Background: Patients with DNM1-encephalopathy
almost exclusively have missense variants, mostly in the GTPase domain of
DNM1. Delayed myelination has been reported in at least three patients with
DNM1-encephalopathy, all with missense mutations in the DNM1 central domain.
Only one DNM1 splice-site variant has previously
been reported, and the authors questioned whether the variant accounted for
all aspects of the patient’s phenotype. Methods:
Case-Report. Results: Our patient had hypotonia and
brief multifocal tonic seizures from age-1-month. He still has profound
global developmental delay, daily seizures and microcephaly. MRI-Brain at
age-21-months showed T2 hyperintensity in the bilateral periventricular and
subcortical white matter; spectroscopy showed a questionable lactate peak
and an elevated choline peak relative to N-acetylaspartate. Clinical
gene-panel identified a heterozygous de novo pathogenic variant in intron 9
of DNM1 (c.1197-8G > A; IVS9- 8G>A). In-silico tools categorized this
variant as deleterious secondary to a splicing defect. RT-PCR analysis on
peripheral blood was unsuccessful as DNM1 expression is extremely low
outside of the brain. Conclusions: Our patient
carried the same DNM1 variant previously reported, indicating this is a
recurrent pathogenic splice-site variant. The spectroscopic abnormalities
suggest a possible element of demyelination in
DNM1 variants of the central domain, though
the mechanism remains unclear.
Centronuclear myopathy due to a de novo nonsense variant and a maternally inherited splice‐site variant in
TTN
: A case report
