TY - JOUR
T1 - Clinical and genetic characterization of AP4B1-associated SPG47
AU - on behalf of CureSPG47
AU - Ebrahimi-Fakhari, Darius
AU - Cheng, Chi
AU - Dies, Kira
AU - Diplock, Amelia
AU - Pier, Danielle B.
AU - Ryan, Conor S.
AU - Lanpher, Brendan C.
AU - Hirst, Jennifer
AU - Chung, Wendy K.
AU - Sahin, Mustafa
AU - Rosser, Elisabeth
AU - Darras, Basil
AU - Bennett, James T.
N1 - Funding Information:
Burroughs Wellcome Fund; Simons Foundation; Fred Lovejoy Research and Education Fund; Health Innovation Challenge Fund, Grant number: HICF-1009-003; Wellcome Trust Sanger Institute, Grant number: WT098051; Cambridge South REC, Grant number: 10/H0305/83; Republic of Ireland REC, Grant number: GEN/284/12
Funding Information:
The authors thank the patients and families who participated in this study. The authors are grateful to the CureSPG47 organization (www. CureSPG47.org) for endorsing and supporting this study. The authors thank Lea Florentino (Boston Children's Hospital) and Ana West-enberger (University of Lübeck) for assistance. D.E.-F. received support from the Fred Lovejoy Research and Education Fund. W.K.C. received support from the Simons Foundation. J.T.B received support from the Burroughs Wellcome Fund Career Award for Medical Scientists and the Arnold Lee Smith Endowed Professorship for Research Faculty Development. Patient 7 and 8 were identified through the Deciphering Developmental Disorders (DDD) study. The following is acknowledged: This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk Funding for the project was provided by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/ 83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.
Publisher Copyright:
© 2017 Wiley Periodicals, Inc.
PY - 2018/2
Y1 - 2018/2
N2 - The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP-AP4B1), is due to bi-allelic loss-of-function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP-4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1-associated SPG47, the majority born to non-consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP-4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non-consanguineous populations, we believe that AP-4 deficiency may be more common than previously appreciated.
AB - The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP-AP4B1), is due to bi-allelic loss-of-function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP-4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1-associated SPG47, the majority born to non-consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP-4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non-consanguineous populations, we believe that AP-4 deficiency may be more common than previously appreciated.
KW - AP4B1
KW - SPG47
KW - cerebral palsy
KW - hereditary spastic paraplegia
KW - intellectual disability
KW - microcephaly
KW - seizures
KW - thin corpus callosum
UR - http://www.scopus.com/inward/record.url?scp=85036514237&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85036514237&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.38561
DO - 10.1002/ajmg.a.38561
M3 - Article
C2 - 29193663
AN - SCOPUS:85036514237
VL - 176
SP - 311
EP - 318
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 2
ER -