Abstract Details

Title A novel frameshift mutation in DNA2 causes early onset myopathy with velopharyngeal weakness and cardiac arrhythmias

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-010

Objective To describe the clinical and histopathologic features of two Mexican patients showing a mitochondrial disease associated with a novel mutation in DNA2 gene.

Background DNA2 encodes a helicase/nuclease involved in mtDNA maintenance/replication. Mutations in DNA2 have been associated to autosomal dominant (AD) progressive ophtalmoplegia, and congenital onset myopathy with ptosis. To date only few DNA2 AD cases have been described, none of them presenting with a cardiac involvement.

Design/Methods P1 and P2, mother and son, aged 44 and 11 yrs, underwent clinical examination, deltoid muscle biopsy (P1) and cardiac workup. Peripheral blood genomic DNA was analyzedwith NGS panel of 244 nuclear mitochondrial disorders genes.

Results

P1 was born to healthy non-consanguineous parents. She showed hypotonia, failure to thrive, and retarded milestones. She never ran and presented frequent falls. Nasal and poorly comprehensible speech were noticed, necessitating a retropharyngeal implant at 7 years. At 28 yrs a type 2 atrioventricular block was diagnosed. Pacemaker was implanted at 35 yrs. Exam at 44 years revealed facial weakness, high-arched palate, nasal voice and diffuse proximal weakness (3/4 MRC). CK were normal. Left deltoid muscle biopsy showed mitochondrial aggregates and ultrastructural studies revealed enlarged mitochondria with disrupted cristae. P2 was born at 38 weeks by caesarian delivery. He showed neonatal hypotonia, failure to thrive and delayed motor skills. He presented frequent falls and he ran with difficulties. Episodes of mental confusion and weight loss during infections were reported. Clinical examination at 11 yrs showed facial weakness, nasal voice and high-arched palate. Muscle weakness was diffuse (3 MRC). CK were normal. Cardiac workup revealed supraventricular tachycardia treated with metoprolol.

Next generation studies in both patient revealed a novel heterozygous DNA2 mutation, c.2346delT, p. Phe782Leufs*3, leading to protein elongation of 3 aminoacids followed by a stop.

Conclusions Here we enlarge the genetic and phenotypic spectrum of DNA2-related mitochondrial disorders.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Edoardo Malfatti, MD (APHP, Inserm U955, Université Paris Est)	Dr. Malfatti has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Spark therapeutics. Dr. Malfatti has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. The institution of Dr. Malfatti has received research support from AFM. The institution of Dr. Malfatti has received research support from Spark Therapeutics. The institution of Dr. Malfatti has received research support from AFM. The institution of Dr. Malfatti has received research support from ANR.

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