P.109Congenital myopathy in patients with Kabuki and Au-Kline syndromes - Double trouble or expansion of the phenotypes?

Abstract

Congenital myopathies (CM) are heterogeneous neuromuscular disorders with hypotonia and weakness, often from birth, classified on the morphological features on muscle biopsy. Cardiac muscle involvement, facial dysmorphisms and involvement of the heart and other organs is well recognized. Here we describe 5 unrelated patients with clinical and histopathological features of CM, assessed in two tertiary UK neuromuscular centers, later diagnosed with Kabuki (KS) or Au-Kline syndrome (AUS). KS and AUS are multisystem disorders, with overlapping features such as distinctive facial dysmorphisms, hypotonia, intellectual disability, growth and skeletal defects and congenital heart defects (CHD). Age of patients ranged from 2 to 13 years. Onset was at birth, with hypotonia, global developmental delay, dysmorphisms, CHD and severe feeding difficulties. On examination patients were hypotonic, but muscle strength was overall satisfactory. Three patients were hypermobile, one had hemivertebrae and one congenital hip dislocation. Microcephaly, Chiari I malformation and craniosynostosis was seen in one patient, each. Three patients had hearing loss. One patient had 3 rhabdomyolysis episodes triggered by viral infections. Respiratory chain enzyme analysis, performed in 3 patients, was normal. Analysis of genes for CM and syndromic conditions with learning disability and CHD identified pathogenic heterozygous variants in the KMT2D (3 patients with KS) or HNRNPK gene (1 patient with AUS), confirming their diagnoses (test ongoing in 5th patient). Muscle biopsies in 3 KMT2D patients showed mild non-specific changes and increased central nuclei with markedly abnormal myofibre architecture in the third case. Biopsy of the patient with variants in HNRNPK showed striking congenital fibre type disproportion. This is the first report of myopathology in KS and AUS patients and might suggest a link between the proteins disrupted in these conditions and muscle structure.