Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

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Ebrahimi-Fakhari, DariusHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. (author)

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Article/chapterEnglish2020

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2020-09-26
OXFORD ENGLAND :Oxford University Press (OUP),2020
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LIBRIS-ID:oai:DiVA.org:uu-435414
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-435414URI
https://doi.org/10.1093/brain/awz307DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

Notes

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Neurologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Neurology hsv//eng
SPG47
SPG50
SPG51
SPG52
neurodegeneration

Added entries (persons, corporate bodies, meetings, titles ...)

Teinert, JulianHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany. (author)
Behne, RobertHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Univ Hosp Wurzburg, Dept Neurol, Wurzburg, Germany. (author)
Wimmer, MiriamHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. (author)
D'Amore, AngelicaHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy. (author)
Eberhardt, KathrinHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. (author)
Brechmann, BarbaraHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. (author)
Ziegler, MarvinHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. (author)
Jensen, Dana M.Univ Washington, Dept Pediat, Div Genet Med, Seattle, WA 98195 USA. (author)
Nagabhyrava, PremsaiHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA. (author)
Geisel, GregoryHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA. (author)
Carmody, ErinHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA. (author)
Shamshad, UzmaHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA. (author)
Dies, Kira A.Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA. (author)
Yuskaitis, Christopher J.Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. (author)
Salussolia, Catherine L.Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. (author)
Ebrahimi-Fakhari, DanielSaarland Univ, Med Ctr, Pediat Neurol, Homburg, Germany.;Univ Childrens Hosp Muenster, Dept Gen Pediat, Munster, Germany. (author)
Pearson, Toni S.Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. (author)
Saffari, AfshinUniv Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany. (author)
Ziegler, AndreasUniv Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany. (author)
Koelker, StefanUniv Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany. (author)
Volkmann, JensUniv Hosp Wurzburg, Dept Neurol, Wurzburg, Germany. (author)
Wiesener, AntjeFriedrich Alexander Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. (author)
Bearden, David R.Univ Rochester, Sch Med, Child Neurol, Rochester, NY USA. (author)
Lakhani, ShenelaWeill Cornell Med Coll, Ctr Neurogenet, New York, NY USA. (author)
Segal, DevorahWeill Cornell Med Coll, Ctr Neurogenet, New York, NY USA.;Weill Cornell Med, Div Child Neurol, New York, NY USA. (author)
Udwadia-Hegde, AnaitaJaslok Hosp & Res Ctr, Dept Pediat Neurol, Mumbai, Maharashtra, India. (author)
Martinuzzi, AndreaIRCCS E Medea, Unita Operat Conegliano, Sci Inst, Treviso, Italy. (author)
Hirst, JenniferUniv Cambridge, Cambridge Inst Med Res, Cambridge, England. (author)
Perlman, SethUniv Iowa, Dept Pediat, Carver Coll Med, Div Neurol, Iowa City, IA 52242 USA. (author)
Takiyama, YoshihisaUniv Yamanashi, Dept Neurol, Kofu, Yamanashi, Japan. (author)
Xiromerisiou, GeorgiaPapageorgiou Hosp, Dept Neurol, Thessaloniki, Greece. (author)
Vill, KatharinaLudwig Maximilians Univ Munchen, Dr von Hauner Childrens Hosp, Pediat Neurol & Dev Med, Munich, Germany. (author)
Walker, William O.Univ Washington, Sch Med, Dept Pediat, Seattle Childrens Hosp, Seattle, WA 98195 USA. (author)
Shukla, AnjuManipal Acad Higher Educ, Kasturba Med Coll, Dept Med Genet, Manipal, Karnataka, India. (author)
Gupta, Rachana DubeyMedanta Hosp, Pediat Neurol, Indore, Madhya Pradesh, India. (author)
Dahl, NiklasUppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik,Barnkirurgisk forskning(Swepub:uu)nikldahl (author)
Aksoy, AyseDr Sami Ulus Hosp, Pediat Neurol, Ankara, Turkey. (author)
Verhelst, HeleneGhent Univ Hosp, Pediat Neurol, Ghent, Belgium. (author)
Delgado, Mauricio R.Univ Texas Southwestern Med Ctr Dallas, Dept Neurol, Dallas, TX USA. (author)
Pourova, Radka KremlikovaCharles Univ Prague, Med Fac 2, Dept Biol & Med Genet, Prague, Czech Republic.;UH Motol, Prague, Czech Republic. (author)
Sadek, Abdelrahim A.Sohag Univ, Fac Med, Pediat Neurol, Sohag, Egypt. (author)
Elkhateeb, Nour M.Cairo Univ, Pediat Neurol, Cairo, Egypt. (author)
Blumkin, LubovTel Aviv Univ, Wolfson Med Ctr, Sackler Sch Med, Pediat Neurol Unit,Movement Disorders Clin, Tel Aviv, Israel. (author)
Brea-Fernandez, Alejandro J.CIBERER, Grp Med Xenom, Santiago De Compostela, Spain. (author)
Dacruz-Alvarez, DavidComplexo Hosp Univ, Neurol Pediat, Santiago De Compostela, Spain. (author)
Smol, ThomasCHU Lille, RADEME, Inst Genet Med, Lille, France. (author)
Ghoumid, JamalCHU Lille, RADEME, Inst Genet Med, Lille, France. (author)
Miguel, DiegoUniv Fed Bahia, Serv Genet Med, Salvador, BA, Brazil. (author)
Heine, ConstanzeUniv Hosp Leipzig, Inst Human Genet, Leipzig, Germany. (author)
Schlump, Jan-UlrichEvangel Krankenhaus, Pediat, Oberhausen, Germany. (author)
Langen, HendrikSozialpadiatr Zentrum Hannover, Hannover, Germany. (author)
Baets, JonathanUniv Antwerp, Neurogenet Grp, Antwerp, Belgium.;Univ Antwerp, Neuromuscular Reference Ctr, Antwerp, Belgium.;Antwerp Univ Hosp, Antwerp, Belgium. (author)
Bulk, SaskiaCtr Hosp Univ Liege, Med Genet, Liege, Belgium. (author)
Darvish, HosseinSemnan Univ Med Sci, Canc Res Ctr, Semnan, Iran.;Semnan Univ Med Sci, Dept Med Genet, Semnan, Iran. (author)
Bakhtiari, SomayehPhoenix Childrens Hosp, Barrow Neurol Inst, Phoenix, AZ USA. (author)
Kruer, Michael C.Phoenix Childrens Hosp, Barrow Neurol Inst, Phoenix, AZ USA. (author)
Lim-Melia, ElizabethMaria Fareri Childrens Hosp, Pediat Med Genet, Valhalla, NY USA. (author)
Aydinli, NurAcibadem Mehmet Ali Aydinlar Univ, Dept Pediat, Pediat Genet, Istanbul, Turkey. (author)
Alanay, YaseminIstanbul Med Fac, Pediat Neurol, Istanbul, Turkey. (author)
El-Rashidy, OmniaAin Shams Univ, Pediat, Cairo, Egypt. (author)
Nampoothiri, SheelaAmrita Inst Med Sci & Res Ctr, Cochin, Kerala, India. (author)
Patel, ChiragRoyal Brisbane & Womens Hosp, Genet Hlth Queensland, Brisbane, Qld, Australia. (author)
Beetz, ChristianCentogene AG, Rostock, Germany. (author)
Bauer, PeterCentogene AG, Rostock, Germany. (author)
Yoon, GraceUniv Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON, Canada. (author)
Guillot, MireilleHosp Sick Children, Dept Paediat, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada. (author)
Miller, Steven P.Hosp Sick Children, Dept Paediat, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada. (author)
Bourinaris, ThomasUCL Inst Neurol, Dept Mol Neurosci, London, England. (author)
Houlden, HenryUCL Inst Neurol, Dept Mol Neurosci, London, England. (author)
Robelin, LauraHop Univ Strasbourg, Serv Neurol, Strasbourg, France. (author)
Anheim, MathieuHop Univ Strasbourg, Serv Neurol, Strasbourg, France. (author)
Alamri, Abdullah S.Natl Neurosci Inst, King Fahad Med City, Pediat Neurol, Riyadh, Saudi Arabia. (author)
Mahmoud, Adel A. H.Imam Abdulrahman Bin Faisal Univ, Pediat, Dammam, Saudi Arabia. (author)
Inaloo, SoroorShiraz Univ Med Sci, Neonatal Res Ctr, Shiraz, Iran. (author)
Habibzadeh, ParhamShiraz Univ Med Sci, Persian BayanGene Res & Training Ctr, Shiraz, Iran. (author)
Faghihi, Mohammad AliShiraz Univ Med Sci, Persian BayanGene Res & Training Ctr, Shiraz, Iran.;Univ Miami, Ctr Therapeut Innovat, Miami, FL USA.;Univ Miami, Dept Psychiat & Behav Sci, Miami, FL USA. (author)
Jansen, Anna C.UZ Brussel, Pediat Neurol Unit, Dept Pediat, Brussels, Belgium. (author)
Brock, StefanieUZ Brussel, Pediat Neurol Unit, Dept Pediat, Brussels, Belgium. (author)
Roubertie, AgatheCHU Montpellier, Pediat Neurol, Montpellier, France. (author)
Darras, Basil T.Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. (author)
Agrawal, Pankaj B.Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Newborn Med, Boston, MA 02115 USA.;Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA 02115 USA. (author)
Santorelli, Filippo M.IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy. (author)
Gleeson, JosephRady Childrens Hosp, Rady Childrens Inst Genom Med, San Diego, CA USA. (author)
Zaki, Maha S.Natl Res Ctr, Clin Genet Human Genet & Genome Res Div, Cairo, Egypt. (author)
Sheikh, Sarah, ICelgene, Translat Neurosci, Cambridge, MA USA. (author)
Bennett, James T.Univ Washington, Dept Pediat, Div Genet Med, Seattle, WA 98195 USA. (author)
Sahin, MustafaHarvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA. (author)
Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany. (creator_code:org_t)

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By the author/editor: Ebrahimi-Fakhari ...; Teinert, Julian; Behne, Robert; Wimmer, Miriam; D'Amore, Angelic ...; Eberhardt, Kathr ...; show more...; Brechmann, Barba ...; Ziegler, Marvin; Jensen, Dana M.; Nagabhyrava, Pre ...; Geisel, Gregory; Carmody, Erin; Shamshad, Uzma; Dies, Kira A.; Yuskaitis, Chris ...; Salussolia, Cath ...; Ebrahimi-Fakhari ...; Pearson, Toni S.; Saffari, Afshin; Ziegler, Andreas; Koelker, Stefan; Volkmann, Jens; Wiesener, Antje; Bearden, David R ...; Lakhani, Shenela; Segal, Devorah; Udwadia-Hegde, A ...; Martinuzzi, Andr ...; Hirst, Jennifer; Perlman, Seth; Takiyama, Yoshih ...; Xiromerisiou, Ge ...; Vill, Katharina; Walker, William ...; Shukla, Anju; Gupta, Rachana D ...; Dahl, Niklas; Aksoy, Ayse; Verhelst, Helene; Delgado, Maurici ...; Pourova, Radka K ...; Sadek, Abdelrahi ...; Elkhateeb, Nour ...; Blumkin, Lubov; Brea-Fernandez, ...; Dacruz-Alvarez, ...; Smol, Thomas; Ghoumid, Jamal; Miguel, Diego; Heine, Constanze; Schlump, Jan-Ulr ...; Langen, Hendrik; Baets, Jonathan; Bulk, Saskia; Darvish, Hossein; Bakhtiari, Somay ...; Kruer, Michael C ...; Lim-Melia, Eliza ...; Aydinli, Nur; Alanay, Yasemin; El-Rashidy, Omni ...; Nampoothiri, She ...; Patel, Chirag; Beetz, Christian; Bauer, Peter; Yoon, Grace; Guillot, Mireill ...; Miller, Steven P ...; Bourinaris, Thom ...; Houlden, Henry; Robelin, Laura; Anheim, Mathieu; Alamri, Abdullah ...; Mahmoud, Adel A. ...; Inaloo, Soroor; Habibzadeh, Parh ...; Faghihi, Mohamma ...; Jansen, Anna C.; Brock, Stefanie; Roubertie, Agath ...; Darras, Basil T.; Agrawal, Pankaj ...; Santorelli, Fili ...; Gleeson, Joseph; Zaki, Maha S.; Sheikh, Sarah, I; Bennett, James T ...; Sahin, Mustafa; show less...

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