C.P.5 Three siblings with multi-minicore myopathy not associated with SEPN1 or RYR1 mutations

Abstract

Multi-minicore disease (MmD) is a congenital myopathy defined by the presence of multiple small zones of sarcomeric disorganization and diminished mitochondrial oxidative activity (“minicores”) in muscle fibers. It has been categorized into four subgroups; classical, moderate with hand involvement, ophthalmoplegic, and antenatal form with arthrogryposis. The classical form is characterized by the predominant axial weakness, severe scoliosis and respiratory insufficiency, although these features are variable. Three siblings, born to non-consanguineous parents, presented with neonatal hypotonia and delayed gross motor milestones. The eldest sibling was most severely affected and had very mild scoliosis, and obstructive sleep apnea requiring BiPAP. The younger siblings had no spine, cardiac or respiratory muscle involvement. All three had normal cognition and CK levels. They had significant weakness of the neck flexors, pelvic girdle, and deltoids. Distal power and extra ocular movements were normal. The muscle biopsy of the middle sibling revealed muscle fibres of variable size with striking type I predominance. There were multiple small core lesions visible on Toluidine Blue,which appeared ultrastructurally as focal disruptions in the myofibrillar striation pattern, with absence of mitochondria in the cores and Z-band streaming. Muscle MRI for all three siblings revealed atrophy throughout most muscle groups, with upper extremity flexors involved more than extensors and scapular muscles most severely involved. In the lower extremities the glutei were most affected with relative sparing of the quadriceps. Microarray analysis and molecular testing of the RYR1, SEPN1, ACTA1 and MYH7 genes was negative. We present three siblings with myopathy and pathological features of MmD in whom appropriate genetic testing has not yielded a diagnosis. This further supports the genetic heterogeneity of MmD, and the need to elucidate the genetic bases of this condition.