Marcella Zollino

Publications (56)217.88 Total impact

• Article: Epilepsy in Mowat-Wilson syndrome: Delineation of the electroclinical phenotype.

  Duccio Maria Cordelli, Livia Garavelli, Salvatore Savasta, Azzurra Guerra, Alessandro Pellicciari, Lucio Giordano, Silvia Bonetti, Ilaria Cecconi, Anita Wischmeijer, Marco Seri, [......], Luigi Tarani, Emanuela Terazzi, Laura Mazzanti, Paola Cerruti Mainardi, Antonella Boni, Francesca Faravelli, Marina Grasso, Paolo Bianchi, Marcella Zollino, Emilio Franzoni
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  ABSTRACT: Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS. © 2013 Wiley Periodicals, Inc.
  American Journal of Medical Genetics Part A 01/2013; · 2.39 Impact Factor
• Article: A novel compound heterozygous ALS2 mutation in two Italian siblings with juvenile amyotrophic lateral sclerosis.

  Marco Luigetti, Serena Lattante, Amelia Conte, Angela Romano, Marcella Zollino, Giuseppe Marangi, Mario Sabatelli
  Amyotrophic lateral sclerosis and frontotemporal degeneration. 01/2013;
• Article: Inherited neuropathies and deafness caused by a PMP22 point mutation: a case report and a review of the literature.

  Marco Luigetti, Marcella Zollino, Guido Conti, Angela Romano, Mario Sabatelli
  Neurological Sciences 12/2012; · 1.32 Impact Factor
• Article: Classification of familial amyotrophic lateral sclerosis by family history: effects on frequency of genes mutation.

  Amelia Conte, Serena Lattante, Marco Luigetti, Alessandra Del Grande, Angela Romano, Alessandro Marcaccio, Giuseppe Marangi, Paolo Maria Rossini, Giovanni Neri, Marcella Zollino, Mario Sabatelli
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  ABSTRACT: OBJECTIVE: To classify familial amyotrophic lateral sclerosis (FALS) on the base of family history, and to determine whether frequency of mutations in major amyotrophic lateral sclerosis (ALS) genes varies in different FALS categories. METHODS: Included in the study are 53 FALS families. Patients were classified as definite, probable and possible FALS, according to recently proposed criteria. Seven ALS-associated genes, including SOD1, TARDBP, FUS, ANG, ATXN2, OPTN and C9ORF72, were analysed. RESULTS: Thirteen patients (24.5%) were included in the definite group. The great majority of our FALS cases (40/53, 75.5%) were families with only two affected relatives; of these, 31 (58.5%) were included in the probable, and 9 (17%) in the possible FALS categories. The percentage of mutations was 61.5% in definite, 41.9% in probable and 11.1% in possible FALS. With respect to probable FALS, if cases with parent-to-child transmission of the disease were considered separately, the mutational load increased to 61.5%, as observed in definite FALS. CONCLUSIONS: Our findings provide evidence that frequency of mutations in currently known ALS genes varies widely among different FALS categories. Families with only two affected relatives have heterogeneous genetic components, the chance to detect mutations being higher in cases with parent-to-child transmission.
  Journal of neurology, neurosurgery, and psychiatry 07/2012; · 4.87 Impact Factor
• Article: Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease.

  Serena Lattante, Amelia Conte, Marcella Zollino, Marco Luigetti, Alessandra Del Grande, Giuseppe Marangi, Angela Romano, Alessandro Marcaccio, Emiliana Meleo, Giulia Bisogni, Paolo Maria Rossini, Mario Sabatelli
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  ABSTRACT: To quantify the overall contribution of mutations in the currently known amyotrophic lateral sclerosis (ALS) genes in a large cohort of sporadic patients and to make genotype-phenotype correlations. Screening for SOD1, TARDBP, FUS, ANG, ATXN2, OPTN, and C9ORF72 was carried out in 480 consecutive patients with sporadic ALS (SALS) and in 48 familial ALS (FALS) index patients admitted to a single Italian referral center. Mutations were detected in 53 patients, with a cumulative frequency of 11. Seven of them were novel. The highest frequencies of positive cases were obtained in TARDBP (2.7%), C9ORF72 (2.5%), and SOD1 (2.1%). The overall group of mutated patients was indistinguishable from that without mutations as no significant differences were observed with regard to age and site of onset, frequency of clinical phenotypes, and survival. However, by separately evaluating genotype-phenotype correlation in single genes, clinical differences were observed among different genes. Duration of disease was significantly shorter in patients harboring the C9ORF72 expansion and longer in the SOD1 group. A high frequency of predominant upper motor neuron phenotype was observed among patients with TARDBP mutations. Two patients, 1 with C9ORF72 and 1 with SOD1 mutation, had concurrent ANG mutations. Mutations were detected in 43.7% of patients with FALS. A considerable proportion of patients with SALS harbored mutations in major ALS genes. This result has relevant implications in clinical practice, namely in genetic counseling. The detection of double mutations in 2 patients raises the hypothesis that multiple mutations model may explain genetic architecture of SALS.
  Neurology 06/2012; 79(1):66-72. · 8.31 Impact Factor
• Article: Frontotemporal dementia, Parkinsonism and lower motor neuron involvement in a patient with C9ORF72 expansion.

  Marco Luigetti, Davide Quaranta, Amelia Conte, Chiara Piccininni, Serena Lattante, Angela Romano, Gabriella Silvestri, Marcella Zollino, Mario Sabatelli
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  ABSTRACT: It has been recently reported that a large proportion of patients with familial and sporadic amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) carries the hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We describe a patient with a complex phenotype characterized by behavioural variant of FTD, Parkinsonism and ALS with predominant lower motor neuron involvement in which the C9ORF72 expansion was detected.
  Amyotrophic Lateral Sclerosis 06/2012; · 3.40 Impact Factor
• Article: Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome.

  Giuseppe Marangi, Stefania Ricciardi, Daniela Orteschi, Romano Tenconi, Matteo Della Monica, Gioacchino Scarano, Domenica Battaglia, Donatella Lettori, Gessica Vasco, Marcella Zollino
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  ABSTRACT: Pitt-Hopkins syndrome (PTHS) is an emerging condition characterized by severe intellectual disability (ID), typical facial gestalt, and additional features, such as breathing abnormalities. Because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly, large mouth, and constipation, differential diagnosis of PTHS with respect to Angelman, Rett, and Mowat-Wilson syndromes represents a relevant clinical issue, and many patients are currently undergoing genetic tests for different conditions that are assumed to fall within the PTHS clinical spectrum. During a search for TCF4 mutations in 78 patients with a suspected PTHS, haploinsufficiency of TCF4 was identified in 18. By evaluating clinical features of patients with a proven TCF4 mutation with those of patients without, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combination of the following characteristics: ID with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing abnormalities, motor incoordination, ocular anomalies, constipation, seizures, typical behavior, and subtle brain abnormalities. On the basis of these observations, here we propose a clinically based score system as useful tool for driving a first choice molecular test for PTHS. This scoring system is also proposed for a clinically based diagnosis of PTHS in absence of a proven TCF4 mutation.
  American Journal of Medical Genetics Part A 06/2012; 158A(7):1604-11. · 2.39 Impact Factor
• Article: TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype.

  Giuseppe Marangi, Vincenzo Leuzzi, Filippo Manti, Serena Lattante, Daniela Orteschi, Vanna Pecile, Giovanni Neri, Marcella Zollino
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  ABSTRACT: Intellectual disability (ID) with autosomal recessive (AR) inheritance is believed to be common; however, very little is known about causative genes and genotype-phenotype correlations. The broad genetic heterogeneity of AR-ID, and its usually nonsyndromic nature make it difficult to pool multiple pedigrees with the same underlying genetic defect to achieve consistent nosology. Nearly all autosomal genes responsible for recessive cognitive disorders have been identified in large consanguineous families from the Middle East, and nonsense mutations in TRAPPC9 have been reported in a total of 5. Although several recurrent phenotypic abnormalities are described in some of these patients, the associated phenotype is usually referred to as nonsyndromic. By means of single-nucleotide polymorphism-array first and then by exome sequencing, we identified a new pathogenic mutation in TRAPPC9 in two Italian sisters born to healthy and apparently nonconsanguineous parents. It consists of a homozygous splice site mutation causing exon skipping with frameshift and premature termination, as confirmed by mRNA sequencing. By detailed phenotypic analysis of our patients, and by critical literature review, we found that homozygous TRAPPC9 loss-of-function mutations cause a distinctive phenotype, characterized by peculiar facial appearance, obesity, hypotonia (all signs resembling a Prader-Willi-like phenotype), moderate-to-severe ID, and consistent brain abnormalities.European Journal of Human Genetics advance online publication, 2 May 2012; doi:10.1038/ejhg.2012.79.
  European journal of human genetics: EJHG 05/2012; · 3.56 Impact Factor
• Article: Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype.

  Marcella Zollino, Daniela Orteschi, Marina Murdolo, Serena Lattante, Domenica Battaglia, Chiara Stefanini, Eugenio Mercuri, Pietro Chiurazzi, Giovanni Neri, Giuseppe Marangi
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  ABSTRACT: The chromosome 17q21.31 deletion syndrome is a genomic disorder characterized by highly distinctive facial features, moderate-to-severe intellectual disability, hypotonia and friendly behavior. Here, we show that de novo loss-of-function mutations in KANSL1 (also called KIAA1267) cause a full del(17q21.31) phenotype in two unrelated individuals that lack deletion at 17q21.31. These findings indicate that 17q21.31 deletion syndrome is a monogenic disorder caused by haploinsufficiency of KANSL1.
  Nature Genetics 04/2012; 44(6):636-8. · 35.53 Impact Factor
• Article: The ring 14 syndrome.

  Marcella Zollino, Emanuela Ponzi, Giuseppe Gobbi, Giovanni Neri
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  ABSTRACT: The ring 14 syndrome is a rare condition, whose precise clinical and genetic characterization is still limited. This review summarizes literature data and it describes our own experience with 27 patients with ring 14 syndrome. Clinically, the ring 14 syndrome is characterized by a recognizable phenotype of shortness of stature, distinctive facial appearance, microcephaly, scoliosis, and ocular abnormalities, consisting mainly of abnormal retinal pigmentation, but also retinitis pigmentosa, strabismus, glaucoma, and abnormal macula. Virtually all patients are intellectually delayed, with aggressive and hyperactive behavior in some. Drug-resistant, mainly focal in type, epilepsy is another highly consistent finding. In our own sample of patients the ring was complete, with no apparent loss of chromosome material, in 6/27 cases, while it showed a small terminal deletion, varying in size from 0.3 to 5 Mb, in the other 21. In two of these a cryptic 14q duplication of 2.5 and 9.7 Mb, respectively, proximal to the deleted segment, was also identified. Deleted rings were 75% paternal and 25% maternal in origin. UPD (14) was excluded in all cases. Based on literature review of linear deletions, affecting either the proximal or the distal 14q region, we could deduce that retinal abnormalities and epilepsy map within the proximal 14q11.2- q12 region. Because this region is preserved in all patients with ring 14, we speculate that genes residing in the proximal 14q interval are disregulated through heterochromatinization spreading from the adjacent short arm of the chromosome. Behavior disorders and susceptibility to infections can be assigned to the 14q32 region, haploinsufficiency being the most likely underlying mechanism.
  European journal of medical genetics 04/2012; 55(5):374-80. · 1.57 Impact Factor
• Article: Founder effect hypothesis of D11Y SOD1 mutation in Italian amyotrophic lateral sclerosis patients.

  Serena Lattante, Giuseppe Marangi, Marco Luigetti, Amelia Conte, Jessica Mandrioli, Alessandra Del Grande, Marcella Zollino, Mario Sabatelli
  Amyotrophic Lateral Sclerosis 02/2012; 13(2):241-2. · 3.40 Impact Factor
• Article: P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis.

  Amelia Conte, Serena Lattante, Marcella Zollino, Giuseppe Marangi, Marco Luigetti, Alessandra Del Grande, Serenella Servidei, Federica Trombetta, Mario Sabatelli
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  ABSTRACT: Some FUS mutations have been observed in patients with the juvenile form of Amyotrophic Lateral Sclerosis starting before 25 years. We report an 11-year-old girl affected by sporadic juvenile ALS with a rapid course resulting in tracheostomy after 14 months from the onset. Sequencing FUS gene revealed a de novo P525L mutation. Our findings, together with literature data, indicate that this mutation is consistently associated with a specific phenotype characterized by juvenile onset, severe course and high proportion of de novo mutations in sporadic cases.
  Neuromuscular Disorders 09/2011; 22(1):73-5. · 2.80 Impact Factor
• Article: Wolf-Hirschhorn syndrome due to pure and translocation forms of monosomy 4p16.1 → pter.

  Piotr S Iwanowski, Barbara Panasiuk, Griet Van Buggenhout, Marina Murdolo, Marta Myśliwiec, Nicole M C Maas, Serena Lattante, Lech Korniszewski, Renata Posmyk, Jacek Pilch, Stanislaw Zajączek, Jean-Pierre Fryns, Marcella Zollino, Alina T Midro
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  ABSTRACT: The aim of this study was to obtain a quantitative definition of Wolf-Hirschhorn syndrome (WHS) through systematic phenotypic analyses in a group of six children with 4p15.32 → pter, 4p15.33 → pter, or 4p16.1 → pter monosomy (considered together as M4p16.1). These results were used for evaluation of the phenotypic effects of a double chromosome imbalance in one child with 4p16.1 → pter monosomy and additional 11q23.3 → qter trisomy. Children with pure M4p16.1 presented with a total of 227 clinical and morphological traits, of which 119 were positive in at least two of them. These traits overlap to a great extent with clinical criteria defining the WHS phenotype. Among the 103 traits identified in the child with unbalanced translocation der(4)t(4;11)(p16.1;q23.3), most clinical and developmental traits (but only 11 morphological) were found to be shared by WHS children with pure M4p16.1 and at least one reported patient with pure 11q trisomy. Forty-six traits of this child corresponded solely to those identified in at least one child with pure M4p16.1. Only five traits of the hybrid phenotype were present in at least one child with pure distal 11q trisomy but in none of the present children with pure M4p16.1. In conclusion, most of the morphological traits of the hybrid phenotype in the child with der(4)t(4;11)(p16.1;q23.3) can be attributed to the M4p16.1, whereas their overlap with those associated with pure distal 11q trisomy is less evident. Phenotype analyses based on the same systematic data acquisition may be useful in understanding the phenotypic effects of different chromosome regions in complex rearrangements. © 2011 Wiley-Liss, Inc.
  American Journal of Medical Genetics Part A 08/2011; 155A(8):1833-47. · 2.39 Impact Factor
• Article: Wolf–Hirschhorn syndrome due to pure and translocation forms of monosomy 4p16.1 → pter

  Piotr S. Iwanowski, Barbara Panasiuk, Griet Van Buggenhout, Marina Murdolo, Marta Myśliwiec, Nicole M.C. Maas, Serena Lattante, Lech Korniszewski, Renata Posmyk, Jacek Pilch, Stanislaw Zajączek, Jean-Pierre Fryns, Marcella Zollino, Alina T. Midro
  [show abstract] [hide abstract]
  ABSTRACT: The aim of this study was to obtain a quantitative definition of Wolf–Hirschhorn syndrome (WHS) through systematic phenotypic analyses in a group of six children with 4p15.32 → pter, 4p15.33 → pter, or 4p16.1 → pter monosomy (considered together as M4p16.1). These results were used for evaluation of the phenotypic effects of a double chromosome imbalance in one child with 4p16.1 → pter monosomy and additional 11q23.3 → qter trisomy. Children with pure M4p16.1 presented with a total of 227 clinical and morphological traits, of which 119 were positive in at least two of them. These traits overlap to a great extent with clinical criteria defining the WHS phenotype. Among the 103 traits identified in the child with unbalanced translocation der(4)t(4;11)(p16.1;q23.3), most clinical and developmental traits (but only 11 morphological) were found to be shared by WHS children with pure M4p16.1 and at least one reported patient with pure 11q trisomy. Forty-six traits of this child corresponded solely to those identified in at least one child with pure M4p16.1. Only five traits of the hybrid phenotype were present in at least one child with pure distal 11q trisomy but in none of the present children with pure M4p16.1. In conclusion, most of the morphological traits of the hybrid phenotype in the child with der(4)t(4;11)(p16.1;q23.3) can be attributed to the M4p16.1, whereas their overlap with those associated with pure distal 11q trisomy is less evident. Phenotype analyses based on the same systematic data acquisition may be useful in understanding the phenotypic effects of different chromosome regions in complex rearrangements. © 2011 Wiley-Liss, Inc.
  American Journal of Medical Genetics Part A 07/2011; 155(8):1833 - 1847. · 2.39 Impact Factor
• Article: Uncovering amyotrophic lateral sclerosis phenotypes: clinical features and long-term follow-up of upper motor neuron-dominant ALS.

  Mario Sabatelli, Marcella Zollino, Marco Luigetti, Alessandra Del Grande, Serena Lattante, Giuseppe Marangi, Mauro Lo Monaco, Francesca Madia, Emiliana Meleo, Giulia Bisogni, Amelia Conte
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  ABSTRACT: The aim of our study was to analyse the natural history and clinical features of upper motor neuron- dominant (UMN-D) ALS. We studied a large series of sporadic ALS patients admitted in a single referral centre over a 23-year period. UMN-D phenotype was compared with other ALS forms, including classic ALS, flail arm and progressive muscular atrophy. Seven hundred and thirty-four sporadic ALS patients were included of which 163 had UMN-D ALS. The mean age of onset in UMN-D ALS (52 years) was 10 years lower than in classic ALS (61.4 years, p < 0.0001); sex ratio by age groups significantly differed with respect to other phenotypes. The pattern of spread of lower motor neuron signs in UMN-D was characterized by early involvement of upper limb muscles and late impairment of respiratory muscles. Duration of the disease was longer in the UMN-D group (56 months) than in classic ALS (33 months, p < 0.001). The UMN-D phenotype was a strong independent predictor of long survival. In summary, UMN-D ALS showed significant differences in age of onset, sex ratio, pattern of spreading and prognosis with respect to other ALS forms, most probably reflecting biological differences.
  Amyotrophic Lateral Sclerosis 07/2011; 12(4):278-82. · 3.40 Impact Factor
• Source

  Available from: Corrado Romano

  Article: The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

  Giuseppe Marangi, Stefania Ricciardi, Daniela Orteschi, Serena Lattante, Marina Murdolo, Bruno Dallapiccola, Chiara Biscione, Rosetta Lecce, Pietro Chiurazzi, Corrado Romano, [......], Cinzia Magnani, Paolo Bonanni, Federica Martinez, Gigliola Serra, Domenica Battaglia, Donatella Lettori, Gessica Vasco, Anna Baroncini, Cecilia Daolio, Marcella Zollino
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  ABSTRACT: Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin.
  American Journal of Medical Genetics Part A 07/2011; 155A(7):1536-45. · 2.39 Impact Factor
• Source

  Available from: Giovanni Sorge

  Article: The Pitt‐Hopkins syndrome: Report of 16 new patients and clinical diagnostic criteria

  Giuseppe Marangi, Stefania Ricciardi, Daniela Orteschi, Serena Lattante, Marina Murdolo, Bruno Dallapiccola, Chiara Biscione, Rosetta Lecce, Pietro Chiurazzi, Corrado Romano, [......], Cinzia Magnani, Paolo Bonanni, Federica Martinez, Gigliola Serra, Domenica Battaglia, Donatella Lettori, Gessica Vasco, Anna Baroncini, Cecilia Daolio, Marcella Zollino
  [show abstract] [hide abstract]
  ABSTRACT: Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin. © 2011 Wiley-Liss, Inc.
  American Journal of Medical Genetics Part A 06/2011; 155(7):1536 - 1545. · 2.39 Impact Factor
• Article: SOD1 G93D sporadic amyotrophic lateral sclerosis (SALS) patient with rapid progression and concomitant novel ANG variant.

  Marco Luigetti, Serena Lattante, Marcella Zollino, Amelia Conte, Giuseppe Marangi, Alessandra Del Grande, Mario Sabatelli
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  ABSTRACT: SOD1 G93D mutation has been described in amyotrophic lateral sclerosis (ALS) patients with slowly progressive disease. We describe an Italian patient affected by sporadic ALS with the SOD1 G93D mutation that disclosed an unusual rapid progression with death occurring after 30 months from the symptom onset. Considering the atypical clinical course further genes associated with ALS or known to be causative were studied including ANG, PGRN, TARDBP, FUS, VCP, CHRNA3, CHRNA4, and CHRNB4. A novel heterozygous ANG missense variant (c.433 C>T, p.R145C) was identified which is neither reported in controls nor in 1000 genomes and single nucleotide polymorphism (SNP) databases. This report confirms that clinical course of SOD1-related ALS may be modulated by other causative or associated genes, including ANG and suggests that extensive screening of ALS-associated genes in patients with an already identified mutation may be helpful for better knowledge of genetic architecture of ALS.
  Neurobiology of aging 05/2011; 32(10):1924.e15-8. · 5.94 Impact Factor
• Article: Characterization of a novel transcript of the EHMT1 gene reveals important diagnostic implications for Kleefstra syndrome.

  Willy M Nillesen, Helger G Yntema, Marco Moscarda, Nienke E Verbeek, Louise C Wilson, Frances Cowan, Marga Schepens, Annick Raas-Rothschild, Orly Gafni-Weinstein, Marcella Zollino, Raymon Vijzelaar, Giovanni Neri, Marcel Nelen, Hans van Bokhoven, Jacques Giltay, Tjitske Kleefstra
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  ABSTRACT: The core phenotype of Kleefstra syndrome (KS) is characterized by intellectual disability, childhood hypotonia, and a characteristic facial appearance. This can be caused by either submicroscopic 9q34 deletions or loss of function mutations of the EHMT1 gene. Remarkably, in three patients with a clinical suspicion of KS, molecular cytogenetic analysis revealed an interstitial 9q34 microdeletion proximal to the coding region of the EHMT1 gene based on the NM_ 024757.3 transcript. Because we found a mono-allelic EHMT1 transcript suggestive for haploinsufficiency of EHMT1 in two of these patients tested, we hypothesized that a deletion of regulatory elements or so far unknown coding sequences in the 5' region of the EHMT1 gene, might result in a phenotype compatible with KS. We further characterized the molecular content of deletions proximal to the transcript NM_ 024757.3 and confirmed presence of a novel predicted open reading frame comprising 27 coding exons (NM_ 024757.4). Further analysis showed that all three deletions included the presumed novel first exon of the EHMT1 gene. Subsequent testing of 75 individuals without previously detectable EHMT1 aberrations showed one additional case with a deletion comprising only this 5' part of the gene. These results have important implications for the genetic screening of KS and for studies of the functional significance of EHMT1.
  Human Mutation 04/2011; 32(7):853-9. · 5.69 Impact Factor
• Article: A novel L67P SOD1 mutation in an Italian ALS patient.

  Alessandra del Grande, Marco Luigetti, Amelia Conte, Irene Mancuso, Serena Lattante, Giuseppe Marangi, Giuseppe Stipa, Marcella Zollino, Mario Sabatelli
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  ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. We describe a novel L67P mutation located in exon 3 of the Cu/Zn superoxide dismutase gene in a patient with pure lower motor neuron signs. To date, 11 mutations involving exon 3 of SOD1 have been described, including the present one. Our data confirm that variable penetrance and predominant lower motor neuron involvement are common characteristics in patients bearing mutations in exon 3 of the SOD1 gene.
  Amyotrophic Lateral Sclerosis 03/2011; 12(2):150-2. · 3.40 Impact Factor