Nemaline Myopathy in a Neonate Secondary To A Mosaic Mutation in ACTA1



Poster Number: 203


Connor Gatewood, MD, UTHSC/LeBonheur, Megan Fonville, MS, CGC, LeBonheur Children's Hospital, Chester Brown, MD, PhD, LeBonheur Children's Hospital, A. Reghan Foley, MD, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Elena Caron, MD, Le Bonheur Children's Hospital The University of Tennessee Health Science Center

Nemaline myopathy (NM) is a form of congenital myopathy characterized on muscle histology by cytoplasmic inclusions called nemaline rods. Typically, NM presents in early childhood with proximal weakness, hypotonia, and depressed deep tendon reflexes. Congenital onset forms manifest with severe hypotonia with respiratory insufficiency. There are at least 12 causative genes for NM which code for thin filament structural or regulatory proteins, with nebulin (NEB) and skeletal α-actin (ACTA1) being the most common.

We present a case of an infant with asymmetric, profound weakness secondary to mosaic mutation in ACTA1. She was born premature at 33 weeks gestation with initial respiratory distress requiring respiratory support including intubation on day of life (DOL) 11. Her initial examination was significant for profound axial weakness with a weak cry and hyporeflexia. Brain and cervical spine MRI were normal. EMG examination was normal, and nerve conduction studies demonstrated absent R median, ulnar, and fibular nerve CMAPs. Examination on DOL 45 showed no head control, axillary slip-through, hypotonia, areflexia, right facial weakness, right wrist drop, hip flexor weakness (right greater than left), and bilateral foot drop. She ultimately demonstrated full-time ventilator dependence due to respiratory insufficiency and had a tracheostomy placed. Next generation sequencing panel identified a variant in ACTA1 c.1004C>T (p.Pro335Leu) with evidence of mosaicism (a level of 9-19% in the proband’s blood). The mutation has been published as de novo and causative in a patient with nemaline and was not present in the proband’s mother. A right vastus lateralis muscle biopsy showed myopathic histology consistent with congenital fiber type disproportion.

Two previous reports of ACTA1-related myopathy with asymmetric weakness have been published. Asymmetric weakness in a newborn is more typical of central nervous system disorders; however, if the examination is more consistent with peripheral nervous system disorder, a mosaic etiology could be considered.