title: Novel GNAL mutation with intra-familial clinical heterogeneity: Expanding the phenotype.
abstract: BACKGROUND
  Mutations in GNAL have been associated with adult-onset cranio-cervical dystonia, but a limited number of cases have been reported so far and the clinical spectrum associated with this gene still needs to be fully characterized.
  
  
  METHODS
  We identified an Italian family with adult-onset, dominantly-inherited dystonia whose members presented with different combinations of dystonia affecting the cervical, oro-mandibular and laryngeal regions associated with prominent tremor in some cases. Pure asymmetric upper limb dystonic tremor was present in one of the members and jerky cervical dystonia was also observed. A dedicate dystonia gene panel (Illumina) was used to screen for dystonia-associated genes and Sanger sequencing was performed to confirm results obtained and to perform segregation analysis.
  
  
  RESULTS
  A novel single-base mutation in GNAL exon 9 (c.628G>A; p.Asp210Asn) leading to an aminoacidic substitution was identified and confirmed by Sanger sequencing. In silico prediction programmes as well as segregation analysis confirmed its pathogenicity. Clinically, no generalization of dystonia was observed after onset and DBS lead to an excellent motor outcome in two cases.
  
  
  CONCLUSIONS
  We report a novel GNAL mutation and expand the clinical spectrum associated with mutations in this gene to comprise pure asymmetric dystonic tremor and a jerky cervical phenotype partially mimicking DYT11 positive cases.
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Neurological Institute C. Besta, Via L. Temolo 4, 20126 Milan, Italy; Department of Pediatric Neurology, IRCCS Neurological Institute C. Besta, Via Celoria 11, 20133 Milan, Italy.
authors.forename: Miryam
authors.initials: M
authors.lastname: Carecchio
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Neurological Institute C. Besta, Via L. Temolo 4, 20126 Milan, Italy.
authors.forename: Celeste
authors.initials: C
authors.lastname: Panteghini
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Neurological Institute C. Besta, Via L. Temolo 4, 20126 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Reale
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Neurological Institute C. Besta, Via L. Temolo 4, 20126 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Barzaghi
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Neurological Institute C. Besta, Via L. Temolo 4, 20126 Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Monti
authors.affiliation: Department of Neurology, IRCCS Neurological Institute C. Besta, Via Celoria 11, 20133 Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Romito
authors.affiliation: Department of Neurology, AO Ospedale di Circolo di Melegnano, Strada Pandina 1, 20070 Vizzolo Predabissi (MI), Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sasanelli
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Neurological Institute C. Besta, Via L. Temolo 4, 20126 Milan, Italy. Electronic address: garavaglia@istituto-besta.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Garavaglia
mesh_terms: D046690:Deep Brain Stimulation; D020821:Dystonic Disorders / Q000235:genetics* / Q000628:therapy; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation
chemical_list: D044385:GTP-Binding Protein alpha Subunits; C084618:olfactory G protein subunit alpha olf
keywords: Dystonia; GNAL; Phenotype; Tremor