title: Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families.
abstract: The term hereditary spastic paraplegia (HSP) covers a spectrum of genetically heterogeneous disorders in which lower limb spasticity is the common clinical feature. Many patients with childhood-onset HSP are mistakenly diagnosed with cerebral palsy (CP).
  
  
  
  A group of as yet molecularly undiagnosed HSP patients were analyzed using SpastoPlex, a customized target re-sequencing panel able to investigate the coding regions of 72 genes linked to HSP, spastic ataxias or related motor diseases.
  
  
  
  Our investigations identified loss-of-function mutations in AP4S1/SPG52 in four children (three families) who had previously received a diagnosis of diplegic/quadriplegic CP. The patients presented spastic paraparesis, mild facial dysmorphisms, moderate-to-severe intellectual disability and severe speech delay. Two patients manifested febrile seizures and childhood-onset focal seizures. In all the patients, brain magnetic resonance imaging (MRI) showed a peculiar hypoplastic posterior corpus callosum, often associated with ventriculomegaly, white matter loss and cerebral atrophy.
  
  
  
  Adaptor protein 4 (AP-4) deficiency disorders should be suspected in children with spastic paraparesis, cognitive deficit and absent speech accompanied by suggestive MRI features. Seizures might be amongst the clinical manifestations of the syndrome.
authors.affiliation: Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tessa
authors.affiliation: Child Neurology, IRCCS Stella Maris, Pisa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Battini
authors.affiliation: Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rubegni
authors.affiliation: Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Storti
authors.affiliation: Pediatric Neurology Unit, Children's Hospital 'A. Meyer', University of Florence, Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Marini
authors.affiliation: Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Galatolo
authors.affiliation: Neuroradiology, IRCCS Stella Maris, Pisa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Pasquariello
authors.affiliation: Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy. filippo3364@gmail.com.|Child Neurology, IRCCS Stella Maris, Pisa, Italy. filippo3364@gmail.com.
authors.forename: F M
authors.initials: FM
authors.lastname: Santorelli
mesh_terms: D033964:Adaptor Protein Complex 4 / Q000235:genetics*; D000293:Adolescent; D002547:Cerebral Palsy / Q000175:diagnosis; D002675:Child, Preschool; D003951:Diagnostic Errors; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C000604469:AP4S1 protein, human; D033964:Adaptor Protein Complex 4
keywords: AP4S1; SPG52; cerebral palsy; hereditary spastic paraparesis; next generation sequencing