RARE DISEASES DOCUMENTATION

AND RESEARCH

STAFF

Head Erica DAINA, M.D.

Genetics for Clinical Research Head Elena BRESIN, M.D. Network Development for Rare Diseases Head Sara GAMBA, Research Nurse

CURRICULA VITAE

Erica Daina got her degree in Medicine at the University of Milan in 1987 and the specialisation in Medical Nephrology in 1990 at the same University. She performed her training at the II° Medical Division - San Raffaele Hospital - Milan, and at the Division of Nephrology and Dialysis - Riuniti Hospital - Bergamo. In March 1988 she started her collaboration with the Mario Negri Institute and since June 1993 she works as full-time clinical researcher at the Clinical Research Center for Rare Diseases Aldo e Cele Daccò. 1996 – 2009: Chief, Information Center for Rare Diseases June 2009: Chief, Laboratory of Rare Diseases Documentation and Research Areas of interest: Rare diseases, Takayasu’s Arteritis, Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura, genetic kidney diseases. Selected publications

1. Daina E, Noris M, Remuzzi G. Eculizumab in a patient with dense-deposit disease. The New England journal of medicine, 2012 Mar;366(12):1161-3

2. Warnock DG, Daina E, Remuzzi G, West M. Enzyme Replacement Therapy and Fabry Nephropathy. Clin J Am Soc Nephrol, 2010 Feb;5(2):371-8

3. Bresin E, Gastoldi S, Daina E, Belotti D, Pogliani E, Perseghin P, Scalzulli PR, Paolini R, Marcenò R, Remuzzi G, Galbusera M. Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies. Thromb Haemost 2009; 101(2):233-8

4. Schieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet. 2008 Jun 14;371(9629):2039-41.

5. Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship T H J, Remuzzi G, International Registry Recurrent Familial HUS/TTP. Outcome of renal transplantation in patients with non-Shiga toxin-associated Hemolytic Uremic Syndrome: Prognostic significance of genetic background. Clinical Journal American Society Nephrology 2006; 1: 88-99

Elena Bresin got her degree in Medicine at the University of Padua in 1994 and the specialisation in Medical Genetics at the University of Verona in 2000. She performed her training at the Department of Pediatrics of the University Policlinic of Padua, then at the Department of Biology and Genetics of the University Policlinic of Verona and since 2000 at t the Clinical Research Center for Rare Diseases Aldo e Cele Daccò. Since January 2001 she works as full-time clinical researcher at the Clinical Research Center for Rare Diseases Aldo e Cele Daccò and since June 2009 she is Unit Head of Genetics for Clinical Research. Areas of interest: thrombotic microangiopathies, membranoproliferative glomerulonephritis, familial focal segmental glomerulosclerosis. Selected publications

1. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype. Clin J Am Soc Nephrol, 2010; 5(10):1844-59

2. Bresin E, Gastoldi S, Daina E, Belotti D, Pogliani E, Perseghin P, Scalzulli PR, Paolini R, Marcenò R, Remuzzi G, Galbusera M. Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies. Thromb Haemost 2009; 101(2):233-8

3. Castelletti F, Donadelli R, Banterla F, Hildebrandt F, Zipfel PF, Bresin E, Otto E, Skerka C, Renieri A, Todeschini M, Caprioli J, Caruso RM, Artuso R, Remuzzi G, Noris M. Mutations in FN1 cause glomerulopathy with fibronectin deposits. Proc Natl Acad Sci U S A 2008 Feb 19;105(7):2538-43

4. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: the impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006;108(4):1267-79

5. Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship T H J, Remuzzi G, International Registry Recurrent Familial HUS/TTP. Outcome of renal transplantation in patients with non-Shiga toxin-associated Hemolytic Uremic Syndrome: Prognostic significance of genetic background. Clinical Journal American Society Nephrology 2006; 1: 88-99

Sara Gamba got her Nurse Diploma on 1994 at Bolognini Hospital Nurses School, Seriate (Bergamo). Educational training: Clinical Research Nurse Diploma on 1996 at IRFMN – Daccò Center. First Level Master on Clinical Research at Milan University on 2008. Areas of interest: rare diseases studied by the Laboratory staff. She is involved with the Italian rare diseases patients’ Associations and she coordinates the documentation service addressed to the patient with rare conditions, their relatives and the health care professionals. Employment: In 1997-2003 she was involved as co-organizing, speaker, co-speaker and tutor for the Clinical Research Course for Nurses at IRFMN – Daccò Center. Since 2009 she is Chief of the Unit Network Development for Rare Diseases. From 2005 she collaborates for training of students that partecipate at the First Level Master in Clinical Research - Milan University.

Since 2007, she collaborates with Turin University for lessons to the students of the Second Level Master in Rare Diseases. Selected publications

1. M. Noris, J. Caprioli, E. Bresin, C. Mossali, G. Pianetti, S. Gamba, E. Daina, C. Fenili, F. Castelletti, A. Sorosina, R. Piras, R. Donadelli, R. Maranta, I. van der Meer, E.M. Conway, P.F. Zipfel, T.H. Goodship, G. Remuzzi. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010 Oct;5(10):1844-59

2. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: the impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006;108(4):1267-79

3. Krulichova I, Gamba S, Ricci E, Garattini L on behalf of the Italian Takayasu Arteritis Study Group. Direct medical costs of monitoring and treating patients with Takayasu arteritis in Italy. Eur J Health Econ Vol. 49, August 2004

4. Noris M, Brioschi S, Caprioli J, Todeschini M, Porrati F, Gamba S, Remuzzi G for the International Registry of Recurrent and Familial HUS/TTP. Familial haemolytic uraemic syndrome and an MCP mutation. The Lancet, Vol. 362, November 8, 2003

5. Gamba S, Cicci L, Stefanov R. Qualità della vita in pazienti con malattie rare:l’esperienza degli infermieri del Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò. Assistenza Infermieristica e Ricerca, Vol. 22, N. 3, July-September 2003.

ACTIVITIES

Rare Diseases (RD) represent about ten percent of all human medical illnesses and infirmities. It is difficult to define what exactly is intended as a RD. The US Congress in the Orphan Drug Act has given the first definition in 1983. Under this law it is considered rare a disease that affects less than 200 000 Americans (prevalence 0.75 per 1 000). The European Parliament adopted a more strict definition; they consider rare a condition that affects not more than five individuals per 10 000 in the European Community (prevalence 0.5 per 1 000). According to the WHO, there are 5-7 000 rare diseases and most of them (about 4 000) are of genetic origin. Rarity often brings a difficult and/or late diagnosis, and represents a difficulty in implementing experimental and clinical research studies. RD comprehend heterogeneous groups of diseases and often require a multidisciplinary approach. The greatest barrier to prevention, diagnosis and treatment of RD is inadequate knowledge. Once a diagnosis of RD is made, a major complaint of patients and of those involved in their care is the difficulty to obtain pertinent information about causes, symptoms and either established or experimental treatments. Often, patients with RD are willing to participate in clinical studies, but they do not know where and how, and physicians or health authorities are seldom able to help them. RD is not a very attracting field for basic and clinical investigators for several reasons: it is difficult to find adequate animal models for many rare disorders; clinical trials may require more patients than available; financial support is insufficient. Few countries have a central body or system to disseminate information on RD. Accurate information on the incidence and prevalence of RD is extremely important for both basic and clinical investigators. Invaluable help to research advances in RD would come from the availability of registries and databases containing diagnostic, clinical and biological data of patients with rare disorders. The Laboratory has been established whit the aim to collect different skills to support patients with rare diseases. Since the beginning of the activities, a Database for rare diseases was created with updated information for patients, their families and professionals. Specific research projects has been developed for some rare conditions such as familial and recurrent forms of Hemolytic Uremic Sindrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP), Fabry disease, Alport Syndrome, Takayasu arteritis, hereditary nephrotic syndromes. During the years the Laboratory role has changed, because of the major attention on rare diseases developed at the Institutional level. In 2001 it has been nominated Coordinating Centre of the Regional Network for Rare Diseases in the Lombardy Region, an area of 9 million people in Northern Italy. As Coordinating Centre, it is also working with the National Centre of Rare Diseases at Istituto Superiore di Sanità in Rome. All the information regarding the activities of the Coordinating Centre are available at the web site: http://malattierare.marionegri.it In 2009 the Genetics for Clinical Research Unit was established with the aim to support research projects on hereditary rare diseases ongoing at the Daccò Centre, through a close collaboration with the Laboratory of Immunology and Genetic of Rare Diseases and Organ Transplantation and the Laboratory of Cell Biology and Xenotransplantation – Negri Bergamo.

The Network Development for Rare Diseases Unit (also established in 2009) represents a suitable tool for the enhancement of collaborations already activated in the past years and for the development of new network on rare diseases. In addition, very relevant are the collaborations with Italian patients’ organisations and whit national (UNIAMO-FIMR) and international (NORD, EURORDIS) Federations for rare diseases. Moreover, particular attention is dedicated to keep up-to-date documentation and scientific bibliography on rare diseases. An help-line service to the public it is also maintained.

MAIN FINDINGS The database of the Information Centre for Rare Diseases contains data about 11769 patients affected by 928 different rare disorders. In the Bank of biological materials, samples from 2175 patients with rare conditions and their families have been collected. The Centre has established contacts with 364 Italian Associations for rare diseases. It was even possible that patients with 89 different rare diseases - for which no Associations have been established in Italy yet - to meet among themselves. In December 2001 (Delibera della Giunta Lombarda n. 7328), the Centre was identified as "Coordinating Centre of the Regional Network for Rare Diseases". The Laboratory coordinates the International Registry of Recurrent and Familial Hemolytic Uremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP), since 1996. The research projects developed in collaboration with the Laboratory of Immunology and Genetic of Rare Diseases and Organ Transplantation and with the Laboratory of Cell Biology and Xenotransplantation, have allowed to better comprehend the pathogenesis of these diseases. The Laboratory coordinates the Italian Registry of Membranoproliferative Glomerulonephritis and the Registry of Steroid-Resistant Nephrotic Syndrome.

NATIONAL COLLABORATIONS

Italian National Institute of Health Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare - Struttura Complessa a Direzione Universitaria di Immunologia Clinica, Torino Coordinamento Interregionale delle Malattie Rare del Piemonte e della Valle d’Aosta Riuniti Hospital, Bergamo Assessorato alla Sanità, Lombardia Region University of Turin, School of Clinical Pathology, Faculty of Medicine and Surgery Italian Network for Promotion of Folic Acid to Prevent Birth Defects University of Turin, Department of Experimental Medicine and Oncology, 2nd Level Master in Rare Diseases Italian Society of Neonatology (Lombardy section), Rare Congenital Respiratory Diseases Study Group University of Milan, 1st Level Master in Clinical Research “BergamoScienza” Association AO Niguarda Cà Granda, Milan, Nursing course degree

INTERNATIONAL COLLABORATIONS

EURenOmics: European Consortium for High-Throughput Research in Rare Kidney Diseases – Coordinator: Heidelberg University Hospital, Germany

Podonet: Consortium for Clinical, Genetic and Experimental Research into Hereditary Diseases of the Podocyte – Coordinator: Heidelberg University Hospital, Germany Information Centre for Rare Diseases and Orphan Drugs – ICRDOD, Bulgaria

EDITORIAL COMMITTEE MEMBERSHIP

Quaderni di Farmacoeconomia

NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP

Network for Rare Diseases – Lombardy Region (Delibera Regione Lombardia N°7328, 11/12/2001) Working group “Classification and coding of rare diseases” coordinated by Italian National Institute of Health Working group “National Registry of Rare Diseases” coordinated by Italian National Institute of Health Working group “Indipendent Research” (DG Sanità – Lombardy Region) Working group “Biobanks for diagnosis and research” (DG Sanità – Lombardy Region)

EVENT ORGANIZATION

Open Day: information, research and treatments A journey dedicated to rare diseases Ranica, (Bergamo) february 27, 2012

Thrombotic microangiopathies: from research to clinical practice Ranica (Bergamo), may 05, 2012

CONFERENCE AND WORKSHOP CONTRIBUTIONS

15° Convegno Patologia Immune e Malattie Orfane 2012 Torino, january 19-22, 2012 Corso elettivo: La rete per le malattie rare Milano, january 24, 2012 Corso elettivo: La rete per le malattie rare Milano, january 26, 2012 Updates sulle malattie metaboliche Cerro Maggiore (Milano), january 28, 2012 Il Registro Nazionale e i Registri Regionali ed Interregionali delle Malattie Rare Roma, february 21-22, 2012 Quinta Giornata Internazionale delle Malattie Rare: promuovere la solidarietà Milano, february 29, 2012 La Sclerosi Laterale Amiotrofica: dalla ricerca alla terapia Bergamo, march 24, 2012 Symposium: Le Malattie Rare incontrano gli Operatori Sanitari Cortona (Arezzo), april 21, 2012

VI Congresso sulle Neurofibromatosi Bergamo, april 27-28, 2012 Giornata Nazionale sulla Malattia di Behçet Reggio Emilia, april 28, 2012 Aggiornamento in tema di Malattie Rare e Pubertà Precoce Prabiago (Milano), may 05, 2012 Hesperis Course - ESOT: European Society for Organ Transplantation Bergamo, may 8 – 13, 2012 6th European Conference on Rare Diseases & Orphan Product Brussels, Belgium, may 23-25, 2012 Incontro Nazionale Associazione Italiana Linfangioleiomiomatosi (LAM) Milano, june 09, 2012 Le Malattie Rare nella ASL Milano1: epidemiologia, diagnosi precoce e percorso assistenziale Parabiago (Milano), june 16, 2012 Working group on Inherited kidney disorders meeting Parigi, july 10-11, 2012 World Regions Forum, WRF Task force, Rare Diseases Cancer Care Biobank Milano, september 12, 2012 Agilent Genomic User Meeting Milano, september 20, 2012 53° Convegno Società Italiana di Nefrologia SIN Milano, october 03-06, 2012 EPIRARE 2012: International Workshop Rare Diseases and Orphan Drugs Roma, october 08-09, 2012 XXIV International Complement Workshop Creta, 10-15 Ottobre 2012 American Society of Nephrology ASN – Kidney Week San Diego (California), october 30-november 5, 2012 Giornata di formazione sulle malattie rare Mantova, november 10, 2012 Milano Pediatria Milano, november 15-18, 2012 Congresso Nazionale di Linfologia Oncologica Milano, november 16-17, 2012 Congresso SIGU Milano, november 21-24, 2012 Seminario sul tema Malattie Rare

Milano, november 26, 2012

Approccio alla gestione organizzativa delle malattie rare Mantova, november 28, 2012 Festival della scienza Genova, november 30, 2012

GRANTS AND CONTRACTS

Fondazione Aiuti per la Ricerca sulle Malattie Rare - ARMR, Bergamo Lombardy Region Telethon Foundation ASL provincia di Bergamo

SCIENTIFIC PUBLICATIONS (2012)

Daina E, Noris M, Remuzzi G Eculizumab in a Patient with Dense-Deposit Disease N Engl J Med ,2012 Mar 22;366(12):1161-3 Benigni A, Orisio S, Noris M, Iatropoulos P, Castaldi D, Kamide K, Rakugi H, Arai Y, Todeschini M, Ogliari G, Imai E, Gondo Y, Hirose N, Mari D, Remuzzi G Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity Age (Dordr). 2012 May 9, Epub Iatropoulos P, Daina E, Mele C, Maranta R, Remuzzi G, Noris M Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation Pediatr Nephrol. 2012 Oct;27(10):1989-93 Gnappi E, Allinovi M, Vaglio A, Bresin E, Sorosina A, Pilato F, Allegri L, Manenti L Membrano-proliferative glomerulonephritis, atypical hemolytic uremic syndrome, and a new complement factor H mutation: report of a case Pediatr Nephrol. 2012 Oct; 27(10):1995-9 Prestidge T D, Rurali E, Wadsworth L, Wu J K, Moore J C, Bresin E Congenital thrombotic thrombocytopenic purpura (cTTP) with two novel mutations Pediatr Blood Cancer. 2012 Dec 15; 59(7): 1296-8 Ertoy Baydar D, Kutlugun AA, Bresin E, Piras R A Case of Familial Glomerulopathy With Fibronectin Deposits Caused by the Y973C Mutation in Fibronectin. Am J Kidney Dis. 2012 Dec 5, Epub

OTHER PUBLICATIONS (2012)

Gamba S, Carrara P Percorsi diagnostici, terapeutici e assistenziali (PDTA) per i malati rari: l'esperienza della Rete lombarda Notiziario ISS, Volume 25, Numero 3 - Supplemento 2 - 2012

RESEARCH ACTIVITIES

Bank of biological samples and description of hereditary nephropathies The aim of this project is to collect clinical data and biological samples from patients and their families with rare genetic conditions. A database with clinical data and a Bank for biological samples collection and preservation has been created. The availability of clinical data and biological samples is useful to perform new biochemical and genetic tests within specific research projects aimed to better reveal the mechanisms of the diseases, their manifestation and therapeutic opportunities. In particular, the attention is focused on rare genetic disorders of the kidney. A thorough clinical evaluation, including clinical data collection, medical physical examination, renal ultrasonography, laboratory tests of blood and urine is offered to patients, affected by hereditary nephropathies (Alport syndrome, Fabry disease, Familial Focal Glomerulosclerosis, Glomerulopathy with Fibronectin deposits, Membranoproliferative glomerulonephritis, Medullary Cystic Kidney disease, Cystinuria), who are addressing our Centre. After obtaining a written informed consent, biological samples from patients and their relatives are collected, labelled with specific codes to assure the anonymity and conserved in the Bank for biological samples. In case the responsible gene for a hereditary nephropathy is known (Alport syndrome, Fabry disease, Medullary Cystic Kidney disease, Cystinuria), the blood samples are redirected to the relevant Laboratory of reference. For other nephropathies, where the identification of the gene mutation is unknown or still in course, the blood samples are conserved with the aim to be used in specific future research projects. International Registry of Recurrent and Familial Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura Hemolytic Uremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP) are two closely related rare diseases characterized by microangiopathic hemolytic anemia and thrombocytopenia with signs of renal (most prevalent in HUS) and cerebral (most prevalent in TTP) damage. An even more rare subset of these diseases (called atypical forms, approximately 10% of all forms) are familial and are characterised by frequent relapses, leading to permanent renal and neurological sequelae. In these familial and recurrent forms of HUS and TTP, the attention is concentrated mainly on the genetic predisposition to the disease. Since 1996 the Laboratory coordinates the ‘International Registry of Recurrent and Familial HUS/TTP’, with the following aims: to collect clinical data of patients and their relatives; to study genetic and biochemical abnormalities of HUS/TTP; to provide up-to-date information to physicians and families; to explore new therapeutic approaches. Clinical and laboratory data of all patients referred to the Registry are collected by a dedicated Case Report Form. The family history and also the personal data of the unaffected relatives are also recorded, when possible. Biological samples are collected from all patients and available relatives, for the biochemical and genetic analyses. All participants receive detailed information on the purpose and design of the study and give their informed consent. Genetic counselling is also provided to patients and relatives, when appropriate. Through this Registry, data of about 920 patients (725 cases of atypical HUS; 195 cases of TTP) referred from around 100 Italian and 80 European and extra-European Centres have been collected. Many research projects are in collaboration with the Laboratory of Immunology and Genetic of Rare Diseases and Organ Transplantation and the Laboratory of Cellular Biology and Xenotransplantation – Kilometro Rosso. Molecular analyses have demonstrated that a genetic predisposition in complement regulatory factors (Factor H, Factor I, Membrane Cofactor Protein, Complement factor C3, Factor B, Thrombomodulin) accounts for the majority of atypical HUS and provided a detailed description of both known and new mutations and polymorphisms involved in sporadic and familial forms. These studies provided data showing that clinical phenotype, response to treatment, and long-term outcomes are predicted by individual gene abnormalities. They also supported the rationale for new therapies such as preemptive plasma exchange, combined liver–kidney transplantation and eculizumab treatment to efficiently prevent or treat disease recurrences of atypical HUS. The maintenance of a centralised bank of biological samples ensures the availability of clinical material for new investigative approaches as they will be developed. Another particularly significant result is represented by the possibility to identify TTP patients at risk for recurrence and effectively provide pre-emptive rituximab treatment. Since 2012, the Registry participates also to EURenOmics, the European Consortium for High-Throughput Research in Rare Kidney Diseases.

MA.RES.CO.: Congenital Respiratory Malformations database The Project originated from the collaboration between the Italian Society of Neonatology (Lombardy section) and the Regional Coordinating Centre for Rare Diseases. The MA.RES.CO (Congenital Respiratory Malformations) Database is conceived to facilitate the diagnostic and assistance procedures for pediatricians facing with respiratory malformations. For each syndrome a description is available with indications about Reference Centres. A link with the OMIM database is also provided. The Database is available at the web site of the Regional Coordinating Center for Rare Diseases: http://malattierare.marionegri.it/ Identification of new genes associated to Steroid-Resistant Nephrotic Syndrome Steroid-Resistant Nephrotic Syndrome (SRNS) is an uncommon cause of chronic renal disease (consisting of massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia) that affects 3−4 of every 100,000 children under the age of 16 and accounts for about 30% of primary forms of glomerulonephritis in adults. SRNS cases are thought to be caused by a primary defect in the glomerular filtration barrier, since do not respond to immunosuppressive therapy (the first-line treatment in NS). Patients with SRNS have an unfavourable prognosis and usually develop end stage renal disease (ESRD) within 10 years from the onset. Minimal Change Disease (MCD) accounts for around 90% of cases; the remaining ones are mostly diagnosed as Focal Segmental Glomerulosclerosis (FSGS), while rarely as Diffuse Mesangial Sclerosis (DMS). In some cases of SRNS, a familial form of IgA Nephropathy can also be recognized. In a subgroup of cases of SRNS, a rare form of glomerulopathy with fibronectin deposits (GFND) can also be diagnosed. Besides isolated SRNS, several syndromes characterized by SRNS with associated extra-renal manifestations have been describes, as Denys-Drash syndrome, MYH9-related disorder, and Renal-Coloboma syndrome. In literature, SRNS is defined as familial when at least two members of the same family are affected by the disease. Among familial forms of SRNS, both autosomal recessive and dominant inheritance patterns have been reported. The autosomal dominant form of SRNS is generally less severe and patients present at a later age (usually in adulthood) than with the autosomal recessive form. Genetic studies have shown that mutations in genes encoding proteins important for the podocyte homeostasis and function can cause SRNS (NPHS1, NPHS2, PLCE1, MYO1E PTPRO, LAMB2, CD2AP, INF2, ACTN4, TRPC6, WT1, and ARHGAP24). Mutations in these genes are found in about 60% of childhood-onset patients and in about 20% of adolescent- or adult-onset patients. Since 2007 the Laboratory coordinates an International Registry dedicated to SRNS, with the following aims: to collect clinical data of patients and their relatives; to study genetic abnormalities of SRNS; to provide the best therapeutic approach for each patient. Clinical and laboratory data from patients with SRNS and available unaffected relatives are collected by a dedicated Case Report Form and re-evaluated by a multidisciplinary team with expertise in rare diseases. Biological samples are stored from all participants. All participants receive detailed information on the purpose and design of the study and give their informed consent. Genetic counselling is also provided to patients and relatives, when appropriate. Data and biological samples of 165 patients (101 sporadic cases and 64 familial cases belonging to 29 unrelated families), referred from 15 Italian and 4 international Nephrology Units, have been collected. Thirty-seven out of 165 present extra-renal manifestations. After clinical data re-evalutation by the multidisciplinary team, 7 patients referred as affected by isolated SRNS received another diagnosis (4 Alport syndrome, 2 Denysh-Drash syndrome and 1 renal-coloboma syndrome). So far, the genetic cause of the disease has been identified in about 17% of the overall patients. INF2 (6.3%), WT1 (7.7%) and PLCE1 (7.5%) were the genes most frequently affected in our cohort. Further mutations in NPHS2 and CD2AP have been found in familial and sporadic cases. A novel mutation in PAX2 was identified in two monozygotic twin sisters affected by renal coloboma syndrome but presenting discordant phenotypes (renal signs in one and optic disc abnormalities in the other), attributed to hypothetical environmental factors or modifier genes. Finally, linkage studies followed by next-generation sequencing on a family recruited through the Registry have allowed the identification of MYO1E (which encodes for myosin 1E) as FSGS causing gene. The establishment of the SRNS Registry allows a better characterization of the patients. A great number of SRNS patients has been recruited increasing the potential to perform epidemiologic, genetic and clinical studies. The Registry participates also in PodoNet, a European research consortium funded under E-Rare first joint call for podocyte affecting diseases, that follows 1469 patients from 34 different countries.

The Registry of Rare Diseases of Lombardy The Registry of Rare Diseases of Lombardy has the objectives of providing information for health planning, monitoring and studying the epidemiology of Rare Diseases. The Registry collect demographic, public assistance and clinical information. Data are collected by specialists of the Reference Centres of the Rare Diseases Network; at present the implementation of the Registry is web-based using a specific software called “Sistema Malattie Rare”. The Coordinating Center is in charge of Registry management which consists in analyzing data and sending “minimum dataset” (data required by the National Registry of Rare Diseases) to Istituto Superiore di Sanità. On 31 December 2012, the Registry contains 20740 records of diagnosis of rare disease. The Registry of Rare Diseases of Lombardy represent a remarkable resource for the study of epidemiology and health planning for rare diseases. Periodic Review Reports has been implemented and are available at the Coordinating Centre web site (http://malattierare.marionegri.it). Complement abnormalities in primary Membranoproliferative glomerulonephritis Primary membranoproliferative glomerulonephritis (MPGN) is a rare form of chronic renal disease that occurs principally in children and young adults, and that frequently progresses to end-stage renal disease. The term MPGN refers to a pattern of glomerular injury with characteristic histopathologic findings. Distinct types of MPGN have been described based on immunofluorescence staining, ultrastructural appearance, and complement profiles: type I MPGN, the most common variant; type II MPGN, also called Dense Deposits Disease (DDD), the rarest variant; type III MPGN; C3 glomerulonephritis (C3GN). Since 2006, the Laboratory coordinates the 'Italian Registry of Primary Membranoproliferative Glomerulonephritis’, with the following aims: to collect clinical data of patients with MPGN; to study the genetic and biochemical abnormalities of MPGN; to provide the best therapeutic approach for each patient. Clinical and laboratory data from patients with MPGN are collected by a dedicated Case Report Form. The family history is also recorded and biological samples are stored from all patients to perform biochemical and genetic analyses. All participants receive detailed information on the purpose and design of the study and give their informed consent. Genetic counselling is also provided to patients and relatives, when appropriate. More than 130 cases of MPGN (age 1-80 years) have been referred to the Registry from 20 Units of Nephrology: 34 patients with type I MPGN, 28 with type II, 4 with type III, 18 with C3GN, 35 with undefined MPGN, 13 with overlapping MPGN and thrombotic microangiopathy. Persistently low C3 levels have been recorded in most patients, including all MPGN types; nephritic factor C3NeF (an antibody binding the C3-convertase) was positive in 40%. Mutations in complement genes encoding Factor H (CFH, 5.3%), Factor I (CFI, 3.1%), Membrane Cofactor Protein (MCP, 1.3%) and Complement factor 3 (C3, 1.5%) have been identified in 12% of MPGN patients. Ongoing studies, in collaboration with the Laboratory of Immunology and Genetic of Rare Diseases and Organ Transplantation, are focused on functional consequences of complement genetic abnormalities and in searching for new gene mutations/variants that may be involved in the predisposition to MPGN. Candidate genes are those encoding proteins of the complement system, due to the evidence that MPGN is a disease of complement hyperactivation. Increased levels of the terminal complement complex sC5b-9 have been also found in around 40% of the evaluated patients. This marker of complement activation should be potentially used to identify patients who could benefit from treatment with Eculizumab, a humanized monoclonal antibody that binds to complement factor C5 and inhibits the generation of the terminal lytic complement complex. In this regard, among patients with MPGN who have been recently treated with Eculizumab, a good clinical response was observed in two patients from the Registry who showed high levels of sC5b-9 before treatment and normalization thereafter. Thus, preliminary findings support a pathogenic role for complement dysregulation in the pathogenesis of MPGN and suggest that Eculizumab could be an effective treatment in the subgroup of MPGN patients with hyperactivation of the terminal pathway of complement. Since 2012, the Registry participates also to EURenOmics, the European Consortium for High-Throughput Research in Rare Kidney Diseases.