Acta Myologica • 2016; XXXV: p. 3-81 PROCEEDINGS OF THE XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY Lecce, Italy June 8-11, 2016 3 PROCEEDINGS OF THE XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY 5 PROCEEDINGS OF THE XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY 6 PROCEEDINGS OF THE XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY 7 PROCEEDINGS OF THE XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY 8 PROCEEDINGS OF THE XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY 9 PROCEEDINGS OF THE XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY 10 PROCEEDINGS OF THE XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY ABSTRACTS OF INVITED LECTURES (in alphabetical order of the first Author) Brain in muscle diseases ciency (CMD1A), also in the mildest cases with a LGMD Bertini E. phenotype. Moreover progressive brain MRI abnormali- Unit of Neuromuscular and Neurodegenerative Disorders, ties are observed in adult DM1 patients as white matter Laboratory of Molecular Medicine, Bambino Gesù Children’s involvement and brain atrophy, and some studies under- Hospital IRCCS, Rome line that WM damage is likely to be the major contributor It is well known that brain involvement is generally to cognitive impairment in DM1. unusual in muscle disease, and should be considered in the algorithm of the differential diagnosis of myopathies. Epigenetics in Myotonic Dystrophies Classification of brain involvement in myopathies, ex- Botta A. cluding mitochondrial encephalomyopathies, can be clas- Dept. of Biomedicine and Prevention, Tor Vergata University of sified for convenience in two main subgroups:1) those Rome, Italy conditions with mental disabilities that are not associated Myotonic dystrophy type 1 (DM1, Steinert’s disease, with brain malformations; and 2) those that are associated MIM#160900) is the most common form of adult-onset with malformations or peculiar brain abnormalities, and muscular dystrophy in humans, characterized by myoto- can be detected by MRI. nia, muscle weakness, cataract, cardiac disease and cen- The main neuromuscular disorders that show men- tral nervous system dysfunctions. The molecular defect tal disability without a brain malformations or distinctive underlying DM1 consists in the expansion of an unstable MRI abnormalities are dystrophinopathies, particularly CTG repetition located in the 3’UTR of the DMPK gene, occurring in 40-50% of boys affected by Duchenne mus- on chromosome 19q13. Given the emphasis on post-tran- cular dystrophy with mutations generally downstream scriptional mechanisms in DM1, only a few publications exon 44, which are associated with involvement of dys- discussed the role of epigenetic alterations in the disease, trophin isoforms expressed at high levels in brain. Moreo- either as a mechanism to explain repeat instability or as ver, another condition with high prevalence that is associ- the cause of altered expression of the DMPK transcript ated with mental disability is DM1. Besides typical motor itself. Additional complexity arises with production of symptoms, DM1 patients also display non-motor symp- an antisense transcript that initiates within the SIX5 ad- toms such as particular personality traits. Around 30% jacent promoter, producing a CAG-containing RNA able of DM1 patients seem to be at high risk of developing a to induce transcriptional silencing and heterochromatin psychiatric disorder. Moreover, psychological traits differ formation. In a recent study, we showed that in DM1 un- across phenotypes, with the most severe phenotype tend- ing to show more severe psychological symptoms. Some interrupted alleles, hypermethylation occurs only in the studies have shown that the presence of higher phobic upstream region of the CTG repeat, and this modifica- anxiety and lower self-esteem are associated with lower tion was present in patients with larger CTG expansion education, a higher number of CTG repeats, more severe (> 1000), earlier age at onset (< 18 years) and in con- muscular impairment, and lower cognitive functioning. genital DM1. The association of hypermethylation with In the subgroup of brain malformations or brain congenital or childhood onset forms, characterized by abnormalities, the classical conditions are congeni- severe cognitive manifestations, suggest that this epige- tal muscular dystrophies (CMDs) with abnormal gly- netic modification might affect the expression of genes cosylation of alpha-dystroglycan (Fukuyama CMD, regulating brain development and/or or synaptic plastici- Muscle-eye-brain disease, Walker-Warburg syndrome, ty. Conversely, in “atypical” DM1 patients carrying CCG/ CMD1C, CMD1D). The spectrum of brain structural CTC/CGG interruptions at the 3’ end of the CTG array, defects is wide, ranging from complete lissencephaly in hypermethylation occurs exclusively in the downstream patients with Walker-Warburg syndrome to isolated cer- region of the DM1 expansion. Our results suggest that ebellar involvement. Cerebellar cysts and/or dysplasia either the inherited size of the expanded allele and the and hypoplasia are also predominant features in patients presence of interruptions in the CTG array are associated with FKRP, POMGnT1 mutations, but rarely seen in with a highly polarized pattern of CpG methylation at the POMT1 and POMT2. Brainstem and pontine abnormal- DM1 locus. Additional studies on different DM1 tissues ities are common in patients with POMT2, POMGnT1, and eventually in DM2 patients will help to understand and LARGE mutations. Abnormalities of the white mat- the functional role of epigenetic modifications in the ter are characteristically seen in CMD with merosin defi- pathogenesis of myotonic dystrophies. 11 PROCEEDINGS OF THE XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY Myofibrillar myopathies ease (IOPD) is characterized by early generalized hypo- Comi G.P. tonia and severe cardiomyopathy with death within the Dino Ferrari Centre, Department of Pathophysiology and first year of life, infantile variant form shows slower pro- Transplantation (DEPT), University of Milan, Neurology gression and less severe cardiomyopathy but onset is in Unit, I.R.C.C.S. Foundation Ca’ Granda, Ospedale Maggiore the first year of life, childhood/juvenile variant is a heter- Policlinico, Milan ogeneous group presenting later than infancy and usually Myofibrillar myopathies (MM) are a heterogeneous without cardiomyopathy. group of diseases characterized by progressive muscle weak- The efficacy of enzyme replacement therapy (ERT) ness and common histological features, including abnormal with recombinant human GAA (rhGAA) had been shown accumulation of myofibrillar degradation products, the ec- in two studies demonstrating a clear improvement of car- diomyopathy and prolonged survival in all treated infants topic expression of intrasarcoplasmic proteins, the presence but it is clear that the early start yielding better results. of vacuoles, foci of myofibril dissolution and a disorganiza- ERT became commercially available only in 2006. A tion of the intermyofibrillar network beginning at the Z-disk. critical point became evident a few years later: patients The underlying mechanisms of the disease are still with high titer anti-rhGAA IgG antibodies had a worse unknown and can differ from a type of disorder to an- outcome than those with low-titers, and those having other. The main abnormalities observed in pathophysi- high titers were mainly CRIM (cross reactive immuno- ological studies include aggregation and decreased logic material)-negative. Aiming to improve response to elimination of abnormal mutant proteins. Severe clinical ERT in CRIM-negative IOPD, several immune tolerance patterns have been observed and six main genes (DES, induction strategies have been reported. CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are Italian data of 29 Italian treated IOPD patients and now classically considered as responsible for Myofibril- the long-term outcome are similar to that reported by lar myopathies. Other entities such as FHL1 myopathy or other national multicenter studies: a consistent number of Hereditary myopathy with early respiratory failure linked patients become ventilatory dependent on the long term to mutations of titin can now as well be included in this and many have a secondary loss of the previously reached group. Occasionally MM patterns have been described motor milestones, age and signs and symptoms at start of in laminopathies or selenopathies. Recently two genes, ERT and CRIM-negative status influenced negatively the HSPB8 and DNAJB6, have been associated to a myopa- outcome. thy with histologic features of MM with aggregates and We underline good outcome in childhood/juvenile rimmed vacuoles. HSPB8 and DNAJB6 are part of the patients with early diagnosis and start ERT. chaperone-assisted selective autophagy (CASA) com- GAA enzyme assay on dried blood spot (DBS) is plex. In these cases the molecular muscle pathology is ap- reliable, non-invasive and specific for early diagnosis in parently mediated through impaired CASA functions and symptomatic patient and in newborn screening programs possibly other complexes needed for the maintenance of (NBS). We have started a pilot NBS program for Pompe the Z-disk and sarcomeric structures. Next-generation se- disease in Tuscany and Umbria since 2014. quencing technology will expand our genetic knowledge. Oral chaperone therapy, modified rhGAA, autophagy The diagnosis of MFM is not always easy as histo- suppression and gene transfer represent potentially prom- logical lesions can be focal, and muscle biopsy may not ising