A Tessa1, R Battini2, A Rubegni1, E Storti1, C Marini3, D Galatolo1, R Pasquariello4, F M Santorelli5,6. 1. Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy. 2. Child Neurology, IRCCS Stella Maris, Pisa, Italy. 3. Pediatric Neurology Unit, Children's Hospital 'A. Meyer', University of Florence, Florence, Italy. 4. Neuroradiology, IRCCS Stella Maris, Pisa, Italy. 5. Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy. filippo3364@gmail.com. 6. Child Neurology, IRCCS Stella Maris, Pisa, Italy. filippo3364@gmail.com.
Abstract
BACKGROUND AND PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND AND PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: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: Darius Ebrahimi-Fakhari; Julian Teinert; Robert Behne; Miriam Wimmer; Angelica D'Amore; Kathrin Eberhardt; Barbara Brechmann; Marvin Ziegler; Dana M Jensen; Premsai Nagabhyrava; Gregory Geisel; Erin Carmody; Uzma Shamshad; Kira A Dies; Christopher J Yuskaitis; Catherine L Salussolia; Daniel Ebrahimi-Fakhari; Toni S Pearson; Afshin Saffari; Andreas Ziegler; Stefan Kölker; Jens Volkmann; Antje Wiesener; David R Bearden; Shenela Lakhani; Devorah Segal; Anaita Udwadia-Hegde; Andrea Martinuzzi; Jennifer Hirst; Seth Perlman; Yoshihisa Takiyama; Georgia Xiromerisiou; Katharina Vill; William O Walker; Anju Shukla; Rachana Dubey Gupta; Niklas Dahl; Ayse Aksoy; Helene Verhelst; Mauricio R Delgado; Radka Kremlikova Pourova; Abdelrahim A Sadek; Nour M Elkhateeb; Lubov Blumkin; Alejandro J Brea-Fernández; David Dacruz-Álvarez; Thomas Smol; Jamal Ghoumid; Diego Miguel; Constanze Heine; Jan-Ulrich Schlump; Hendrik Langen; Jonathan Baets; Saskia Bulk; Hossein Darvish; Somayeh Bakhtiari; Michael C Kruer; Elizabeth Lim-Melia; Nur Aydinli; Yasemin Alanay; Omnia El-Rashidy; Sheela Nampoothiri; Chirag Patel; Christian Beetz; Peter Bauer; Grace Yoon; Mireille Guillot; Steven P Miller; Thomas Bourinaris; Henry Houlden; Laura Robelin; Mathieu Anheim; Abdullah S Alamri; Adel A H Mahmoud; Soroor Inaloo; Parham Habibzadeh; Mohammad Ali Faghihi; Anna C Jansen; Stefanie Brock; Agathe Roubertie; Basil T Darras; Pankaj B Agrawal; Filippo M Santorelli; Joseph Gleeson; Maha S Zaki; Sarah I Sheikh; James T Bennett; Mustafa Sahin Journal: Brain Date: 2020-10-01 Impact factor: 15.255
Authors: Susana Carmona; Clara Marecos; Marta Amorim; Ana C Ferreira; Carla Conceição; José Brás; Sofia T Duarte; Rita Guerreiro Journal: Neurol Genet Date: 2018-09-19
Authors: Angelica D'Amore; Alessandra Tessa; Valentina Naef; Maria Teresa Bassi; Andrea Citterio; Romina Romaniello; Gianluca Fichi; Daniele Galatolo; Serena Mero; Roberta Battini; Giulia Bertocci; Jacopo Baldacci; Federico Sicca; Federica Gemignani; Ivana Ricca; Anna Rubegni; Jennifer Hirst; Maria Marchese; Mustafa Sahin; Darius Ebrahimi-Fakhari; Filippo M Santorelli Journal: Ann Clin Transl Neurol Date: 2020-03-25 Impact factor: 4.511