Neurologic phenotypes associated with COL4A1/2 mutations

Expanding the spectrum of disease

Sara Zagaglia, Christina Selch, Jelena Radic Nisevic, Davide Mei, Zuzanna Michalak, Laura Hernandez-Hernandez, S Krithika, Katharina Vezyroglou, Sophia M Varadkar, Alexander Pepler, Saskia Biskup, Miguel Leão, Jutta Gärtner, Andreas Merkenschlager, Michaela Jaksch, Rikke S Møller, Elena Gardella, Britta Schlott Kristiansen, Lars Kjærsgaard Hansen, Maria Stella Vari & 29 others Katherine L Helbig, Sonal Desai, Constance L Smith-Hicks, Naomi Hino-Fukuyo, Tiina Talvik, Rael Laugesaar, Pilvi Ilves, Katrin Õunap, Ingrid Körber, Till Hartlieb, Manfred Kudernatsch, Peter Winkler, Mareike Schimmel, Anette Hasse, Markus Knuf, Jan Heinemeyer, Christine Makowski, Sondhya Ghedia, Gopinath M Subramanian, Pasquale Striano, Rhys H Thomas, Caroline Micallef, Maria Thom, David J Werring, Gerhard Josef Kluger, J Helen Cross, Renzo Guerrini, Simona Balestrini, Sanjay M Sisodiya

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation.

METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations.

RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge.

CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

Original languageEnglish
Pages (from-to)e2078-e2088
JournalNeurology
Volume91
Issue number22
DOIs
Publication statusPublished - Nov 27 2018

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Nervous System
Epilepsy
Phenotype
Mutation
Electroencephalography
Brain
Genetic Association Studies
Cysts
Seizures
Leukoencephalopathies
Status Epilepticus
Pedigree
Neuroimaging
Anticonvulsants
Research

Cite this

Zagaglia, S., Selch, C., Nisevic, J. R., Mei, D., Michalak, Z., Hernandez-Hernandez, L., ... Sisodiya, S. M. (2018). Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease. Neurology, 91(22), e2078-e2088. https://doi.org/10.1212/WNL.0000000000006567

Neurologic phenotypes associated with COL4A1/2 mutations : Expanding the spectrum of disease. / Zagaglia, Sara; Selch, Christina; Nisevic, Jelena Radic; Mei, Davide; Michalak, Zuzanna; Hernandez-Hernandez, Laura; Krithika, S; Vezyroglou, Katharina; Varadkar, Sophia M; Pepler, Alexander; Biskup, Saskia; Leão, Miguel; Gärtner, Jutta; Merkenschlager, Andreas; Jaksch, Michaela; Møller, Rikke S; Gardella, Elena; Kristiansen, Britta Schlott; Hansen, Lars Kjærsgaard; Vari, Maria Stella; Helbig, Katherine L; Desai, Sonal; Smith-Hicks, Constance L; Hino-Fukuyo, Naomi; Talvik, Tiina; Laugesaar, Rael; Ilves, Pilvi; Õunap, Katrin; Körber, Ingrid; Hartlieb, Till; Kudernatsch, Manfred; Winkler, Peter; Schimmel, Mareike; Hasse, Anette; Knuf, Markus; Heinemeyer, Jan; Makowski, Christine; Ghedia, Sondhya; Subramanian, Gopinath M; Striano, Pasquale; Thomas, Rhys H; Micallef, Caroline; Thom, Maria; Werring, David J; Kluger, Gerhard Josef; Cross, J Helen; Guerrini, Renzo; Balestrini, Simona; Sisodiya, Sanjay M.

In: Neurology, Vol. 91, No. 22, 27.11.2018, p. e2078-e2088.

Research output: Contribution to journalArticle

Zagaglia, S, Selch, C, Nisevic, JR, Mei, D, Michalak, Z, Hernandez-Hernandez, L, Krithika, S, Vezyroglou, K, Varadkar, SM, Pepler, A, Biskup, S, Leão, M, Gärtner, J, Merkenschlager, A, Jaksch, M, Møller, RS, Gardella, E, Kristiansen, BS, Hansen, LK, Vari, MS, Helbig, KL, Desai, S, Smith-Hicks, CL, Hino-Fukuyo, N, Talvik, T, Laugesaar, R, Ilves, P, Õunap, K, Körber, I, Hartlieb, T, Kudernatsch, M, Winkler, P, Schimmel, M, Hasse, A, Knuf, M, Heinemeyer, J, Makowski, C, Ghedia, S, Subramanian, GM, Striano, P, Thomas, RH, Micallef, C, Thom, M, Werring, DJ, Kluger, GJ, Cross, JH, Guerrini, R, Balestrini, S & Sisodiya, SM 2018, 'Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease', Neurology, vol. 91, no. 22, pp. e2078-e2088. https://doi.org/10.1212/WNL.0000000000006567
Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L et al. Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease. Neurology. 2018 Nov 27;91(22):e2078-e2088. https://doi.org/10.1212/WNL.0000000000006567
Zagaglia, Sara ; Selch, Christina ; Nisevic, Jelena Radic ; Mei, Davide ; Michalak, Zuzanna ; Hernandez-Hernandez, Laura ; Krithika, S ; Vezyroglou, Katharina ; Varadkar, Sophia M ; Pepler, Alexander ; Biskup, Saskia ; Leão, Miguel ; Gärtner, Jutta ; Merkenschlager, Andreas ; Jaksch, Michaela ; Møller, Rikke S ; Gardella, Elena ; Kristiansen, Britta Schlott ; Hansen, Lars Kjærsgaard ; Vari, Maria Stella ; Helbig, Katherine L ; Desai, Sonal ; Smith-Hicks, Constance L ; Hino-Fukuyo, Naomi ; Talvik, Tiina ; Laugesaar, Rael ; Ilves, Pilvi ; Õunap, Katrin ; Körber, Ingrid ; Hartlieb, Till ; Kudernatsch, Manfred ; Winkler, Peter ; Schimmel, Mareike ; Hasse, Anette ; Knuf, Markus ; Heinemeyer, Jan ; Makowski, Christine ; Ghedia, Sondhya ; Subramanian, Gopinath M ; Striano, Pasquale ; Thomas, Rhys H ; Micallef, Caroline ; Thom, Maria ; Werring, David J ; Kluger, Gerhard Josef ; Cross, J Helen ; Guerrini, Renzo ; Balestrini, Simona ; Sisodiya, Sanjay M. / Neurologic phenotypes associated with COL4A1/2 mutations : Expanding the spectrum of disease. In: Neurology. 2018 ; Vol. 91, No. 22. pp. e2078-e2088.
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abstract = "OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation.METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations.RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4{\%} of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge.CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.",
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TY - JOUR

T1 - Neurologic phenotypes associated with COL4A1/2 mutations

T2 - Expanding the spectrum of disease

AU - Zagaglia, Sara

AU - Selch, Christina

AU - Nisevic, Jelena Radic

AU - Mei, Davide

AU - Michalak, Zuzanna

AU - Hernandez-Hernandez, Laura

AU - Krithika, S

AU - Vezyroglou, Katharina

AU - Varadkar, Sophia M

AU - Pepler, Alexander

AU - Biskup, Saskia

AU - Leão, Miguel

AU - Gärtner, Jutta

AU - Merkenschlager, Andreas

AU - Jaksch, Michaela

AU - Møller, Rikke S

AU - Gardella, Elena

AU - Kristiansen, Britta Schlott

AU - Hansen, Lars Kjærsgaard

AU - Vari, Maria Stella

AU - Helbig, Katherine L

AU - Desai, Sonal

AU - Smith-Hicks, Constance L

AU - Hino-Fukuyo, Naomi

AU - Talvik, Tiina

AU - Laugesaar, Rael

AU - Ilves, Pilvi

AU - Õunap, Katrin

AU - Körber, Ingrid

AU - Hartlieb, Till

AU - Kudernatsch, Manfred

AU - Winkler, Peter

AU - Schimmel, Mareike

AU - Hasse, Anette

AU - Knuf, Markus

AU - Heinemeyer, Jan

AU - Makowski, Christine

AU - Ghedia, Sondhya

AU - Subramanian, Gopinath M

AU - Striano, Pasquale

AU - Thomas, Rhys H

AU - Micallef, Caroline

AU - Thom, Maria

AU - Werring, David J

AU - Kluger, Gerhard Josef

AU - Cross, J Helen

AU - Guerrini, Renzo

AU - Balestrini, Simona

AU - Sisodiya, Sanjay M

N1 - Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

PY - 2018/11/27

Y1 - 2018/11/27

N2 - OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation.METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations.RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge.CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

AB - OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation.METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations.RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge.CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

U2 - 10.1212/WNL.0000000000006567

DO - 10.1212/WNL.0000000000006567

M3 - Article

VL - 91

SP - e2078-e2088

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 22

ER -