Unpacking Genotype-Phenotype Correlation in DNM1 Encephalopathy: Two unusually mild cases with variants in the GTPase and proline-rich domains
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Pathogenic variants in DNM1 are known to cause a spectrum of severe neurodevelopmental symptoms, including intellectual disability, autism spectrum disorder, epilepsy, and non-specific structural changes in the brain. Amongst those with Lennox-Gastaut syndrome, up to 2% are thought to have a pathogenic change in DNM1. Pathogenic variants commonly cluster in the GTPase domain of dynamin1, though it is unclear how genotype variation affects the phenotypic spectrum of this condition.
Case Presentation
Patient 1 is a 6-year-old female who initially presented with concern for seizures after experiencing brief periods of facial twitching at two years of age. EEG was notable for possible epileptiform discharges in the fronto-central-temporal lobe and electrical status epilepticus of sleep. She otherwise demonstrated no dysmorphic features, and the neurological exam was normal. The patient is reportedly clumsy, but no gross ataxia has been visualized. Developmentally, the patient has met all milestones as expected.
Patient 2 is an 8-year-old female who presented at 19 months of age with febrile seizures. By two years of age, she began to have frequent episodes of shoulder myoclonus that prompted an evaluation by neurology. EEG demonstrated multiple myoclonic seizures and epileptiform discharges. The physical exam was remarkable for frontal bossing, malar flattening, retrognathia, and bilateral proximally placed 5th toes. However, the remainder of her exam as well as her development has been typical.
Diagnostic Workup
While undergoing evaluation for her seizures, Patient 1 received trio clinical exome sequencing with mitochondrial analysis, revealing a de novo likely pathogenic variant (c.2261 T>C, p.(M754T)) in the proline-rich domain (PRD) of DNM1 leading to the diagnosis of DNM1 encephalopathy. This is the first reported variant in the PRD. Similarly, Patient 2 received trio ES with mitochondrial analysis as part of her seizure evaluation that was notable for a de novo likely pathogenic variant (c.689 G>A, p.(G230D)) in the GTPase domain of DNM1. An exome sequencing re-analysis was ordered in August 2024 to ensure that no additional variants could account for her phenotype and was negative for explanatory variants.
Treatment and Management
Patient 1 has maintained seizure remission on clobazam and levetiracetam, and she has been seizure-free since the age of four. At age two, Patient 2 was started on levetiracetam which was soon discontinued due to behavioral side effects. She was then switched to zonisamide that provided minimal seizure control. Finally, she was placed on clobazam which resulted in sustained seizure remission.
Outcome and Follow-Up
Both patients are excelling in school and continue to have no behavioral, developmental, academic, or intellectual concerns.
Discussion
While variable expressivity of conditions has numerous underpinnings beyond simply genotype, understanding the role that genotype may play in the phenotypic variability of a condition may help shed light on the range of possible manifestations. The implication of the structure and function of the PRD on this mild phenotype is discussed at length. Hypotheses include increased variant tolerance due to intrinsic disorder and the role of allosteric regulation of the GTPase by the PRD. Furthermore, the possibility of a mild phenotype arising from a variant to a highly conserved residue within the catalytic domain of the GTPase is contrasted with previously reported phenotypes.
Conclusion
By presenting two cases of patients with a history of well-controlled seizures who lack any other known symptoms of DNM1 encephalopathy, this case expands on the known phenotypic possibilities for patients with variants in DNM1. These reports are notable as they implicate the possibility of a milder phenotype for variants in the GTPase domain and provide the first known report of a variant in the PRD.
Pathogenic variants in DNM1 are known to cause a spectrum of severe neurodevelopmental symptoms, including intellectual disability, autism spectrum disorder, epilepsy, and non-specific structural changes in the brain. Amongst those with Lennox-Gastaut syndrome, up to 2% are thought to have a pathogenic change in DNM1. Pathogenic variants commonly cluster in the GTPase domain of dynamin1, though it is unclear how genotype variation affects the phenotypic spectrum of this condition.
Case Presentation
Patient 1 is a 6-year-old female who initially presented with concern for seizures after experiencing brief periods of facial twitching at two years of age. EEG was notable for possible epileptiform discharges in the fronto-central-temporal lobe and electrical status epilepticus of sleep. She otherwise demonstrated no dysmorphic features, and the neurological exam was normal. The patient is reportedly clumsy, but no gross ataxia has been visualized. Developmentally, the patient has met all milestones as expected.
Patient 2 is an 8-year-old female who presented at 19 months of age with febrile seizures. By two years of age, she began to have frequent episodes of shoulder myoclonus that prompted an evaluation by neurology. EEG demonstrated multiple myoclonic seizures and epileptiform discharges. The physical exam was remarkable for frontal bossing, malar flattening, retrognathia, and bilateral proximally placed 5th toes. However, the remainder of her exam as well as her development has been typical.
Diagnostic Workup
While undergoing evaluation for her seizures, Patient 1 received trio clinical exome sequencing with mitochondrial analysis, revealing a de novo likely pathogenic variant (c.2261 T>C, p.(M754T)) in the proline-rich domain (PRD) of DNM1 leading to the diagnosis of DNM1 encephalopathy. This is the first reported variant in the PRD. Similarly, Patient 2 received trio ES with mitochondrial analysis as part of her seizure evaluation that was notable for a de novo likely pathogenic variant (c.689 G>A, p.(G230D)) in the GTPase domain of DNM1. An exome sequencing re-analysis was ordered in August 2024 to ensure that no additional variants could account for her phenotype and was negative for explanatory variants.
Treatment and Management
Patient 1 has maintained seizure remission on clobazam and levetiracetam, and she has been seizure-free since the age of four. At age two, Patient 2 was started on levetiracetam which was soon discontinued due to behavioral side effects. She was then switched to zonisamide that provided minimal seizure control. Finally, she was placed on clobazam which resulted in sustained seizure remission.
Outcome and Follow-Up
Both patients are excelling in school and continue to have no behavioral, developmental, academic, or intellectual concerns.
Discussion
While variable expressivity of conditions has numerous underpinnings beyond simply genotype, understanding the role that genotype may play in the phenotypic variability of a condition may help shed light on the range of possible manifestations. The implication of the structure and function of the PRD on this mild phenotype is discussed at length. Hypotheses include increased variant tolerance due to intrinsic disorder and the role of allosteric regulation of the GTPase by the PRD. Furthermore, the possibility of a mild phenotype arising from a variant to a highly conserved residue within the catalytic domain of the GTPase is contrasted with previously reported phenotypes.
Conclusion
By presenting two cases of patients with a history of well-controlled seizures who lack any other known symptoms of DNM1 encephalopathy, this case expands on the known phenotypic possibilities for patients with variants in DNM1. These reports are notable as they implicate the possibility of a milder phenotype for variants in the GTPase domain and provide the first known report of a variant in the PRD.