Abstract Details

Title Seizures, dystonia and progressive cerebellar degeneration in homozygous DNAJC19 mutation without dilated cardiomyopathy or 3-methylglutaconic aciduria

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) P2 - Poster Session 2 (5:30 PM-6:30 PM)

Poster/Presentation
Number 6-013

Objective To describe an expanded DNAJC19 phenotype with more severe neurological and less systemic
manifestations.

Background DNAJC19 homozygous mutations have been linked to dilated cardiomyopathy and ataxia syndrome (DCMA). DNAJC19 is a human homologue of yeast inner mitochondrial membrane co-chaperone
that affects the functional integrity of the mitochondria.

Design/Methods Trio whole genome sequencing (WGS) of patient with unexplained epilepsy. Chart review and
clinical phenotyping.

Results The patient is a 25 year-old female, presenting with intractable epilepsy, severe dystonia, severe intellectual disability, severe and progressively deterioration of ataxia (wheelchair bound) and tremor. Metabolic investigations, including 3-methylglutaconic (3-MGC) and 3-methylglutaric acids (3-MGA) in plasma and urine showed normal levels at age 3 years and 25 years. The echocardiogram showed no structural abnormalities and the EKG at age 25 showed a prolonged QT interval with a flattened T wave. HGS revealed a homozygous splice site region variant in DNAJC19 affecting the consensus 5’ splice site of its third exon, NM_145261.3:c.55+5G>T. Both parents are heterozygous. This variant has not been reported in any public variant database and no other likely pathogenic variants explaining patient’s phenotype were identified. A splice site predictor model suggests that this variant significantly weakens the 5’splice site likely leading to exon 3 skipping.

Conclusions Here we describe a patient with a DNAJC19 splice site mutation predicted to disrupt the splicing of exon 3, presenting with a much more severe neurological and much more mild systemic phenotype. We hypothesize that the putative splicing mutation leads to higher level of exon 3 skipping in the brain compared to other organs. This scenario leads to a prolonged lifespan, since there are no systemic manifestations. However, there are accumulating brain dysfunction leading to a much more severe neurological disorder.

Authors/Disclosures
Marta Ruiz Lopez, MD (Toronto Western Hospital) PRESENTER	Dr. Ruiz Lopez has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Berge A. Minassian, MD (Univeristy of Texas Southwestern Medical Center)	Dr. Minassian has nothing to disclose.
Patrick Cossette, MD (CHUM)	No disclosure on file
	No disclosure on file
Elizabeth Slow, MD, PhD	Dr. Slow has nothing to disclose.
Danielle M. Andrade, MD (University of Toronto)	The institution of Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jazz Pharmaceutical. The institution of Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke Therapeutics. The institution of Dr. Andrade has received research support from Epilepsy Canada. The institution of Dr. Andrade has received research support from SynGAP Research Fund. Dr. Andrade has received publishing royalties from a publication relating to health care. Dr. Andrade has a non-compensated relationship as a Former Chair of task force on Transition with International League Against Epilepsy that is relevant to AAN interests or activities. Dr. Andrade has a non-compensated relationship as a President with Canadian League Against Epilepsy that is relevant to AAN interests or activities.

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