Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders

Reza Maroofian; Rauan Kaiyrzhanov; Elisa Cali; Mina Zamani; Maha S. Zaki; Matteo Ferla; Domenico Tortora; Saeid Sadeghian; Saadia Maryam Saadi; Uzma Abdullah; Ehsan Ghayoor Karimiani; Stephanie Efthymiou; Gözde Yeşil; Shahryar Alavi; Aisha M. Al Shamsi; Homa Tajsharghi; Mohamed S. Abdel-Hamid; Nebal Waill Saadi; Fuad Al Mutairi; Lama Alabdi; Christian Beetz; Zafar Ali; Mehran Beiraghi Toosi; Sabine Rudnik-Schöneborn; Meisam Babaei; Pirjo Isohanni; Jameel Muhammad; Sheraz Khan; Maha Al Shalan; Scott E. Hickey; Daphna Marom; Emil Elhanan; Manju A. Kurian; Dana Marafi; Alihossein Saberi; Mohammad Hamid; Robert Spaull; Linyan Meng; Seema Lalani; Shazia Maqbool; Fatima Rahman; Jürgen Seeger; Timothy Blake Palculict; Tracy Lau; David Murphy; Niccolo Emanuele Mencacci; Katharina Steindl; Anais Begemann; Anita Rauch; Sinan Akbas; Ayça Dilruba Aslanger; Vincenzo Salpietro; Hammad Yousaf; Shay Ben-Shachar; Katarina Ejeskär; Aida I. Al Aqeel; Frances A. High; Amy E. Armstrong-Javors; Seyed Mohammadsaleh Zahraei; Tahereh Seifi; Jawaher Zeighami; Gholamreza Shariati; Alireza Sedaghat; Samaneh Noroozi Asl; Mohmmad Shahrooei; Giovanni Zifarelli; Lydie Burglen; Claudia Ravelli; Johannes Zschocke; Ulrich A. Schatz; Maryam Ghavideldarestani; Walaa A. Kamel; Hilde Van Esch; Annette Hackenberg; Jenny C. Taylor; Lihadh Al-Gazali; Peter Bauer; Joseph J. Gleeson; Fowzan Sami Alkuraya; James R. Lupski; Hamid Galehdari; Reza Azizimalamiri; Wendy K. Chung; Shahid Mahmood Baig; Henry Houlden; Mariasavina Severino

doi:10.1093/brain/awad257

Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders

Reza Maroofian^*, Rauan Kaiyrzhanov, Elisa Cali, Mina Zamani, Maha S. Zaki, Matteo Ferla, Domenico Tortora, Saeid Sadeghian, Saadia Maryam Saadi, Uzma Abdullah, Ehsan Ghayoor Karimiani, Stephanie Efthymiou, Gözde Yeşil, Shahryar Alavi, Aisha M. Al Shamsi, Homa Tajsharghi, Mohamed S. Abdel-Hamid, Nebal Waill Saadi, Fuad Al Mutairi, Lama AlabdiChristian Beetz, Zafar Ali, Mehran Beiraghi Toosi, Sabine Rudnik-Schöneborn, Meisam Babaei, Pirjo Isohanni, Jameel Muhammad, Sheraz Khan, Maha Al Shalan, Scott E. Hickey, Daphna Marom, Emil Elhanan, Manju A. Kurian, Dana Marafi, Alihossein Saberi, Mohammad Hamid, Robert Spaull, Linyan Meng, Seema Lalani, Shazia Maqbool, Fatima Rahman, Jürgen Seeger, Timothy Blake Palculict, Tracy Lau, David Murphy, Niccolo Emanuele Mencacci, Katharina Steindl, Anais Begemann, Anita Rauch, Sinan Akbas, Ayça Dilruba Aslanger, Vincenzo Salpietro, Hammad Yousaf, Shay Ben-Shachar, Katarina Ejeskär, Aida I. Al Aqeel, Frances A. High, Amy E. Armstrong-Javors, Seyed Mohammadsaleh Zahraei, Tahereh Seifi, Jawaher Zeighami, Gholamreza Shariati, Alireza Sedaghat, Samaneh Noroozi Asl, Mohmmad Shahrooei, Giovanni Zifarelli, Lydie Burglen, Claudia Ravelli, Johannes Zschocke, Ulrich A. Schatz, Maryam Ghavideldarestani, Walaa A. Kamel, Hilde Van Esch, Annette Hackenberg, Jenny C. Taylor, Lihadh Al-Gazali, Peter Bauer, Joseph J. Gleeson, Fowzan Sami Alkuraya, James R. Lupski, Hamid Galehdari, Reza Azizimalamiri, Wendy K. Chung, Shahid Mahmood Baig, Henry Houlden, Mariasavina Severino^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'.

Original language	English (US)
Pages (from-to)	5031-5043
Number of pages	13
Journal	Brain
Volume	146
Issue number	12
DOIs	https://doi.org/10.1093/brain/awad257
State	Published - Dec 1 2023

Funding

Part of this research was possible thanks to the Deciphering Developmental Disorders (DDD) study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). R.K. was supported by the European Academy of Neurology Research Training Fellowship and Rosetrees Trust PhD Plus award (PhD2022\\100042). J.R.L. was supported by the National Institute for Neurological Disorders and Stroke Research Program Award R35 NS105078 and the Baylor College of Medicine-GREGoR Program (NHGRI U01 HG001758). H.T. was supported by the European Union\u2019s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 608473. M.A.K. and R.S. were supported by a National Institute for Health Research professorship, Sir Jules Thorn Charitable Trust Award for Biomedical Research and the Rosetrees Trust. This study was also supported by the Wellcome Trust (WT093205MA and WT104033AIA), the Medical Research Council (H.H.), European Union\u2019s Seventh Framework Programme (FP7/2007-2013, under grant agreement no. 2012-305121), the National Institute for Health Research (NIHR), University College London Hospitals (UCLH) and UCLH Biomedical Research Centre (BRC). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The NIHR Oxford Biomedical Research Centre Programme and a Wellcome Trust Core Award (203141/Z/16/Z). P.I. was supported by Foundation for Pediatric Research.

Keywords

cerebellar atrophy
cerebello-lental degeneration
dystonia
gene transcription
mediator complex
neurodevelopmental disorders

ASJC Scopus subject areas

Clinical Neurology

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10.1093/brain/awad257

Cite this

Maroofian, R., Kaiyrzhanov, R., Cali, E., Zamani, M., Zaki, M. S., Ferla, M., Tortora, D., Sadeghian, S., Saadi, S. M., Abdullah, U., Karimiani, E. G., Efthymiou, S., Yeşil, G., Alavi, S., Al Shamsi, A. M., Tajsharghi, H., Abdel-Hamid, M. S., Saadi, N. W., Al Mutairi, F., ... Severino, M. (2023). Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders. Brain, 146(12), 5031-5043. https://doi.org/10.1093/brain/awad257

@article{24b9e334208347b6912c68a01ceb3c7c,

title = "Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders",

abstract = "MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'.",

keywords = "cerebellar atrophy, cerebello-lental degeneration, dystonia, gene transcription, mediator complex, neurodevelopmental disorders",

author = "Reza Maroofian and Rauan Kaiyrzhanov and Elisa Cali and Mina Zamani and Zaki, {Maha S.} and Matteo Ferla and Domenico Tortora and Saeid Sadeghian and Saadi, {Saadia Maryam} and Uzma Abdullah and Karimiani, {Ehsan Ghayoor} and Stephanie Efthymiou and G{\"o}zde Ye{\c s}il and Shahryar Alavi and {Al Shamsi}, {Aisha M.} and Homa Tajsharghi and Abdel-Hamid, {Mohamed S.} and Saadi, {Nebal Waill} and {Al Mutairi}, Fuad and Lama Alabdi and Christian Beetz and Zafar Ali and Toosi, {Mehran Beiraghi} and Sabine Rudnik-Sch{\"o}neborn and Meisam Babaei and Pirjo Isohanni and Jameel Muhammad and Sheraz Khan and {Al Shalan}, Maha and Hickey, {Scott E.} and Daphna Marom and Emil Elhanan and Kurian, {Manju A.} and Dana Marafi and Alihossein Saberi and Mohammad Hamid and Robert Spaull and Linyan Meng and Seema Lalani and Shazia Maqbool and Fatima Rahman and J{\"u}rgen Seeger and Palculict, {Timothy Blake} and Tracy Lau and David Murphy and Mencacci, {Niccolo Emanuele} and Katharina Steindl and Anais Begemann and Anita Rauch and Sinan Akbas and Aslanger, {Ay{\c c}a Dilruba} and Vincenzo Salpietro and Hammad Yousaf and Shay Ben-Shachar and Katarina Ejesk{\"a}r and {Al Aqeel}, {Aida I.} and High, {Frances A.} and Armstrong-Javors, {Amy E.} and Zahraei, {Seyed Mohammadsaleh} and Tahereh Seifi and Jawaher Zeighami and Gholamreza Shariati and Alireza Sedaghat and Asl, {Samaneh Noroozi} and Mohmmad Shahrooei and Giovanni Zifarelli and Lydie Burglen and Claudia Ravelli and Johannes Zschocke and Schatz, {Ulrich A.} and Maryam Ghavideldarestani and Kamel, {Walaa A.} and {Van Esch}, Hilde and Annette Hackenberg and Taylor, {Jenny C.} and Lihadh Al-Gazali and Peter Bauer and Gleeson, {Joseph J.} and Alkuraya, {Fowzan Sami} and Lupski, {James R.} and Hamid Galehdari and Reza Azizimalamiri and Chung, {Wendy K.} and Baig, {Shahid Mahmood} and Henry Houlden and Mariasavina Severino",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2023",

month = dec,

day = "1",

doi = "10.1093/brain/awad257",

language = "English (US)",

volume = "146",

pages = "5031--5043",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "12",

}

Maroofian, R, Kaiyrzhanov, R, Cali, E, Zamani, M, Zaki, MS, Ferla, M, Tortora, D, Sadeghian, S, Saadi, SM, Abdullah, U, Karimiani, EG, Efthymiou, S, Yeşil, G, Alavi, S, Al Shamsi, AM, Tajsharghi, H, Abdel-Hamid, MS, Saadi, NW, Al Mutairi, F, Alabdi, L, Beetz, C, Ali, Z, Toosi, MB, Rudnik-Schöneborn, S, Babaei, M, Isohanni, P, Muhammad, J, Khan, S, Al Shalan, M, Hickey, SE, Marom, D, Elhanan, E, Kurian, MA, Marafi, D, Saberi, A, Hamid, M, Spaull, R, Meng, L, Lalani, S, Maqbool, S, Rahman, F, Seeger, J, Palculict, TB, Lau, T, Murphy, D, Mencacci, NE, Steindl, K, Begemann, A, Rauch, A, Akbas, S, Aslanger, AD, Salpietro, V, Yousaf, H, Ben-Shachar, S, Ejeskär, K, Al Aqeel, AI, High, FA, Armstrong-Javors, AE, Zahraei, SM, Seifi, T, Zeighami, J, Shariati, G, Sedaghat, A, Asl, SN, Shahrooei, M, Zifarelli, G, Burglen, L, Ravelli, C, Zschocke, J, Schatz, UA, Ghavideldarestani, M, Kamel, WA, Van Esch, H, Hackenberg, A, Taylor, JC, Al-Gazali, L, Bauer, P, Gleeson, JJ, Alkuraya, FS, Lupski, JR, Galehdari, H, Azizimalamiri, R, Chung, WK, Baig, SM, Houlden, H & Severino, M 2023, 'Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders', Brain, vol. 146, no. 12, pp. 5031-5043. https://doi.org/10.1093/brain/awad257

TY - JOUR

T1 - Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders

AU - Maroofian, Reza

AU - Kaiyrzhanov, Rauan

AU - Cali, Elisa

AU - Zamani, Mina

AU - Zaki, Maha S.

AU - Ferla, Matteo

AU - Tortora, Domenico

AU - Sadeghian, Saeid

AU - Saadi, Saadia Maryam

AU - Abdullah, Uzma

AU - Karimiani, Ehsan Ghayoor

AU - Efthymiou, Stephanie

AU - Yeşil, Gözde

AU - Alavi, Shahryar

AU - Al Shamsi, Aisha M.

AU - Tajsharghi, Homa

AU - Abdel-Hamid, Mohamed S.

AU - Saadi, Nebal Waill

AU - Al Mutairi, Fuad

AU - Alabdi, Lama

AU - Beetz, Christian

AU - Ali, Zafar

AU - Toosi, Mehran Beiraghi

AU - Rudnik-Schöneborn, Sabine

AU - Babaei, Meisam

AU - Isohanni, Pirjo

AU - Muhammad, Jameel

AU - Khan, Sheraz

AU - Al Shalan, Maha

AU - Hickey, Scott E.

AU - Marom, Daphna

AU - Elhanan, Emil

AU - Kurian, Manju A.

AU - Marafi, Dana

AU - Saberi, Alihossein

AU - Hamid, Mohammad

AU - Spaull, Robert

AU - Meng, Linyan

AU - Lalani, Seema

AU - Maqbool, Shazia

AU - Rahman, Fatima

AU - Seeger, Jürgen

AU - Palculict, Timothy Blake

AU - Lau, Tracy

AU - Murphy, David

AU - Mencacci, Niccolo Emanuele

AU - Steindl, Katharina

AU - Begemann, Anais

AU - Rauch, Anita

AU - Akbas, Sinan

AU - Aslanger, Ayça Dilruba

AU - Salpietro, Vincenzo

AU - Yousaf, Hammad

AU - Ben-Shachar, Shay

AU - Ejeskär, Katarina

AU - Al Aqeel, Aida I.

AU - High, Frances A.

AU - Armstrong-Javors, Amy E.

AU - Zahraei, Seyed Mohammadsaleh

AU - Seifi, Tahereh

AU - Zeighami, Jawaher

AU - Shariati, Gholamreza

AU - Sedaghat, Alireza

AU - Asl, Samaneh Noroozi

AU - Shahrooei, Mohmmad

AU - Zifarelli, Giovanni

AU - Burglen, Lydie

AU - Ravelli, Claudia

AU - Zschocke, Johannes

AU - Schatz, Ulrich A.

AU - Ghavideldarestani, Maryam

AU - Kamel, Walaa A.

AU - Van Esch, Hilde

AU - Hackenberg, Annette

AU - Taylor, Jenny C.

AU - Al-Gazali, Lihadh

AU - Bauer, Peter

AU - Gleeson, Joseph J.

AU - Alkuraya, Fowzan Sami

AU - Lupski, James R.

AU - Galehdari, Hamid

AU - Azizimalamiri, Reza

AU - Chung, Wendy K.

AU - Baig, Shahid Mahmood

AU - Houlden, Henry

AU - Severino, Mariasavina

PY - 2023/12/1

Y1 - 2023/12/1

N2 - MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'.

AB - MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'.

KW - cerebellar atrophy

KW - cerebello-lental degeneration

KW - dystonia

KW - gene transcription

KW - mediator complex

KW - neurodevelopmental disorders

UR - http://www.scopus.com/inward/record.url?scp=85178648913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85178648913&partnerID=8YFLogxK

U2 - 10.1093/brain/awad257

DO - 10.1093/brain/awad257

M3 - Article

C2 - 37517035

AN - SCOPUS:85178648913

SN - 0006-8950

VL - 146

SP - 5031

EP - 5043

JO - Brain

JF - Brain

IS - 12

ER -

Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders

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