Sirs: Central core disease (CCD) is a rare congenital myopathy whose phenotype ranges from asymptomatic to severe muscle weakness. Histologically, type I skeletal muscle fibres predominate and show amorphous myofibrillar cores lacking mitochondria and oxidative enzyme activity. Clinical manifestations include hypotonia, delayed motor milestones, proximal muscle weakness, and skeletal anomalies [3, 5]. CCD is usually autosomal dominant with variable penetrance, but can be autosomal recessive [4]. CCD is usually associated with mutations in the ryanodine receptor gene (RYR1), which encodes a homotetrameric Ca-release channel (RyR1) of the sarcoplasmic reticulum crucially involved in excitationcontraction coupling [1, 9]. RYR1 mutations are also associated with malignant hyperthermia susceptibility (MH) and certain forms of the usually recessive multiminicore disease (MmD). About 41% of known RYR1 mutations produce MH, are located in the N-terminal (cytoplasmic) or central region (transmembrane) of the homotetramer, and recur sporadically. CCD-producing mutations are mainly confined to a few families and localize in the C-terminal (also cytoplasmic) domain [5, 7, 8, 10]. We describe two sisters with CCD and their asymptomatic consanguineous parents. The daughters were homozygous and the parents heterozygous for an RYR1 mutation. A 36-year-old woman and her 31-year-old sister were referred to us in 2007 for genetic counselling. We had seen them during childhood for early onset hypotonia and muscle weakness, with delayed motor milestones, and mild deterioration of motor abilities as childhood progressed. There was no family history of neuromuscular disease, but the parents were first cousins (Fig. 1a). Quadriceps needle biopsies from each sister had shown variable fibre size and central nuclei. Oxidative enzyme staining had shown one or more large cores in most fibres (Fig. 2) and type I fibre predominance. CCD was diagnosed. In 2007 the sisters had closely similar phenotypes: elongated face, congenital hip dislocation, foot deformities (repaired surgically during childhood), and thoraco-lumbar scoliosis. There was mild facial muscle weakness, scapular winging, normal arm muscle strength, but evident weakness of lower limb muscles; external ophthalmoplegia was absent. Neither sister could run; they could rise from the floor with difficulty using Gower’s manoeuvre, and climb stairs using a handrail. Serum creatine kinase and respiratory function were normal. Electromyography showed myopathic findings. The parents were asymptomatic with normal neurological examination; they refused muscle biopsy. After receiving written informed consent from each family member, genomic DNA from peripheral blood was screened for RYR1 mutations by PCR and sequencing. The sisters (II1 and II2) were homozygous for c.11708G[A mutation in exon 85 resulting in R3903Q substitution (arginine to glutamine); the parents (I1 and I2) were heterozygous for the same mutation (Fig. 1b). Galli et al. [2] described the same heterozygous mutation associated with MH. Our data suggest that this mutation causes classic CCD only when inherited homozygously, as in our sisters, since the heterozygous parents L. Colleoni G. Melli L. Morandi P. Cudia S. Romaggi R. Mantegazza P. Bernasconi (&) Neurology IV, Neuromuscular Diseases and Neuroimmunology, Neurological Institute Foundation ‘‘Carlo Besta’’, Via Celoria 11, 20133 Milan, Italy e-mail: pbernasconi@istituto-besta.it