DNM1 encephalopathy

Sarah Von Spiczak, Katherine L. Helbig, Deepali N. Shinde, Robert Huether, Manuela Pendziwiat, Charles Lourenço, Mark E. Nunes, Dean P. Sarco, Richard A. Kaplan, Dennis J. Dlugos, Heidi Kirsch, Anne Slavotinek, Maria R. Cilio, Mackenzie Cervenka, Julie S. Cohen, Rebecca McClellan, Ali Fatemi, Amy Yuen, Yoshimi Sagawa, Rebecca Littlejohn & 17 others Scott D. McLean, Laura Hernandez-Hernandez, Bridget Maher, Rikke S. Møller, Elizabeth Palmer, John A. Lawson, Colleen A. Campbell, Charuta N. Joshi, Diana L. Kolbe, Georgie Hollingsworth, Bernd A. Neubauer, Hiltrud Muhle, Ulrich Stephani, Ingrid E. Scheffer, Sérgio D.J. Pena, Sanjay M. Sisodiya, Ingo Helbig

Research output: Contribution to journalArticle

Abstract

Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. Results: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. Conclusions: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)385-394
Number of pages10
JournalNeurology
Volume89
Issue number4
DOIs
StatePublished - Jul 25 2017

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Dynamin I
Brain Diseases
Mutation
Epilepsy
Infantile Spasms
Muscle Hypotonia
GTP Phosphohydrolases
Genetic Association Studies
Intellectual Disability
Siblings
Seizures
Proteins
Fever

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Von Spiczak, S., Helbig, K. L., Shinde, D. N., Huether, R., Pendziwiat, M., Lourenço, C., ... Helbig, I. (2017). DNM1 encephalopathy. Neurology, 89(4), 385-394. https://doi.org/10.1212/WNL.0000000000004152

DNM1 encephalopathy. / Von Spiczak, Sarah; Helbig, Katherine L.; Shinde, Deepali N.; Huether, Robert; Pendziwiat, Manuela; Lourenço, Charles; Nunes, Mark E.; Sarco, Dean P.; Kaplan, Richard A.; Dlugos, Dennis J.; Kirsch, Heidi; Slavotinek, Anne; Cilio, Maria R.; Cervenka, Mackenzie; Cohen, Julie S.; McClellan, Rebecca; Fatemi, Ali; Yuen, Amy; Sagawa, Yoshimi; Littlejohn, Rebecca; McLean, Scott D.; Hernandez-Hernandez, Laura; Maher, Bridget; Møller, Rikke S.; Palmer, Elizabeth; Lawson, John A.; Campbell, Colleen A.; Joshi, Charuta N.; Kolbe, Diana L.; Hollingsworth, Georgie; Neubauer, Bernd A.; Muhle, Hiltrud; Stephani, Ulrich; Scheffer, Ingrid E.; Pena, Sérgio D.J.; Sisodiya, Sanjay M.; Helbig, Ingo.

In: Neurology, Vol. 89, No. 4, 25.07.2017, p. 385-394.

Research output: Contribution to journalArticle

Von Spiczak, S, Helbig, KL, Shinde, DN, Huether, R, Pendziwiat, M, Lourenço, C, Nunes, ME, Sarco, DP, Kaplan, RA, Dlugos, DJ, Kirsch, H, Slavotinek, A, Cilio, MR, Cervenka, M, Cohen, JS, McClellan, R, Fatemi, A, Yuen, A, Sagawa, Y, Littlejohn, R, McLean, SD, Hernandez-Hernandez, L, Maher, B, Møller, RS, Palmer, E, Lawson, JA, Campbell, CA, Joshi, CN, Kolbe, DL, Hollingsworth, G, Neubauer, BA, Muhle, H, Stephani, U, Scheffer, IE, Pena, SDJ, Sisodiya, SM & Helbig, I 2017, 'DNM1 encephalopathy', Neurology, vol. 89, no. 4, pp. 385-394. https://doi.org/10.1212/WNL.0000000000004152
Von Spiczak S, Helbig KL, Shinde DN, Huether R, Pendziwiat M, Lourenço C et al. DNM1 encephalopathy. Neurology. 2017 Jul 25;89(4):385-394. https://doi.org/10.1212/WNL.0000000000004152
Von Spiczak, Sarah ; Helbig, Katherine L. ; Shinde, Deepali N. ; Huether, Robert ; Pendziwiat, Manuela ; Lourenço, Charles ; Nunes, Mark E. ; Sarco, Dean P. ; Kaplan, Richard A. ; Dlugos, Dennis J. ; Kirsch, Heidi ; Slavotinek, Anne ; Cilio, Maria R. ; Cervenka, Mackenzie ; Cohen, Julie S. ; McClellan, Rebecca ; Fatemi, Ali ; Yuen, Amy ; Sagawa, Yoshimi ; Littlejohn, Rebecca ; McLean, Scott D. ; Hernandez-Hernandez, Laura ; Maher, Bridget ; Møller, Rikke S. ; Palmer, Elizabeth ; Lawson, John A. ; Campbell, Colleen A. ; Joshi, Charuta N. ; Kolbe, Diana L. ; Hollingsworth, Georgie ; Neubauer, Bernd A. ; Muhle, Hiltrud ; Stephani, Ulrich ; Scheffer, Ingrid E. ; Pena, Sérgio D.J. ; Sisodiya, Sanjay M. ; Helbig, Ingo. / DNM1 encephalopathy. In: Neurology. 2017 ; Vol. 89, No. 4. pp. 385-394.
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abstract = "Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. Results: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3{\%}) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. Conclusions: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.",
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AU - Von Spiczak, Sarah

AU - Helbig, Katherine L.

AU - Shinde, Deepali N.

AU - Huether, Robert

AU - Pendziwiat, Manuela

AU - Lourenço, Charles

AU - Nunes, Mark E.

AU - Sarco, Dean P.

AU - Kaplan, Richard A.

AU - Dlugos, Dennis J.

AU - Kirsch, Heidi

AU - Slavotinek, Anne

AU - Cilio, Maria R.

AU - Cervenka, Mackenzie

AU - Cohen, Julie S.

AU - McClellan, Rebecca

AU - Fatemi, Ali

AU - Yuen, Amy

AU - Sagawa, Yoshimi

AU - Littlejohn, Rebecca

AU - McLean, Scott D.

AU - Hernandez-Hernandez, Laura

AU - Maher, Bridget

AU - Møller, Rikke S.

AU - Palmer, Elizabeth

AU - Lawson, John A.

AU - Campbell, Colleen A.

AU - Joshi, Charuta N.

AU - Kolbe, Diana L.

AU - Hollingsworth, Georgie

AU - Neubauer, Bernd A.

AU - Muhle, Hiltrud

AU - Stephani, Ulrich

AU - Scheffer, Ingrid E.

AU - Pena, Sérgio D.J.

AU - Sisodiya, Sanjay M.

AU - Helbig, Ingo

PY - 2017/7/25

Y1 - 2017/7/25

N2 - Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. Results: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. Conclusions: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.

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