G.O.2 A clinical and pathological study of congenital fibre type disproportion

Congenital fibre type disproportion (CFTD) is a clinicopathological diagnosis characterised by (i) type 1 (slow twitch) muscle fibres that are at least 12% smaller than type 2 (fast twitch) fibres as the principal histological abnormality and (ii) clinical features of a congenital myopathy. A paucity of large clinical studies has resulted in uncertainty about the clinical spectrum of disease and genetic basis of this condition. To clarify the clinical and pathological characteristics of CFTD we ascertained 120 patients with possible CFTD from neurology and pathology services around Australia and internationally. We measured fibre sizes from ATPase stains, collected clinical information, excluded other disease processes and selected patient with CFTD using previously proposed criteria (Clarke NF, North KN. J Neuropath Exp Neurol 2003;62:977–89). We analysed this cohort for common phenotypes and genetic causes. In 90 unrelated patients the mean type 1 fibre diameter was at least 12% smaller than the mean type 2 fibre diameter. Thirty eight patients qualified for a diagnosis of CFTD. Five patients had prominent axial weakness and respiratory impairment in mild/late childhood. Homozygous mutations in SEPN1 were found in one family. Novel missense mutations in ACTA1 were found in three out of six patients who presented with severe congenital generalised weakness. A distinctive presentation of congenital ptosis, facial and respiratory weakness was present in one family with an X-linked inheritance pattern and one other male patient. Seven patients died from respiratory failure; one with an axial phenotype, one with X-linked CFTD and five with severe congenital weakness. The majority of patients had a stable or improving course. In conclusion, we emphasise the importance of excluding other disease processes that can share similar histological patterns, particularly in young children. CFTD is genetically heterogeneous with ACTA1 and SEPN1 representing the first two genetic causes to be identified. Respiratory muscle weakness is an important source of morbidity and mortality. Sub-classifying CFTD by clinical features may aid molecular diagnosis and management. We also propose guidelines to help the clinician diagnose and manage children with CFTD.