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> (2020) >
Defining the clinic...
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
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- Ebrahimi-Fakhari, Darius (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.
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- Teinert, Julian (author)
- 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.
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- Behne, Robert (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Univ Hosp Wurzburg, Dept Neurol, Wurzburg, Germany.
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show more...
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- Wimmer, Miriam (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.
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- D'Amore, Angelica (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy.
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- Eberhardt, Kathrin (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.
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- Brechmann, Barbara (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.
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- Ziegler, Marvin (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.
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- Jensen, Dana M. (author)
- Univ Washington, Dept Pediat, Div Genet Med, Seattle, WA 98195 USA.
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- Nagabhyrava, Premsai (author)
- 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.
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- Geisel, Gregory (author)
- 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.
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- Carmody, Erin (author)
- 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.
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- Shamshad, Uzma (author)
- 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.
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- Dies, Kira A. (author)
- 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.
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- Yuskaitis, Christopher J. (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.
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- Salussolia, Catherine L. (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.
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- Ebrahimi-Fakhari, Daniel (author)
- Saarland Univ, Med Ctr, Pediat Neurol, Homburg, Germany.;Univ Childrens Hosp Muenster, Dept Gen Pediat, Munster, Germany.
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- Pearson, Toni S. (author)
- Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA.
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- Saffari, Afshin (author)
- Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany.
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- Ziegler, Andreas (author)
- Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany.
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- Koelker, Stefan (author)
- Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany.
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- Volkmann, Jens (author)
- Univ Hosp Wurzburg, Dept Neurol, Wurzburg, Germany.
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- Wiesener, Antje (author)
- Friedrich Alexander Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany.
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- Bearden, David R. (author)
- Univ Rochester, Sch Med, Child Neurol, Rochester, NY USA.
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- Lakhani, Shenela (author)
- Weill Cornell Med Coll, Ctr Neurogenet, New York, NY USA.
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- Segal, Devorah (author)
- Weill Cornell Med Coll, Ctr Neurogenet, New York, NY USA.;Weill Cornell Med, Div Child Neurol, New York, NY USA.
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- Udwadia-Hegde, Anaita (author)
- Jaslok Hosp & Res Ctr, Dept Pediat Neurol, Mumbai, Maharashtra, India.
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- Martinuzzi, Andrea (author)
- IRCCS E Medea, Unita Operat Conegliano, Sci Inst, Treviso, Italy.
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- Hirst, Jennifer (author)
- Univ Cambridge, Cambridge Inst Med Res, Cambridge, England.
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- Perlman, Seth (author)
- Univ Iowa, Dept Pediat, Carver Coll Med, Div Neurol, Iowa City, IA 52242 USA.
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- Takiyama, Yoshihisa (author)
- Univ Yamanashi, Dept Neurol, Kofu, Yamanashi, Japan.
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- Xiromerisiou, Georgia (author)
- Papageorgiou Hosp, Dept Neurol, Thessaloniki, Greece.
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- Vill, Katharina (author)
- Ludwig Maximilians Univ Munchen, Dr von Hauner Childrens Hosp, Pediat Neurol & Dev Med, Munich, Germany.
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- Walker, William O. (author)
- Univ Washington, Sch Med, Dept Pediat, Seattle Childrens Hosp, Seattle, WA 98195 USA.
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- Shukla, Anju (author)
- Manipal Acad Higher Educ, Kasturba Med Coll, Dept Med Genet, Manipal, Karnataka, India.
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- Gupta, Rachana Dubey (author)
- Medanta Hosp, Pediat Neurol, Indore, Madhya Pradesh, India.
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- Dahl, Niklas (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik,Barnkirurgisk forskning
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- Aksoy, Ayse (author)
- Dr Sami Ulus Hosp, Pediat Neurol, Ankara, Turkey.
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- Verhelst, Helene (author)
- Ghent Univ Hosp, Pediat Neurol, Ghent, Belgium.
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- Delgado, Mauricio R. (author)
- Univ Texas Southwestern Med Ctr Dallas, Dept Neurol, Dallas, TX USA.
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- Pourova, Radka Kremlikova (author)
- Charles Univ Prague, Med Fac 2, Dept Biol & Med Genet, Prague, Czech Republic.;UH Motol, Prague, Czech Republic.
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- Sadek, Abdelrahim A. (author)
- Sohag Univ, Fac Med, Pediat Neurol, Sohag, Egypt.
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- Elkhateeb, Nour M. (author)
- Cairo Univ, Pediat Neurol, Cairo, Egypt.
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- Blumkin, Lubov (author)
- Tel Aviv Univ, Wolfson Med Ctr, Sackler Sch Med, Pediat Neurol Unit,Movement Disorders Clin, Tel Aviv, Israel.
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- Brea-Fernandez, Alejandro J. (author)
- CIBERER, Grp Med Xenom, Santiago De Compostela, Spain.
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- Dacruz-Alvarez, David (author)
- Complexo Hosp Univ, Neurol Pediat, Santiago De Compostela, Spain.
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- Smol, Thomas (author)
- CHU Lille, RADEME, Inst Genet Med, Lille, France.
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- Ghoumid, Jamal (author)
- CHU Lille, RADEME, Inst Genet Med, Lille, France.
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- Miguel, Diego (author)
- Univ Fed Bahia, Serv Genet Med, Salvador, BA, Brazil.
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- Heine, Constanze (author)
- Univ Hosp Leipzig, Inst Human Genet, Leipzig, Germany.
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- Schlump, Jan-Ulrich (author)
- Evangel Krankenhaus, Pediat, Oberhausen, Germany.
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- Langen, Hendrik (author)
- Sozialpadiatr Zentrum Hannover, Hannover, Germany.
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- Baets, Jonathan (author)
- Univ Antwerp, Neurogenet Grp, Antwerp, Belgium.;Univ Antwerp, Neuromuscular Reference Ctr, Antwerp, Belgium.;Antwerp Univ Hosp, Antwerp, Belgium.
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- Bulk, Saskia (author)
- Ctr Hosp Univ Liege, Med Genet, Liege, Belgium.
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- Darvish, Hossein (author)
- Semnan Univ Med Sci, Canc Res Ctr, Semnan, Iran.;Semnan Univ Med Sci, Dept Med Genet, Semnan, Iran.
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- Bakhtiari, Somayeh (author)
- Phoenix Childrens Hosp, Barrow Neurol Inst, Phoenix, AZ USA.
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- Kruer, Michael C. (author)
- Phoenix Childrens Hosp, Barrow Neurol Inst, Phoenix, AZ USA.
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- Lim-Melia, Elizabeth (author)
- Maria Fareri Childrens Hosp, Pediat Med Genet, Valhalla, NY USA.
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- Aydinli, Nur (author)
- Acibadem Mehmet Ali Aydinlar Univ, Dept Pediat, Pediat Genet, Istanbul, Turkey.
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- Alanay, Yasemin (author)
- Istanbul Med Fac, Pediat Neurol, Istanbul, Turkey.
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- El-Rashidy, Omnia (author)
- Ain Shams Univ, Pediat, Cairo, Egypt.
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- Nampoothiri, Sheela (author)
- Amrita Inst Med Sci & Res Ctr, Cochin, Kerala, India.
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- Patel, Chirag (author)
- Royal Brisbane & Womens Hosp, Genet Hlth Queensland, Brisbane, Qld, Australia.
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- Beetz, Christian (author)
- Centogene AG, Rostock, Germany.
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- Bauer, Peter (author)
- Centogene AG, Rostock, Germany.
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- Yoon, Grace (author)
- Univ Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON, Canada.
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- Guillot, Mireille (author)
- Hosp Sick Children, Dept Paediat, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada.
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- Miller, Steven P. (author)
- Hosp Sick Children, Dept Paediat, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada.
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- Bourinaris, Thomas (author)
- UCL Inst Neurol, Dept Mol Neurosci, London, England.
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- Houlden, Henry (author)
- UCL Inst Neurol, Dept Mol Neurosci, London, England.
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- Robelin, Laura (author)
- Hop Univ Strasbourg, Serv Neurol, Strasbourg, France.
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- Anheim, Mathieu (author)
- Hop Univ Strasbourg, Serv Neurol, Strasbourg, France.
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- Alamri, Abdullah S. (author)
- Natl Neurosci Inst, King Fahad Med City, Pediat Neurol, Riyadh, Saudi Arabia.
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- Mahmoud, Adel A. H. (author)
- Imam Abdulrahman Bin Faisal Univ, Pediat, Dammam, Saudi Arabia.
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- Inaloo, Soroor (author)
- Shiraz Univ Med Sci, Neonatal Res Ctr, Shiraz, Iran.
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- Habibzadeh, Parham (author)
- Shiraz Univ Med Sci, Persian BayanGene Res & Training Ctr, Shiraz, Iran.
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- Faghihi, Mohammad Ali (author)
- Shiraz 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.
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- Jansen, Anna C. (author)
- UZ Brussel, Pediat Neurol Unit, Dept Pediat, Brussels, Belgium.
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- Brock, Stefanie (author)
- UZ Brussel, Pediat Neurol Unit, Dept Pediat, Brussels, Belgium.
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- Roubertie, Agathe (author)
- CHU Montpellier, Pediat Neurol, Montpellier, France.
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- Darras, Basil T. (author)
- Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.
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- Agrawal, Pankaj B. (author)
- 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.
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- Santorelli, Filippo M. (author)
- IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy.
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- Gleeson, Joseph (author)
- Rady Childrens Hosp, Rady Childrens Inst Genom Med, San Diego, CA USA.
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- Zaki, Maha S. (author)
- Natl Res Ctr, Clin Genet Human Genet & Genome Res Div, Cairo, Egypt.
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- Sheikh, Sarah, I (author)
- Celgene, Translat Neurosci, Cambridge, MA USA.
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- Bennett, James T. (author)
- Univ Washington, Dept Pediat, Div Genet Med, Seattle, WA 98195 USA.
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- Sahin, Mustafa (author)
- 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.
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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)
- 2020-09-26
- 2020
- English.
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In: Brain. - OXFORD ENGLAND : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:10, s. 2929-2944
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Abstract
Subject headings
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- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Keyword
- SPG47
- SPG50
- SPG51
- SPG52
- neurodegeneration
Publication and Content Type
- ref (subject category)
- art (subject category)
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Ebrahimi-Fakhari ...
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Teinert, Julian
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Behne, Robert
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Wimmer, Miriam
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D'Amore, Angelic ...
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Eberhardt, Kathr ...
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Brechmann, Barba ...
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Ziegler, Marvin
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Geisel, Gregory
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Carmody, Erin
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Shamshad, Uzma
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Dies, Kira A.
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Yuskaitis, Chris ...
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Salussolia, Cath ...
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Ebrahimi-Fakhari ...
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Pearson, Toni S.
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Saffari, Afshin
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Ziegler, Andreas
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Koelker, Stefan
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Volkmann, Jens
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Wiesener, Antje
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Bearden, David R ...
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Lakhani, Shenela
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Segal, Devorah
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Udwadia-Hegde, A ...
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Martinuzzi, Andr ...
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Hirst, Jennifer
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Perlman, Seth
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Takiyama, Yoshih ...
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Xiromerisiou, Ge ...
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Vill, Katharina
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Walker, William ...
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Shukla, Anju
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Gupta, Rachana D ...
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Dahl, Niklas
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Aksoy, Ayse
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Verhelst, Helene
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Delgado, Maurici ...
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Pourova, Radka K ...
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Sadek, Abdelrahi ...
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Elkhateeb, Nour ...
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Blumkin, Lubov
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Brea-Fernandez, ...
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Dacruz-Alvarez, ...
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Smol, Thomas
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Ghoumid, Jamal
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Miguel, Diego
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Heine, Constanze
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Schlump, Jan-Ulr ...
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Langen, Hendrik
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Baets, Jonathan
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Bulk, Saskia
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Darvish, Hossein
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Bakhtiari, Somay ...
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Kruer, Michael C ...
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Lim-Melia, Eliza ...
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Aydinli, Nur
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Alanay, Yasemin
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El-Rashidy, Omni ...
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Nampoothiri, She ...
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Patel, Chirag
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Beetz, Christian
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Bauer, Peter
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Yoon, Grace
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Guillot, Mireill ...
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Miller, Steven P ...
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Bourinaris, Thom ...
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Houlden, Henry
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Robelin, Laura
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Anheim, Mathieu
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Alamri, Abdullah ...
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Mahmoud, Adel A. ...
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Inaloo, Soroor
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Habibzadeh, Parh ...
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Faghihi, Mohamma ...
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Jansen, Anna C.
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Brock, Stefanie
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Roubertie, Agath ...
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Darras, Basil T.
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Agrawal, Pankaj ...
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Santorelli, Fili ...
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Gleeson, Joseph
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Zaki, Maha S.
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Sheikh, Sarah, I
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Bennett, James T ...
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Sahin, Mustafa
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Uppsala University