatic hernia and nasopharyngeal teratoma. The case is compared with one already reported and possible diagnoses discussed. These cases appear to represent a new syndrome.
    Clinical Dysmorphology 11/2004; 13(4):255-6. · 0.38 Impact Factor
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    ABSTRACT: Fetal face malformations represent one of the most challenging prenatal diagnoses mainly because of the wide range of morphological features involved. We tested an approach based on a combination of conventional two-dimensional ultrasound with the more recent three-dimensional technique plus magnetic resonance imaging, in order to improve parents' understanding of fetal face anomalies, thereby facilitating parent counselling. Two cases of fetal facial anomaly were studied using these combined techniques; one had severe micrognathia and malformation of the ears with preauricular tags, while the other had bilateral dacryocystocele and severe hypertelorism. The images generated by three-dimensional ultrasound enabled the parents to visualize their child immediately and helped them to adjust to the diagnosis of facial defects and its clinical consequences. An approach based on combined use of different imaging techniques was found useful in both cases.
    Prenatal Diagnosis 08/2004; 24(7):508-12. · 2.68 Impact Factor
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    ABSTRACT: Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
    Am J Med Genet A. 149A(10):2173-80.

Publication Stats

112 Citations
46.51 Total Impact Points

Institutions

  • 2007–2013
    • Ospedale dei Bambini Vittore Buzzi
      Milano, Lombardy, Italy
  • 2009
    • IRCCS Ospedale Casa Sollievo della Sofferenza
      Giovanni Rotondo, Apulia, Italy
    • IRCCS Eugenio Medea
      Bosisio Parini, Lombardy, Italy
  • 2004
    • Istituti Clinici di Perfezionamento
      Milano, Lombardy, Italy