title: TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients.
abstract: BACKGROUND
  Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases.
  
  
  METHODS
  The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood.
  
  
  RESULTS
  The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients.
  
  
  CONCLUSIONS
  TUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms.
authors.affiliation: Department of Child Neurology, Neurological Institute C. Besta Foundation IRCCS, Milan, Italy; INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France. Electronic address: davidetondu@hotmail.com.
authors.forename: Davide
authors.initials: D
authors.lastname: Tonduti
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Aiello
authors.affiliation: INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France; AP-HP, Departement of Neuropediatrics and Metabolic Diseases, National Reference Center for Leukodystrophies, Robert Debré Hospital, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Renaldo
authors.affiliation: INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France.
authors.forename: Imen
authors.initials: I
authors.lastname: Dorboz
authors.affiliation: AP-HP, Department of Human Genetic, Molecular Biology Unit, Robert Debré Hospital, Paris, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Saaman
authors.affiliation: INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France; AP-HP, Department of Child Neurology, Hôpital Armand-Trousseau, GHUEP, Paris, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.affiliation: AP-HP, Departement of Neuropediatrics and Metabolic Diseases, National Reference Center for Leukodystrophies, Robert Debré Hospital, Paris, France; INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France.
authors.forename: Houda
authors.initials: H
authors.lastname: Fettah
authors.affiliation: AP-HP, Department of Child Radiology, Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Elmaleh
authors.affiliation: Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Biancheri
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, Rome, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Barresi
authors.affiliation: Genetics and Rare Diseases Unit, II Division of Pediatrics, Ospedale Microcitemico, Cagliari, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Boccone
authors.affiliation: Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Orcesi
authors.affiliation: Department of Neuroradiology, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pichiecchio
authors.affiliation: Movement Disorders Unit, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Zangaglia
authors.affiliation: AP-HP, Neuropediatric Departement, Reference Center for Leukodystrophies Kremlin Bicêtre Hospital, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Maurey
authors.affiliation: Department of Child Neurology, Neurological Institute C. Besta Foundation IRCCS, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rossi
authors.affiliation: INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France; AP-HP, Departement of Neuropediatrics and Metabolic Diseases, National Reference Center for Leukodystrophies, Robert Debré Hospital, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
mesh_terms: D000328:Adult; D018450:Disease Progression; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059906:Neuroimaging; D010641:Phenotype; D014404:Tubulin / Q000235:genetics*
chemical_list: C582076:TUBB4A protein, human; D014404:Tubulin
keywords: Atrophy; Cerebellar; H-ABC; Hypomyelination; Leukodystrophy; TUBB4A