Studio multicentrico sulle Distrofie Muscolari dei Cingoli Telethon-UILDM

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Studio multicentrico sulle Distrofie Muscolari dei Cingoli Telethon-UILDM Centro Dino Ferrari, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, DEPT, UO Neurologia, Università di Milano

Collagene VI Laminina α2 LARGE ISPD POMGnT1 Complesso dei sarcoglicani α-dg POMT1 FKRP Fukutin Integrina Caveolina-3 Disferlina Sarcospan δ-sg β-sgα α-sg γ γ-sg β-dg Anoctamina-5 nnos Distrobrevina TRIM32 Distrofina Sintrofina Calpaina-3 Citoscheletro associato ad actina Sarcomero Teletonina Z I A M A I Miotilina α-actinina Actina Tropomiosina Tropomodulina PLEC1 Z ZASP Nebulina Miosina Titina Desmina DNAJB6 TPNO3 Emerina Lamina A/C Nucleo

Molecular classification Gene Gene location Protein Gene Gene location Protein LGMD 1A MYOT 5q31 Myotilin LGMD 1B LMNA 1q21.2 Lamin A/C LGMD 1C CAV3 3p25 Caveolin-3 LGMD1D DES 2q35 Desmin LGMD 1E DNAJB6 7q36 DnaJ homolog subfamily B member 6 LGMD 1F TNPO3 7q32 Transportin3 LGMD 1G HNRPDL 4p21 Heterogeneous nuclear ribonucleoprotein D- like protein LGMD 1H? 3p23-p25? 8 Autosomal Dominat (LGMD1) 23 Autosomal Recessive (LGMD2) 3% without a molecular diagnosis LGMD 2A CAPN3 15q15.1-q21.1 Calpain-3 LGMD 2B DYSF 2p13.3-913.1 Dysferlin LGMD 2C SGCG 13q12 γ-sarcoglycan LGMD 2D SGCA 17q12-q21,33 α-sarcoglycan LGMD 2E SGCB 4q12 ß-Sarcoglycan LGMD 2F SGCD 5q33 δ-sarcoglycan LGMD 2G TCAP 17q12 Telethonin LGMD 2H TRIM32 9q31-9q34 TRIM32 LGMD 2I FKRP 19q13,3 Fukutin Related Protein LGMD 2J TTN 2q24.3 Titin LGMD 2K POMT1 9q34.1 O-Mannosyl transferase-1 LGMD 2L ANO5 11p12-p13 Anoctamin-5 LGMD 2M FKNT 9q31-q99 Fukutin LGMD 2N POMT2 14q24 O-Mannosyl transferase-2 LGMD 2O POMGnT1 1p34 LGMD 2P DAG1 3p21 Protein O-mannose beta-1,2- N-acetylglucosaminyltransferase Dystrophin-associated glycoprotein LGMD 2Q PLEC1 8q24.3 Plectin LGMD 2R LAMA2 6q22 Merosin LGMD2S TRAPPC11 4q35 LGMD2T GMPPB 3p21 LGMD2U ISPD 7p21 Transport protein particle complex 11 GDP-mannose pyrophosphorylase B Isoprenoid synthase domain containing protein LGMD2V POMK 8p11.21 Protein O-mannose kinase LGMD2W PINCH2/LIMS2 2q14.3 Particularly interesting new cys-his protein 2

Clinical and laboratory network for LGMD diagnosis, in view of a national registry Telethon GUP16 Department of Neurological Sciences, I.R.C.C.S. Foundation Cà Granda Ospedale Maggiore Policlinico, University of Milan NeuroMuscular Unit-IRCCS E Medea Bosisio Parini, Department of General Pathology, University of Naples, Naples Telethon Institute of Genetics and Medicine, Naples IRCCS Fondazione "San Camillo" Hospital, Lido di Venezia Department of Neurosciences, University of Torino Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Messina Department of Neurological Sciences, Verona Department of Clinical and Experimental Medicine, University of Pisa Center of Myology and Neurodegenerative Diseases, Istituto Giannina Gaslini, Genova Department of Neurology, Policlinico Universitario A. Gemelli, University Cattolica del Sacro Cuore of Rome Department of Neurosciences, University of Padua IRCCS Fondazione Stella Maris, Calambrone, Pisa

Objectives Create a national registry of LGMD Italian patients Collect clinical data about neuromuscular, respiratory, cardiac, cognitive involvement Delineate natural history of each sub-group Define outcome measures Further investigate patients without molecular diagnosis

Patient Selection INCLUSION CRITERIA: 1. limb girdle and proximal upper and lower limb muscle weakness (Proximo-distal phenotypes may be included) 2. dystrophic pattern at muscle biopsy and/or 3. proven deficiency of LGMD proteins at IHC or WB analysis and/or molecular confirmation EXCLUSION CRITERIA: Limb Girdle syndrome with identified alternative etiology (inflammatory, metabolic myopathies, congenital myopathies, congenital myasthenic syndromes, SMA type II and III, FSH, dystrophinopathies, DM1, DM2 and mitochondrial myopathies)

Data collection Data collection ANAMNESTIC DATA Familiarity Onset CK values Muscular involvement (distribution) Tendon retraction Scoliosis MUSCLE BIOPSY Morphology IHC analysis WB analysis RESPIRATORY FUNCTION Spirometry Nocturnal saturimetry NIV FUNCTIONAL EVALUATIONS MRC Walton MFM 6MWT MOLECULAR ANALYSIS CARDIAC FUNCTION ECG Holter ECG Echocardiogram MAGNETIC RESONANCE Muscular MRI Brain MRI DATABASE containing retrospective and prospective data

LGMD National registry 599 LGMD patients Un-diagnosed 31% Heterozygous mutation in AR gene 7% Molecularly diagnosed 62% 188 undiagnosed patients 37 molecularly defined

LGMD registry 37 molecularly defined,3%,7% 5,6% 9,7% 5,2% Probands,3%,7% 4,2% 3,1% 1,%,3% 7,3%,3% 8,7% 2% 29.9% 22.6% 22,6% 29,9% LGMD1B LGMD1C LGMD1D LGMD2F LGMD2G LGMD2L LGMD2J LGMD2 POMT2 LGMD2 LAMA2 LGMD2 ISPD 3,7% 9,6%,5%,3% 5,6% 9,3% 4,5% Patients,3%,8% 1,3%,3% 22,6% 5,1% 1,6% 1,1% 24,5% Mean follow-up 17, ± 11,6 years

27 different mutations 128 in-frame 8 Molecular aspects 79 truncating N of mutations 7 6 5 4 3 2 1 12 7 5 5 4 17 8 3 46 29 1 1 2 3 3 12 1 7 1 3 4 Splice-site mutations Out-of-frame Del/Dup Nonsense In-frame Del/Dup Missense 4 1 3 9 5 1 2 3 LGMD1B LGMD1C LGMD2L No hot-spots Most frequent mutations: c.826c>a (p.leu276ile) exon 4 (FKRP) 23/38 alleles (6%) c.525delt (p. Phe175LeufsX2) exon 6 (SGCG) 8/22 (36%) c.85c>t (p.arg284cys) exon 7 (SGCA) 16/5 (32%) c.377_384dup (p.gly128glnfsx2) exon 3 (SGCB ) 9/3 (3%)

Muscle biopsy Connective Tissue Muscular biopsies performed 45 4 35 3 25 2 15 1 5 LGMD1B LGMD1C LGMD2L Necrosis Yes No Muscular biopsies performed Muscular biopsies performed 45 4 35 3 25 2 15 1 5 8 7 6 5 4 3 2 1 LGMD1B LGMD1C Severe increase Moderate increase Mild increase Normal LGMD2L Inflammation Yes No LGMD1B LGMD1C LGMD2L

Clinical evolution Age of onset 7 6 5 Age at onset (yr) 4 3 2 1 35,3 24,4 28, 16,7 1, 1,1 15,5 6,4 4, 18,1 17, 35, 36, 9,7 17, 5, LGMD1B LGMD1C LGMD1D LGMD2F LGMD2G LGMD2J LGMD2L LGMD2 POMT2 LGMD2 LAMA2 LGMD2 ISPD 3 25 2 Patients (n ) 15 1 5-1 yr 11-2 yr 21-4 yr > 4 yr LGMD1B LGMD1C LGMD2L

Clinical evolution CK levels 3 25 CK levels at onset (UI/L) 2 15 1 5 45 1624 4334 4899 4573 769 7462 3556 5314 LGMD1B LGMD1C LGMD2L CK levels (UI/L) Age (years)

Clinical evolution Loss of independent ambulation N patients 7 6 5 4 3 2 Loss of ambulation No Yes C LGMD1B LGMD1C 1 Age at loss of ambulation (yr) 7 6 5 4 3 2 1 39,9 43,1 26, 14,3 LGMD1D LGMD2F LGMD2L LGMD2 POMT2 LGMD2 LAMA2 LGMD2 ISPD 12,4 11, 48 55 LGMD2F LGMD2 LAMA2

A 6 5 Clinical evolution Cardiac involvement No Yes B 4 N patients 3 2 1 7 Age at onset of cardiac involvement 6 5 4 3 2 1 36,4 51, 4,5 41, 2,3 25,7 2,6 9, 31, LGMD1B LGMD1C LGMD2F

A 6 5 Clinical evolution Respiratory involvement No Yes B N patients 4 3 2 1 LGMD1B LGMD1C LGMD1D LGMD2F LGMD2L LGMD2N LGMD2R LGMD2S Age at onset of respiratory involvement 8 7 6 5 4 3 2 1 37,8 34,7 23,2 24,8 2,4 LGMD2F 14, 3,4 LGMD POMT2 16,

LGMD differential diagnosis Age at onset CK levels Ambulation loss Earlier onset in -2E, dystroglycanopathies Later onset and 2L High levels in, Low levels in LGMD1B, 1C Early in, 2E Late, 2B, 2C Cardiac involvement,, LGMD2F,, LGMD2M Respiratory involvement,, LGMD2M Muscle biopsy analysis LGMD1C, 2A, 2B, sarcoglycanopathies, dystroglycanopathies

LGMD national registry LGMD molecular epidemiology in Italy is extremely heterogenous. The relative frequency of the predominant LGMD types differs in Southern Europe from that other Northern countries Deacreasing the proportion of genetically undiagnosed cases is probably possible by Next Generation Sequencing. New common or rare pahogenetic pathways may emerge from this effort. Building an itemised disease natural history database for at least 3 different diseases (often with allelic early onset and late onset phenotypes) is a complex and time consuming task. Therapeutic trials involving this population are scarce and reflect into less attention paid to the data collection to establish a reference clinical database for these disorders.

What about?

B POPULATION 8,7% 4,2%,3%,7% 3,1% 1,%,3% 7,3%,3% 86 probands 92 patients F:M= 1.3/1,3%,7% 5,6% 9,7% 29.9% 29,9% Mean follow-up 18.8 ± 9.2 years 5,2% 22,6% Age ot last evaluation 37.1 ± 14.2 years

7% 16% Molecular aspects 5% 9% 63% Missense In-frame del Nonsense Splice-site Frame-shift Diagnostic clues 69% of mutations are located in exons 4,11,1,13,1,21,5,6 Most frequent mutations: c.55dela 6.8% c.1469g>a 6.1% c.2242c>t 4.5% Muscular biopsies performed 8 7 6 5 4 3 2 1 Bioptical aspects LGMD1B LGMD1C Connective Tissue Severe increase Moderate increase Mild increase Normal LGMD2L 1 patients without connective tissue increase (7 quadriceps femori) No correlation with age or disease duration Muscular biopsies performed 45 4 35 3 25 2 15 1 5 LGMD1B LGMD1C Protein analysis Inflammation LGMD2L Western-blot analysis: reduction in 57 patients, normal expression in 3 subjects Yes No

Clinical evolution 1 Age at onset 7 6 5 Age at onset (yr) 4 3 2 1 35,3 24,4 28, 16,7 1, 1,1 15,5 6,4 4, 17, 18,1 35, 36, 9,7 17, 5, Symptoms at onset 7 6 LGMD1B LGMD1C LGMD1D LGMD2F LGMD2G Onset of weakness 17.6 ± 11.8 years (range 1-51). LGMD2J LGMD2L LGMD2 POMT2 LGMD2 LAMA2 LGMD2 ISPD 5 4 3 2 1 < 1 years of age 3 pt (5%) 2 years of age 47 pt (75%) 2-4 years of age 12 pt (19%) > 4 years of age 4 pt (6%) Weakness HyperCKemia Weakness + cramps Cramps Familiarity

Clinical evolution 2 Distribution of muscular involvement 55 patients pelvic + shoulder girdle 8 patients pelvic girdle (4-75 years old, 3-3 years from onset) 3 patient early distal involvement Difficulties in postural changes 27/42 31.9 ± 15.9 years 17.2 ± 7. years from onset Loss of ambulation 2/65 31% mean age 39.9 ± 11.5 years Wheelchair-bound patients have earlier onset (15.4 ± 8.3 vs 19.6 ± 12.1 years) N patients 7 6 5 4 3 2 Loss of ambulation No Yes LGMD1B LGMD1C LGMD1D LGMD2F LGMD2L LGMD2 POMT2 LGMD2 LAMA2 LGMD2 ISPD 1

Clinical evolution 3 CK values 425 ± 3393 UI/L (range 217-153 ) Cardiac involvement 4/56 7% Mean age at onset 39 ± 22 years Onset respectively at 19, 2, 55 and 62 years of age Range 8-17 years from disease onset 2 patients with dilatative cardiomyopathy Furthermore 12 patients with rhythm alteration Respiratory involvement 11/53 21% Mean age at onset 37.8 ± 22.8 years Restrictive pattern Peculiar aspects Tendon retraction 29/51 64% Sural hypertrophy 15/49 pt Scoliosis 16/44

Thank you UO Neurologia - IRCCS Ca Granda Milano Prof. Bresolin, Prof. Comi, Dr. Magri, Prof. Corti, Dr. Govoni, Dr. Brusa, Dr. Del Bo, Dr. Ronchi, Dr Piga UOD Neuromuscolari, IRCCS Ca Granda, University Milan Prof Moggio, Dr. Sciacco, Dr. Colombo, Dr Peverelli, Dr Villa Ist. E. Medea Bosisio Parini Lecco Dr. D Angelo, Dr. Gandossini Dr. Brighina, Dr. Micoli Istituto Neurologico C. Besta- Milano Prof. Mora, Dr. Moroni, Dr Morandi, Telethon Institute of Genetics and Medicine (TIGEM) Napoli Prof. Nigro, Dr Savarese, Dr. Di Fruscio Dipartimento di Neuroscienze Padova,l Prof. Pegoraro, Dr. Semplicini Dipartimento di Neuroscienze Torino Prof. Mongini Dipartimento di Neuroscienze, Messina Prof. Toscano, Dr. Musumeci, Dr. Vita, Dr. Messina, Dipartimento di Scienze Neurologiche, Verona Dr. Tomelleri, Dr Tonin Centro di Miologia, Istituto Giannina Gaslini, Genova Prof. Minetti, Dr. Bruno Dipartimento di neurologia, Università Cattolica del Sacro Cuore, Roma Dr. Ricci, Dr. Monforte, Dr Tasca Dipartimento di Neuroscienze, Pisa Prof. Siciliano, Dr. Ricci IRCCS Fondazione "San Camillo" Prof. Angelini IRCCS Fondazione Stella Maris, Calambrone Dr. Fiorillo