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Cold Spring Harb Mol Case Stud. 2019 Jun 3;5(3). pii: a003673. doi: 10.1101/mcs.a003673. Print 2019 Jun.

De novo missense variant in the GTPase effector domain (GED) of DNM1L leads to static encephalopathy and seizures.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
2
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.
3
Baylor Genetics, Houston, Texas 77021, USA.
4
Texas Children's Hospital, Houston, Texas 77030, USA.
5
BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, ShaTin, New Territories, Hong Kong, SAR.
6
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
#
Contributed equally

Abstract

DNM1L encodes a GTPase of the dynamin superfamily, which plays a crucial role in mitochondrial and peroxisomal fission. Pathogenic variants affecting the middle domain and the GTPase domain of DNM1L have been implicated in encephalopathy because of defective mitochondrial and peroxisomal fission 1 (EMPF1, MIM #614388). Patients show variable phenotypes ranging from severe hypotonia leading to death in the neonatal period to developmental delay/regression, with or without seizures. Familial pathogenic variants in the GTPase domain have also been associated with isolated optic atrophy. We present a 27-yr-old woman with static encephalopathy, a history of seizures, and nystagmus, in whom a novel de novo heterozygous variant was detected in the GTPase effector domain (GED) of DNM1L (c.2072A>G, p.Tyr691Cys). Functional studies in Drosophila demonstrate large, abnormally distributed peroxisomes and mitochondria, an effect very similar to that of middle domain missense alleles observed in pediatric subjects with EMPF1. To our knowledge, not only is this the first report of a disease-causing variant in the GED domain in humans, but this is also the oldest living individual reported with EMPF1. Longitudinal data of this kind helps to expand our knowledge of the natural history of a growing list of DNM1L-related disorders.

KEYWORDS:

abnormal mitochondria in muscle tissue; central hypotonia; epileptic encephalopathy; slowly progressive spastic quadriparesis

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