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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. / Ebrahimi-Fakhari, Darius; Teinert, Julian; Behne, Robert; Wimmer, Miriam; D'Amore, Angelica; Eberhardt, Kathrin; Brechmann, Barbara; Ziegler, Marvin; Jensen, Dana M; Nagabhyrava, Premsai; Geisel, Gregory; Carmody, Erin; Shamshad, Uzma; Dies, Kira A; Yuskaitis, Christopher J; Salussolia, Catherine L; Ebrahimi-Fakhari, Daniel; Pearson, Toni S; Saffari, Afshin; Ziegler, Andreas; Kölker, Stefan; Volkmann, Jens; Wiesener, Antje; Bearden, David R; Lakhani, Shenela; Segal, Devorah; Udwadia-Hegde, Anaita; Martinuzzi, Andrea; Hirst, Jennifer; Perlman, Seth; Takiyama, Yoshihisa; Xiromerisiou, Georgia; Vill, Katharina; Walker, William O; Shukla, Anju; Dubey Gupta, Rachana; Dahl, Niklas; Aksoy, Ayse; Verhelst, Helene; Delgado, Mauricio R; Kremlikova Pourova, Radka; Sadek, Abdelrahim A; Elkhateeb, Nour M; Blumkin, Lubov; Brea-Fernández, Alejandro J; Dacruz-Álvarez, David; Smol, Thomas; Ghoumid, Jamal; Miguel, Diego; Heine, Constanze; Schlump, Jan-Ulrich; Langen, Hendrik; Baets, Jonathan; Bulk, Saskia; Darvish, Hossein; Bakhtiari, Somayeh; Kruer, Michael C; Lim-Melia, Elizabeth; Aydinli, Nur; Alanay, Yasemin; El-Rashidy, Omnia; Nampoothiri, Sheela; Patel, Chirag; Beetz, Christian; Bauer, Peter; Yoon, Grace; Guillot, Mireille; Miller, Steven P; Bourinaris, Thomas; Houlden, Henry; Robelin, Laura; Anheim, Mathieu; Alamri, Abdullah S; Mahmoud, Adel A H; Inaloo, Soroor; Habibzadeh, Parham; Faghihi, Mohammad Ali; Jansen, Anna C; Brock, Stefanie; Roubertie, Agathe; Darras, Basil T; Agrawal, Pankaj B; Santorelli, Filippo M; Gleeson, Joseph; Zaki, Maha S; Sheikh, Sarah I; Bennett, James T; Sahin, Mustafa.

In: Brain, Vol. 143, No. 10, 2020, p. 2929-2944.

Research output: Contribution to journalArticle

Harvard

Ebrahimi-Fakhari, D, Teinert, J, Behne, R, Wimmer, M, D'Amore, A, Eberhardt, K, Brechmann, B, Ziegler, M, Jensen, DM, Nagabhyrava, P, Geisel, G, Carmody, E, Shamshad, U, Dies, KA, Yuskaitis, CJ, Salussolia, CL, Ebrahimi-Fakhari, D, Pearson, TS, Saffari, A, Ziegler, A, Kölker, S, Volkmann, J, Wiesener, A, Bearden, DR, Lakhani, S, Segal, D, Udwadia-Hegde, A, Martinuzzi, A, Hirst, J, Perlman, S, Takiyama, Y, Xiromerisiou, G, Vill, K, Walker, WO, Shukla, A, Dubey Gupta, R, Dahl, N, Aksoy, A, Verhelst, H, Delgado, MR, Kremlikova Pourova, R, Sadek, AA, Elkhateeb, NM, Blumkin, L, Brea-Fernández, AJ, Dacruz-Álvarez, D, Smol, T, Ghoumid, J, Miguel, D, Heine, C, Schlump, J-U, Langen, H, Baets, J, Bulk, S, Darvish, H, Bakhtiari, S, Kruer, MC, Lim-Melia, E, Aydinli, N, Alanay, Y, El-Rashidy, O, Nampoothiri, S, Patel, C, Beetz, C, Bauer, P, Yoon, G, Guillot, M, Miller, SP, Bourinaris, T, Houlden, H, Robelin, L, Anheim, M, Alamri, AS, Mahmoud, AAH, Inaloo, S, Habibzadeh, P, Faghihi, MA, Jansen, AC, Brock, S, Roubertie, A, Darras, BT, Agrawal, PB, Santorelli, FM, Gleeson, J, Zaki, MS, Sheikh, SI, Bennett, JT & Sahin, M 2020, 'Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia', Brain, vol. 143, no. 10, pp. 2929-2944. https://doi.org/10.1093/brain/awz307

APA

Ebrahimi-Fakhari, D., Teinert, J., Behne, R., Wimmer, M., D'Amore, A., Eberhardt, K., ... Sahin, M. (2020). Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain, 143(10), 2929-2944. https://doi.org/10.1093/brain/awz307

Vancouver

Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K et al. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain. 2020;143(10):2929-2944. https://doi.org/10.1093/brain/awz307

Author

Ebrahimi-Fakhari, Darius ; Teinert, Julian ; Behne, Robert ; Wimmer, Miriam ; D'Amore, Angelica ; Eberhardt, Kathrin ; Brechmann, Barbara ; Ziegler, Marvin ; Jensen, Dana M ; Nagabhyrava, Premsai ; Geisel, Gregory ; Carmody, Erin ; Shamshad, Uzma ; Dies, Kira A ; Yuskaitis, Christopher J ; Salussolia, Catherine L ; Ebrahimi-Fakhari, Daniel ; Pearson, Toni S ; Saffari, Afshin ; Ziegler, Andreas ; Kölker, Stefan ; Volkmann, Jens ; Wiesener, Antje ; Bearden, David R ; Lakhani, Shenela ; Segal, Devorah ; Udwadia-Hegde, Anaita ; Martinuzzi, Andrea ; Hirst, Jennifer ; Perlman, Seth ; Takiyama, Yoshihisa ; Xiromerisiou, Georgia ; Vill, Katharina ; Walker, William O ; Shukla, Anju ; Dubey Gupta, Rachana ; Dahl, Niklas ; Aksoy, Ayse ; Verhelst, Helene ; Delgado, Mauricio R ; Kremlikova Pourova, Radka ; Sadek, Abdelrahim A ; Elkhateeb, Nour M ; Blumkin, Lubov ; Brea-Fernández, Alejandro J ; Dacruz-Álvarez, David ; Smol, Thomas ; Ghoumid, Jamal ; Miguel, Diego ; Heine, Constanze ; Schlump, Jan-Ulrich ; Langen, Hendrik ; Baets, Jonathan ; Bulk, Saskia ; Darvish, Hossein ; Bakhtiari, Somayeh ; Kruer, Michael C ; Lim-Melia, Elizabeth ; Aydinli, Nur ; Alanay, Yasemin ; El-Rashidy, Omnia ; Nampoothiri, Sheela ; Patel, Chirag ; Beetz, Christian ; Bauer, Peter ; Yoon, Grace ; Guillot, Mireille ; Miller, Steven P ; Bourinaris, Thomas ; Houlden, Henry ; Robelin, Laura ; Anheim, Mathieu ; Alamri, Abdullah S ; Mahmoud, Adel A H ; Inaloo, Soroor ; Habibzadeh, Parham ; Faghihi, Mohammad Ali ; Jansen, Anna C ; Brock, Stefanie ; Roubertie, Agathe ; Darras, Basil T ; Agrawal, Pankaj B ; Santorelli, Filippo M ; Gleeson, Joseph ; Zaki, Maha S ; Sheikh, Sarah I ; Bennett, James T ; Sahin, Mustafa. / Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. In: Brain. 2020 ; Vol. 143, No. 10. pp. 2929-2944.

BibTeX

@article{39eeedfe25b04c97948fdcc50475174f,
title = "Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia",
abstract = "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.",
keywords = "SPG47, SPG50, SPG51, SPG52, neurodegeneration",
author = "Darius Ebrahimi-Fakhari and Julian Teinert and Robert Behne and Miriam Wimmer and Angelica D'Amore and Kathrin Eberhardt and Barbara Brechmann and Marvin Ziegler and Jensen, {Dana M} and Premsai Nagabhyrava and Gregory Geisel and Erin Carmody and Uzma Shamshad and Dies, {Kira A} and Yuskaitis, {Christopher J} and Salussolia, {Catherine L} and Daniel Ebrahimi-Fakhari and Pearson, {Toni S} and Afshin Saffari and Andreas Ziegler and Stefan K{\"o}lker and Jens Volkmann and Antje Wiesener and Bearden, {David R} and Shenela Lakhani and Devorah Segal and Anaita Udwadia-Hegde and Andrea Martinuzzi and Jennifer Hirst and Seth Perlman and Yoshihisa Takiyama and Georgia Xiromerisiou and Katharina Vill and Walker, {William O} and Anju Shukla and {Dubey Gupta}, Rachana and Niklas Dahl and Ayse Aksoy and Helene Verhelst and Delgado, {Mauricio R} and {Kremlikova Pourova}, Radka and Sadek, {Abdelrahim A} and Elkhateeb, {Nour M} and Lubov Blumkin and Brea-Fern{\'a}ndez, {Alejandro J} and David Dacruz-{\'A}lvarez and Thomas Smol and Jamal Ghoumid and Diego Miguel and Constanze Heine and Jan-Ulrich Schlump and Hendrik Langen and Jonathan Baets and Saskia Bulk and Hossein Darvish and Somayeh Bakhtiari and Kruer, {Michael C} and Elizabeth Lim-Melia and Nur Aydinli and Yasemin Alanay and Omnia El-Rashidy and Sheela Nampoothiri and Chirag Patel and Christian Beetz and Peter Bauer and Grace Yoon and Mireille Guillot and Miller, {Steven P} and Thomas Bourinaris and Henry Houlden and Laura Robelin and Mathieu Anheim and Alamri, {Abdullah S} and Mahmoud, {Adel A H} and Soroor Inaloo and Parham Habibzadeh and Faghihi, {Mohammad Ali} and Jansen, {Anna C} and Stefanie Brock and Agathe Roubertie and Darras, {Basil T} and Agrawal, {Pankaj B} and Santorelli, {Filippo M} and Joseph Gleeson and Zaki, {Maha S} and Sheikh, {Sarah I} and Bennett, {James T} and Mustafa Sahin",
note = "{\circledC} The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.",
year = "2020",
doi = "10.1093/brain/awz307",
language = "English",
volume = "143",
pages = "2929--2944",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "10",

}

RIS

TY - JOUR

T1 - Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

AU - Ebrahimi-Fakhari, Darius

AU - Teinert, Julian

AU - Behne, Robert

AU - Wimmer, Miriam

AU - D'Amore, Angelica

AU - Eberhardt, Kathrin

AU - Brechmann, Barbara

AU - Ziegler, Marvin

AU - Jensen, Dana M

AU - Nagabhyrava, Premsai

AU - Geisel, Gregory

AU - Carmody, Erin

AU - Shamshad, Uzma

AU - Dies, Kira A

AU - Yuskaitis, Christopher J

AU - Salussolia, Catherine L

AU - Ebrahimi-Fakhari, Daniel

AU - Pearson, Toni S

AU - Saffari, Afshin

AU - Ziegler, Andreas

AU - Kölker, Stefan

AU - Volkmann, Jens

AU - Wiesener, Antje

AU - Bearden, David R

AU - Lakhani, Shenela

AU - Segal, Devorah

AU - Udwadia-Hegde, Anaita

AU - Martinuzzi, Andrea

AU - Hirst, Jennifer

AU - Perlman, Seth

AU - Takiyama, Yoshihisa

AU - Xiromerisiou, Georgia

AU - Vill, Katharina

AU - Walker, William O

AU - Shukla, Anju

AU - Dubey Gupta, Rachana

AU - Dahl, Niklas

AU - Aksoy, Ayse

AU - Verhelst, Helene

AU - Delgado, Mauricio R

AU - Kremlikova Pourova, Radka

AU - Sadek, Abdelrahim A

AU - Elkhateeb, Nour M

AU - Blumkin, Lubov

AU - Brea-Fernández, Alejandro J

AU - Dacruz-Álvarez, David

AU - Smol, Thomas

AU - Ghoumid, Jamal

AU - Miguel, Diego

AU - Heine, Constanze

AU - Schlump, Jan-Ulrich

AU - Langen, Hendrik

AU - Baets, Jonathan

AU - Bulk, Saskia

AU - Darvish, Hossein

AU - Bakhtiari, Somayeh

AU - Kruer, Michael C

AU - Lim-Melia, Elizabeth

AU - Aydinli, Nur

AU - Alanay, Yasemin

AU - El-Rashidy, Omnia

AU - Nampoothiri, Sheela

AU - Patel, Chirag

AU - Beetz, Christian

AU - Bauer, Peter

AU - Yoon, Grace

AU - Guillot, Mireille

AU - Miller, Steven P

AU - Bourinaris, Thomas

AU - Houlden, Henry

AU - Robelin, Laura

AU - Anheim, Mathieu

AU - Alamri, Abdullah S

AU - Mahmoud, Adel A H

AU - Inaloo, Soroor

AU - Habibzadeh, Parham

AU - Faghihi, Mohammad Ali

AU - Jansen, Anna C

AU - Brock, Stefanie

AU - Roubertie, Agathe

AU - Darras, Basil T

AU - Agrawal, Pankaj B

AU - Santorelli, Filippo M

AU - Gleeson, Joseph

AU - Zaki, Maha S

AU - Sheikh, Sarah I

AU - Bennett, James T

AU - Sahin, Mustafa

N1 - © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - SPG47

KW - SPG50

KW - SPG51

KW - SPG52

KW - neurodegeneration

U2 - 10.1093/brain/awz307

DO - 10.1093/brain/awz307

M3 - Article

C2 - 32979048

VL - 143

SP - 2929

EP - 2944

JO - Brain

JF - Brain

SN - 0006-8950

IS - 10

ER -

ID: 54050614