La maladie de Barth – vu à travers l’expérience française

1. La maladie de Barth – vu à travers l’expérience française Jean Donadieu Hôpital Trousseau – Registre des neutropénies

2. 3 ans d’engagement Automne 2011 Printemps 2012 - mise en place de l’étude : Etat de l’art A need for a global approach Agreement between Reference centers : Mitochondriopathy / Hear disease/ Immune deficiency The french SCN registry offered an infrastructure A resident is available for a semester Patient’ association is sponsoring the study Summer 2012: data collection and analysis End 2012 – Early 2013: Publication /// Sept 2013 – working party – with Bristol group 2014 : guidelines in French / National consultation for Barth‘ patients in Paris

3. Barth syndrome: the challenge • Rare… extremely rare • Scattered • Multi systemic • Chronic disease • Not a single expert in France

4. Barth syndrome/ france • Existing competences • Cardiologists • Geneticians • Biochemists • Networks – national plan for rare diseases • Reference center for cardiac defect • Reference center for mitochondriopathies • Reference center for immune deficiency • Learning society for pediatric immuno hematology and for pediatric cardiology • Registry for chronic neutropenia • a parent’s association

5. Method • Observational, longitudinal, retrospective, multicentric survey • Patients: • who lived in France • Diagnosed between 1983 and 2012 • Complete diagnosis: TAZ Mutation • Presumptive: Cardiopathy and Neutropenia and * X-linked * Cardiolipid profile

6. Identification of cases • French SCN registry • Networks from learning society • Société d’hématologie et immunologie pédiatrique • Société de Cardiologie pédiatrique et congénitale • Networks of centre of refernces • Genetic laboratories (n=2) • Biochemistry / Necker • Request to pathologists in charge of Sudden death program • Patients’ association • Administrative data base: Death certificate / Organ transplantation / Discharge records

7. Data collection • ON SITE • Medical file / CBC / Echocardiography • Definition: Date of diagnosis = date of first symptoms • Diagnosis Echocardiography: the first within 3 months after date of diagnosis

8. Results - Logistic • Death certificate, Discharge records, Heart transplantation data base: No data ! • International Classification of Disease: neglects BtHS ! • A complex medical networks • 22 patients • 27 centers • 70 physicians

9. Demography: 22 patients 16 families • Gender : 21 male 1 female (XO) • Familial history : 2/3 • Median age At diagnosis = 3.1 weeks (p25:0 -p75:6,2) • Diagnosis first symptoms • Cardiomyopathy = 16 patients (73%) • Infection = 4 patients (18 %) • Failure to thrive 1 • Hypoglycemia at birth • No Metabolic coma • IUGR= 7 patients (32%) • Diagnosis • 18 Complete diagnosis TAZ mutated • 4 Presumptive • 3 siblings • 1 Biochemistry profile

10. Epidemiology • Incidence at birth = 1.5/million of birth (IC95%: 0.6 – 2.3) (or 1 / 700 000 birth) • Between 0 and 3 new cases/ year expected in France (850 000 birth/year) • Prevalence is difficult to extrapolate. Probably no more than 30 cases living in France / 60 millions inhabitants • About 200 cases in EU ?

11. Genetic • TAZ mutations: in 15 families out 16 • Among 13 mothers evaluated: • 9 carriers • 1 had proven somatic mosaicism

12. Hematological features • Initial • ANC value : 1.3 G/L (p25: 0.6- p75: 2.9) • 4 patients with ANC ≤ 0.5 G/L • Follow up : 8 CBC per patient • Median ANC : 0.98 G/L (p25: 0.69 – p75: 12.1) • 16 patients (72%) ANC ≤ 0,5 G/L at least ONCE • 2 patients (9%) médian ANC ≤ 0,5 G/L • Bone marrow : Rarely performed (n=2 )Myeloid maturation arrest

13. Hematological features • Follow up : 8 CBC per patient • Median ANC : 0.98 G/L (p25: 0.69 – p75: 12.1) • 16 patients (72%) ANC ≤ 0,5 G/L at least ONCE • 2 patients (9%) médian ANC ≤ 0,5 G/L

14. Hematological features • Follow up : 8 CBC per patient • Median ANC : 0.98 G/L (p25: 0.69 – p75: 12.1) • 16 patients (72%) ANC ≤ 0,5 G/L at least ONCE • 2 patients (9%) médian ANC ≤ 0,5 G/L

15. Hematological features • Initial • ANC value : 1.3 G/L (p25: 0.6- p75: 2.9) • 4 patients with ANC ≤ 0.5 G/L • Follow up : 8 CBC per patient • Median ANC : 0.98 G/L (p25: 0.69 – p75: 12.1) • 16 patients (72%) ANC ≤ 0,5 G/L at least ONCE • 2 patients (9%) médian ANC ≤ 0,5 G/L • Bone marrow : Rarely performed (n=2 )Myeloid maturation arrest • Heterogeneous usually NOT A DEEP NEUTROPENIA

16. Infections • 94 infectious events, • 10 severe in 5 patients (23%). • Median age at first severe infection was 3.7 months (range: 0.2–30.7 months). • 84 mild infections. • Recurrent stomatitis was observed in 1 patient • Mild infections are associated to heart failure

17. Heart • 91 % (n=20) with a symptomatic cardiomyopathy • 1 : never (till age of 12 years) • 1 dyed very early – septic shok / autospy revealed no cardiopathy • 54 hospitalisations for heart failure • 16 patients (73%) needed inotropic support, • 14 (64%) needed invasive ventilation • 11 (50%) were treated with both inotropic agents and invasive ventilation at least once • 4 on cardiac transplant list / 2 heart transplant • 9 death related to cardiomyopathy

18. Echocardiography/ Diagnosis data • 11 patients with valuable information • 6 dilated cardiomyopathy (DCM) and hypertrophy cardiomyopathy (HCM) • 2 had DCM only • 1 had HCM only

19. Echocardiography/ Longitudinal data Shortening fraction (SF) Functional myocardic parameters improve with time (>2-3 years)

20. Electro cardiography • Repolarisation abnormalities in 77 % of patients • QTc: 440 ms (p25: 420 – p75: 466) • No arythmia observed

21. Other results • Age at walk : 19 months ( p25: 18 – p75: 21,8) • Failure to thrive: - 50% weight < 3 SD - 50% height – 3 SD • Aciduria 3 – méthylglutaconic = 50% at diagnosis

22. Amino acid chromatography Low Arginine levels Blockage in the krebs cycle at isocitratre deshydrogenase step

23. Follow–Up Mortality • Median Age At last visit = 4.75 years (min: 2.17-max: 13.4) among 11 survivors • 11 death, median age: 5.1 months (min: 1.2 – max: 30.7)

24. Survival - risk factors • Neutrophil count: if ANC <0.5 G/L: - 1 year survival : 25% vs 68% - 5 year survival : 0 vs 62% • 9 /11 deaths related to heart failure almost always at the occasion of common viral infections • Medical management of heart failure ?

26. Conclusion of our study BTHS exists in France !

27. Conclusion for the diagnosis • Not so easy ! • The diagnosis has mainly to be considered in boys with very early heart failure • Do not excluded quickly the diagnosis of BTHS ! • Neonatalogist and general pediatricians Has to be involved in the diagnosis/ detection of cases

28. Conclusions.. No room for a randomized trial The best approach: The 2 first years are determinant ! Guidelines For physicians and general pediatricians IV Ig for BTHS babies before age of 2 ? Diet with arginine support ? To maintain a network BUT also to set up a central expert center for the long term follow up. To participate to cooperative studies – at international or EU levels To stimulate basic science research / Data collection/ bio bank ?

30. Acknowledgement • The french barth association

31. The physicians of the networks Barth Working party in France Charlotte Rigaud Anne-Sophie Lebre Renaud Touraine Chris Ottolenghi Allel Chabli Philippe Charron, Marlene Rio Pascale De Lonlay Damien Bonnet L’équipe registre B Beaupain Students C Rigaud, S Cohen Les laboratoires de génétiques Pitié C Bellanné Chantelot CHU Dijon B Aral L Faivre Necker AS Lebbre Laboratoire CERMIT F Bachelerie Laboratoire Hémato CHU toulouse E Delabesse M Pasquet E rare: Neutro Net C Klein K Boztug Whim ther net : R Badolato Thanks Grants : Inserm Invs ANR neutro Net Whimthernet/ Amgen / Chugai / AS st quentin fallavier / Ceredih / Barth France