Autosomal-dominant distal myopathy with a myotilin S55F mutation: sorting out the phenotype J Berciano, 1 E Gallardo, 2 R Domı ´nguez-Perles, 3 E Gallardo, 3 A Garcı ´a, 4 R Garcı ´a-Barredo, 2 O Combarros, 1 J Infante, 1 I Illa 3 1 Service of Neurology, ‘‘Marque ´s de Valdecilla’’ University Hospital (IFIMAV), ‘‘Centro de Investigacio ´n Biome ´dica en Red de Enfermedades Neurodegenerativas’’ (CIBERNED), University of Cantabria, Santander, Spain; 2 Service of Radiology, ‘‘Marque ´s de Valdecilla’’ University Hospital (IFIMAV), University of Cantabria, Santander, Spain; 3 Service of Neurology and Laboratory of Experimental Neurology, ‘‘Hospital de la Santa Creu i Sant Pau i Institut de Recerca de HSCSP, Universitat Autonoma’’, Barcelona, Spain; 4 Service of Clinical Neurophysiology, ‘‘Marque ´s de Valdecilla’’ University Hospital (IFIMAV), University of Cantabria, Santander, Spain Correspondence to: Prof. Jose ´ Berciano, Service of Neurology, ‘‘Marque ´s de Valdecilla’’ University Hospital, 39008 Santander, Spain; jaberciano@humv.es Received 21 May 2007 Revised 12 July 2007 Accepted 16 July 2007 Published Online First 13 August 2007 ABSTRACT Objective: To describe the clinical phenotype of an autosomal-dominant pedigree with myotilinopathy. Methods: Two symptomatic patients and six asympto- matic gene mutation carriers were examined. We performed serum chemistry, electrophysiological assess- ments, magnetic resonance imaging (MRI) of lower limb musculature, histochemical and immunohistochemical studies of a muscle biopsy and mutation analysis of the myotilin gene. Results: Both symptomatic patients, aged 76 and 61 years, presented with late-onset, distal lower-limb weakness involving the ankle and toe flexo-extensor muscles extending up to the thigh muscles; there was mild weakness of the intrinsic hand musculature in the eldest patient. Electromyography revealed a myopathic pattern. Serum creatine kinase levels were slightly elevated. Muscle biopsy revealed myopathic changes with myotilin- and desmin-positive aggregates. Gene sequencing identified a myotilin S55F mutation. In both patients, MRI showed moderate to severe fatty atrophy of all four leg muscle compartments, extending up to the thigh musculature, mainly involving the biceps, femoris, semimembranosus, vasti and glutei muscles; intrinsic foot musculature was involved but to a lesser degree. In all six gene mutation carriers, aged from 21 to 63 years, clinical examinations showed no myopathic signs. MRI was normal in the youngest individual, whereas in the remaining five individuals the outstanding finding was fatty infiltration of the soleus muscles. Conclusions: Myotilin S55F mutations may cause a clinically distinct autosomal-dominant late-onset and lower-limb distal myopathic syndrome involving all four leg muscle compartments. MRI helps to reliably depict the topography of fatty muscle atrophy and to detect early leg muscle changes in asymptomatic gene mutation carriers. Myotilin is a recently identified Z-disc component that interacts with other major Z-disc filamentous molecules. 12 Seven missense mutations in the myotilin gene (MYOT) have been reported so far, which are all located in the same region of the gene—the serine-rich exon 2. 3–8 Currently known disorders associated with these mutations include autosomal-dominant limb girdle muscular dystro- phy type 1A (LGMD1A) and a subgroup of either sporadic or familial myofibrillar myopathy. In familial myotilinopathies, the definition of clinical phenotypes has usually been based on the study of the corresponding proband patients. The purpose of this paper is to further refine the clinical phenotype in a three-generation autoso- mal-dominant pedigree with distal myopathy due to the MYOT S55F mutation. PATIENTS AND METHODS Patients The pedigree of the family is shown in figure 1A. Prior to genetic testing, two patients and their 10 at-risk asymptomatic adult descendants or rela- tives were examined. The hospital ethics commit- tee approved the study. Patient consent was obtained to take and publish the pictures. Electrophysiological study and muscle biopsy Electrophysiological study and muscle biopsy were performed as reported elsewhere. 9 10 MRI study All magnetic resonance imaging (MRI) studies were performed following the protocol reported elsewhere. 11 Increase of the T1 signal intensity in the muscle belly due to fatty infiltration was estimated in a semi-quantitative manner, 12 adapted to MRI specifications: stage 0 = no evidence of fatty infiltration; stage 1 = some fatty streaks; stage 2 = fat evident but less extensive than muscle; stage 3 = fat equal to muscle; and stage 4 = fat more extensive than muscle. The distribu- tion of these changes along the longitudinal axis of leg muscles was specifically analysed. We consid- ered that there was: a positive gradient when fatty infiltration increased distally throughout the long axis of the muscle belly; absence of a gradient when muscle signal was similar proximally and distally; and an inverse gradient when fatty infiltration predominated proximally. Mutation analysis With informed consent, mutation analysis of MYOT was performed by PCR sequencing of the coding exons on genomic DNA of the patients. RESULTS Clinical data The proband (case II-3 in fig 1A) is a 76-year-old man evaluated yearly since 1996. He had slowly progres- sive leg weakness since the age of 50 years, which consisted of ankle twisting and stumbling. Initial examination revealed atrophy of the right calf muscles (fig 1B, C) and gait steppage; muscle power was MRC grade 3/5 for ankle flexo-extensors and 4– 5/5 for thigh musculature. On his most recent examination, there was thigh and leg muscle atrophy (fig 1D, E), gait only being possible with support combining bilateral steppage and waddling. There was almost complete paralysis (0–2/5) of ankle flexo- extensors and evertor-invertor muscles, and toe flexo-extensor muscles with power preservation Short report J Neurol Neurosurg Psychiatry 2008;79:205–208. doi:10.1136/jnnp.2007.125435 205