Newbees in genetics of pediatric hypertrophic cardiomyopathy

Transcription

1 Département de Génétique Newbees in genetics of pediatric hypertrophic cardiomyopathy Alain Verloes Dpt de Génétique AH-Hôpital Robert DEBRE

2 CMH Hypertrophy of the parietal wall of the left ventricle not explained by mechanical constraints Rare disorder of childhood ( adults) Incidence among children is unprecise USA: 1/100000? Does not fit with data on Noonan Complex ethiopathogeny Genetics : > 100 genes Environnementally induced Familial implications and genetic counseling Autosomal dominant disorders : parents! Autosomal recessive disorders : sibs FCC 2015 novembre 15 2

3 Extreme genetic heterogeneity of cardiomyopathies 100 genes!!! 27 «common» Tatiq & Ware WJC 2014 FCC 2015 novembre 15 3

4 Etiopathogenic landscape of HCM in children HCM Genetics Inborn error of metabolism Glycogenoses Fatty acids oxydation defect Lysosomes Mitochondrial disorders (resp. chain) CDG Refsum Amino- and organic acidemias Muscle disorders Sarcomeric proteins Z zone proteins Calcium trafficking Syndromal Noonan & related disorders Friedreich Steinert Beckwith-Wiedemann Acquired Hyperglycemia IDM Corticoids In pediatrics 35% explained by sarcomeric proteins usually involved in adult HCM 80%: MYBC3, MYH7 TNNT2, TM1, ACTC1, TNNI3, TTN, MYL2 Investigate parents in all cases Not true for perinatal CM FCC 2015 novembre 15 4

5 Etiopathogenic landscape in newborn/infant HCM Genetics Inborn error of metabolism Glycogenoses Fatty acids oxydation defect Lysosomes Mitochondrial disorders (resp. chain) CDG Refsum Amino- and organic acidemias Acquired Hyperglycemia IDM Corticoids Muscle disorder Sarcomeric proteins Z zone proteins Calcium trafficking Syndromal Noonan & related disorders Friedreich Steinert Beckwith-Wiedemann FCC 2015 novembre 15 5

6 Clinical orientation in newborn/infant (1) Encephalopathy Metabolic acidosis Hypotonia Hypoglycemia ± Hypotonia Hypotonia Syndromal Mitochondrial cytopathy Barth FA oxydation defect ompe Noonan Mitochondrial cytopathy Carnitine transport Others Glycogenosis (Beckwith Wiedemann) (IDM) First tier metabolic work up: lasma: Ionogram, urea, creatinine, glucose, TGO, TG, CK Amino Acids chromato, NH3, lactate, pyruvate, acylcarnitines Urines: Organic Acids chromato FCC 2015 novembre 15 6

7 Clinical orientation in newborn/infant (2) syndromes 42 syndromes in dysmorphology database FCC 2015 novembre 15 7

8 Clinical orientation in newborn/infant (3) Noonan syndrome Context Commonest syndromal genetic HCM HCM of prenatal onset Usually normal neurological presentation Absence of «metabolic clues» Diagnostic handles HCM associated with CHD HCM and lymphatic anomalies (hands, feet, pleural effusion ) FCC 2015 novembre 15 8

9 The new face of Noonan syndrome High incidence But many mild cases sychomotor delay? > 80% normal IQ Growth retardation? 50 % normal stature Spectrum of phenotypes : the RASopathies New clinical concerns Hematology : leukemias Immunology: auto-immune syndromes: LED Neurology: medullary compression by late Chiari anomaly Vascular: moya-moya, dilation of coronary arteries Cardiology & oncology: lack of data about long term issues Targeted treatments? FCC 2015 novembre 15 9

10 Focus on RAS/MAK signaling pathway Gab1 An universal signaling cascade Canonical pathway RTK RAS RAF MEK ERKGD RAS acts as an upstream switch CBL SH2 GF RTK Grb2 Sprouty Sos1 RAS GD i GT GD RAS GT RAF Mek MAKKK MAKK RAS/MAK pathway involved in basic developmental processes Hyperactivated in >70% cancers Gene expression Cell cycle control roliferation Differenciation RSK2 Nucleus Erk MAK FCC 2015 novembre 15 10

11 Gab1 Before 2001 Growth GF factor NF-Noonan < NF1 mutations Reduce inhibition of ERK activation Neurofibromatosis I3K TEN Shp2 Y Grb2 Sos1 Ras GD i GA GT NRas KRas HRas ARaf BRaf CRaf Akt TSC1/2 mtor RAS pathway has strong Involvement in cancerogenesis: ERK overexpressed in > 50% of cancers Mek 1 Mek 2 Erk 1 Erk 2 S6K FCC 2015 Gene expression Cell cycle control roliferation Differenciation novembre 15 11

12 HCM in Noonan syndrome HCM: about 20% of NS patients In 70% : associated with CHD 15-25% with subaortic obstruction Median age of diagnosis : 6 months Overal survival at 15 years : 70% Three main presentation < 50% cases : severe, clinical dg < 6 months With congestive HF : 70% mortality Without congestive HF: 25% mortality Rarely slow progression Few arrythmias (<< than common HCM) > 50% cases : mild, clinical dg > 6 months 5% mortality 20% regression to normal before age 10 Rare cases of late onset HCM Monitor heart / 5years for life Few data beyond 30ies Hahn AJMG 2015 FCC 2015 novembre 15 12

13 HCM in Noonan syndrome Genetics Most commonly with TN11 but more common in patients with RAF1 or RIT1 mutation, and in CFC/Costello/NS-ML No geno/pheno expt HRAS (Costello syndrome) : severe arrythmias NB: NS + MYBC3/MYH7-related CM reported Long term outcome poorly known Rarely sudden death Arrhythmia uncommon Annual cardiac-specific mortality: 1.2% (Shaw 2007) FCC 2015 novembre 15 13

14 Therapeutic perspectives Major pathogenesis: Increased RAS signaling Blockade of Ras/Mapk signaling with MEK inhibitor is efficient in Raf1L613V mice (Wu, JCI 2012) In Noonan with multiple lentigines: increased AKT/mTOR signaling mtor inhibitor Rapamycin reduces cell hypertrophy and heart weight in tpn11y279c/+ mice (Marin, JCI 2012) FCC 2015 novembre 15 14

15 Therapeutic perspectives Human targets: HCM, ID, growth RAS inhibition Clinical trial of lovastatin and simvastatin in NF1 (inhibits RAS isoprenylation) Contradictory results on cognition hase II open-label study examining the safety, pharmacokinetics and tolerability of MEK inhibitor(mek162), in adults with Noonan syndrome and HCM(ClinicalTrials.gov NCT ). mtor/akt inhibition Clinical trials of sirolimus & everolimus (mtor inhibitors) in tuberous sclerosis Transposition to Noonan S with Xple lentigines? FCC 2015 novembre 15 15

16 Hopes but revention or even reversion of HCM with small-molecule therapy Important issue: risks/benefits balance Most RASopathy-associated HCM associated with low mortality Novel therapy would need to have rare/minor side effects, despite year-long treatment Low power anti-ras pathway (e.a. statins) Are used in phase II clinical trials for NF1 FCC 2015 novembre 15 16

17 Genetic diagnosis of RASopathies Useful in young patients for prognosis Mandatory if CFC/Costello is considered because of specific cancer risk in CS Available routinely as a gene panel by new generation sequencing in Robert DEBRE (RASopathy panel with > 30 genes) FCC 2015 novembre 15 17

18 Last minute HRC Noonan & CFC En cours de finalisation administrative Dispo début 2016 Call for patients RASopathies with Moya-moya or other CNS vasc. disorder Dilation of coronary arteries Merci de votre attention! FCC 2015 novembre 15 18