Isolated remethylation disorders

Transcription

1 3/12/213 université PARIS DIDEROT PARIS 7 Clinical Management & Outcome of Remethylation disorders Does our intervention have benefit for patients? Manuel Schiff, Hélène Ogier de Baulny, Jean-François Benoist, Hôpital Robert Debré Paris SFEIM, Outline Overview & Introduction One center experience: Clinical examples Therapy & Outcome Lessons from the patients: Can we improve therapy & the (poor) outcome? 1 2 Isolated remethylation disorders Inherited disorders of enzymes involved in the remethylation of HCY to Methionine MTHFR deficiency, MTHFR > # 15 published cases Methionine synthase reductase (CblE) deficiency, MTRR Methionine synthase deficiency (CblG), MTR # 5 reports METABOLIC PATHWAYS CH3THF METH OHCbl SAM CH2THF CH3Cbl SAH THF HCY ADOCbl OHCbl MMA Succinyl-CoA 3 METABOLIC PATHWAYS & PATHOGENESIS Diagnostic workup Systemic (CNS) Methionine deficiency AdoMet deficiency Low methylation Major consequences (hypomyelination) High HCY levels (thrombosis) Adapted from Rosenblatt, ASH 23 5 Clinical signs (Neurologic>>) Hematological abnormalities Absent in MTHFR def. (no impairment of DNA bases synthesis) Pancytopenia + megaloblastic BM (CblE/G) Ser-B12 N Ser/RBC/CSF- Folates N (CblE/G) N/low (MTHFR, CH3-THF) Hypo-Meth Hyper-HCY No umma Functional tests (Fibroblasts) Molecular analyses 6 1

2 3/12/213 Clinical signs-overview Neurological distress Neonatal / Early infancy Progressive encephalopathy Subacute degeneration of the cord Childhood Adulthood Neonatal Remethylation defects 7 8 First: a short clinical story with poor outcome J.Y. 1st child, consanguineous parents BW: 274 gr, BH: 51 cm, HC:? 1st admission at 19d for poor growth (Weight: 274 gr.) Neurologically Progressive hypo reactivity and hypotonia during the preceding week On admission: Axial hypotonia Poor gesticulation Poor contact No suck No visceral abnormality Routine, inflammatory, infectious workup: negative Neurological investigations MRI; Hyper signal in posterior white matter (T2 weighted) Plasma amino acids: thcy 224µM, Methionine 7µM B12 224pM (N) 9 J.Y. Treatment: B6 25 mg/d, B12 (oral) 1 mg/d, Folinic acid 5 mg/d. Progressive recovery At 1m ½, Head circumference -2SD (34.5cm) 3 months: Enlarged ventricles Ventriculo peritoneal shunt Post operatively, dependence to the ventilatory support for the following month Metabolic workup: thcy 131µM, Methionine 2µM Treatment OH-B12 (IM) 1 mg/d 1 month later Folinic ac. 5 mg/d thcy 84µM Betaine 1.5 gr. /d Methionine 148µM Methionine 15 mg/d MTHFR gene: exon 4, G792+1A homozygous exon 6, T168C polymorphism Poorly treated at diagnosis with a classical sequelae (hydrocephalus) 1 A. M. 2nd child of non consanguineous parents 1st child died at 5 weeks of age following a progressive neurological deterioration Anemia Homocystinuria, hypomethioninemia No methylmalonic aciduria On fibroblasts: putative diagnosis was CblG (MTR) 2nd pregnancy, prenatal diagnosis: normal MTR activity A.M normal pregnancy and delivery at 4 WG BW 34gr., BH 49 cm, HC 36 cm Normal immediate postnatal adaptation - 7 days: progressive hypo reactivity, hypotonia, poor weight gain D7: Phone advice Treatment: OH-B12: 1mg/d IM, Folinic ac. 5 mg/d PO B6: 1mg/d PO, Betaine (citrate) - PO 11 D8: Admission in neonatology (RDB) for further investigations Pallor, jaundice, dehydration, hypokinesia and hypotonia Symptomatic treatment -Betaine 1.5g/d PO, -methionine 1mg/d PO, -B6 1mg/d PO -CH3-THF 15 mg/d PO, -OH-B12 1mg/d IM. Progressive recovery on the following 2 weeks Normal clinical examination at 1 month of age. Cerebral MRI: Hypersignal of the white matter 12 2

3 3/12/213 Diagnosis No anemia nor any visceral involvement. Plasma D6 D8 Methionine 7 1 FHC 29 thcy Acylcarnitines Nle Urine Methionine 11 FHC 38 Disulfures ++ MMA Fibroblasts (B Fowler) MTHFR activity: 1% control Reduction of Meth synthesis Molecular analysis (1 allele without mutation). Definite results pending 13 A. M D m 5m 9m 14m 22m Meth thcy Betaine (mm) DiCH3G (µm) Sarcos. (µm) Weight (kg) CH3THFmg/d 15 Folinic 5 B6 mg/d 1 Betaine gr/d Meth mg/d 1 5 Carnitine gr/d 1.5 IM-B12 mg 1/d 2/w 1/w PO 1 1/w 14 D8 Excellent outcome! Normal child 28mo: speaks, walks, normal dev 12.2Kg; HC 5.5cm (M) thcy 74µM; Meth 21µM thcy µm Bonne observance du traitement: -Betaine 2 mg/kg/j -L-Methionine 3 mgx4/j -Ac. Folinique 5 mg/j -OH-B12 oral Meth µm 1mg/sem -6A1/2: Examen normal Difficultés attentionnelles CP 28mo 28mo J8 6,5A J.M. 3/6/26 Fist child, consanguineous parents D15: Admitted for repeated seizures and coma The previous week: probable access and lethargy poor feeding Laboratory investigations: normal Treatment BCC, NH3, lactate AB TDM normal Zovirax EEG focalized crises Gardenal No improvement: repeated apneas Dilantin TA: 6/12 Alterning EEG "burst suppression" Intensive care unit Neonatal EEG (under sedation) Ventilation support Amines B6 test Metabolic workup thcy Meth MMA 17 Age 18d m 4 ½ 5 ½ 7 Plasma Meth thcy CSF Meth THC 6 CH3F 4 nm MTHFR: homozygous deletion of exon 9 Betaine Meth Folinic 1 B6 5 IMB12 1/d 1/W 1/2W 18 3

4 3/12/213 Outcome: 16mo, normal development, walks but HC -2SD MRI:1Y thcy 88µM White matter abnormalities Meth 5µM Ventricular enlargment Mauvaise observance du traitement: -Betaine 12 mg/kg/j -L-Methionine 2 mg/j -Ac. Folinique 5 mg/j -OH-B12 oral 1mg/15j -5A: PC -2DS Retard psychomoteur global modéré à sévère thcy µm Meth µm 19 J15 2 5A J F (1/8/98), first child, non consanguineous parents - 2 months: investigations for anemia and neutropenia 1m: bone marrow aspirate: dyserythropoietic + megaloblastic Metabolic workup: Meth: 11µM, HCT (15µM), umma: NL B12, folates, TCII Defective synthesis of CH3-B12 (7%) CblE (MTRR) Treatment OH-B12 IM: 1mg/mo Betaine: 3gr/d Folic 5 mg/d Meth 25-5µM thcy 4-6µM MCV 1fl Outcome 11Y: normal development MCV > 11fl without pancytopenia Meth 2µM, thcy 62µM OH-B12 1mg/2mo IM + 1mg/d oral Betaine: 6gr/d Folinic 1mg/d + 1mg/d oral Infantile Remethylation defects Y(1) 4th child consanguineous parents (Tunisia) Normal pregnancy & delivery 15mo: investigation of unspecific psychomotor delay: Speach Hypotonia thcy 18µM, Meth 1µM, umma= No hematol abnormalities Ser B12 2 pm; Folates na Y(2) IM OH-B12 1mg/d 1w Folinic 1mg/d oral Betaine 3g/d MTHFR Exon 9 homozygous c.1615c>t Respiratory deterioration (15mo) Apnea diaphragmatic palsy ventilatory support Bacterial infection Subsequent neurol degradation Death 17mo

5 3/12/213 Poor outcome Late-onset Remethylation defects ) Ha. First child consanguineous parents (Pakistan) 1) Normal dev -18mo Mild psychomotor retardation #2Y with aggressivity 9y: seizures 3) 11y: Acute neurological deterioration Tetrapyramidal Sd ( gait lost) Cerebellar signs Peripheral neuropathy Ha.(2) Normal hematol parameters Ser Vit B12 85pM (N>15) RBC folates 45nM (N>58) thcy 186µM, Meth 6µM, umma CSF: CH3THF <1nM (N>4) MTHFR: c.616a>t homozygous Meth plasma µM THCY µM Meth CSF µM RBCfolates CH3-THF CSF Betaine Meth OH-B12 oral Folinic 5-CH3-THF B nM < nM 4mg/d 5mg/d 4 5 8g/d 45mg/d 5 8g/d 45mg/d 5 Nv Diagnosis: 12Y POOR OUTCOME: Moderate to severe psychomotor delay HC -2SD Gait impairment Mild tetraparesis Peripheral neuropathy Behavioral troubles Chronic demyelination: 2mg/d 5 16Y 29 Diagnosis: 12Y 3 MRI VEP Stabilization? 16Y 5

6 3/12/213 Relative observance du traitement: -Betaine 4x2g/j - L-Methionine 4x2 mg/j -Folinique thcy µm -2A: Encéphalopathie 11,5A 2A sévère Meth µm Marche possible avec cannes 14A 31 2A Remethylation defects treatment /Lessons from the patients Goals: thcy<7µm Plasma Meth at least Normal Normal haematol parameters (CblE/G) Means: B12: cofactor Meth-synthase OH- natural form > CN- parenteral for CblE/G Rythm of administration??? Folates: Folic, folinic or methyl-thf No matter in Cbl E/G MTHFR? Betaine L-Methionine? B6 (transsulf) / Carnitine (needs SAM for its biosynthesis) 32 Folates in MTHFR-deficiency Folates in MTHFR-deficiency Folinic more than folic Rationale for CH3-THF in MTHFR? There would be a rationale for treating the severe systemic CH3-THF depletion Our experience: Long-term 5-CH3THF supplementation does not correct CSF CH3-THF Why? Because of its unstability? Because folate membrane transport is highly complex Would there be a rationale for treating the severe systemic CH3- THF depletion Our experience: Long-term 5-CH3THF supplementation does not correct CSF CH3-THF Why? Because of its unstability? Because folate membrane transport is highly complex Andrews NC. Cell Metab Andrews NC. Cell Metab Betaine-therapy in remethylation defects Substrate of liver Betaine: homocysteine methyltransferase (BHMT) Alternative pathway for remethylation Corrects Methionine depletion (plasma & CSF) Decreases HCY accumulation Would enhance Meth uptake in the CNS (Strauss et al. MGM 27) Lowers thcy but HCY remains high during the first year of life Oral Methionine therapy in remethylation defects Lessons from the patients Rationale: Correct Meth depletion (CNS) Few reports: clinical benefits Our patients: Neonatal presentations: LT follow-up needed Late-onset: Should be used in synergy with betaine (Meth alone: higher thcy levels) Acute load (1mg/kg) does not increase HCY accumulation Meth (µm) thcy (µm) H1 H2 H3 H4 H6 H8 H24 35 Strauss et al. MGM 27 L-Methionine 1mg/Kg oral 36 6

7 3/12/213 What about clinical benefits of our intervention? Poor outcome if treatment comes too late Neonatal distress chronic neurological impairment Infantile death Late-onset: stabilization of a poor condition? In early recognized/treated patients, favourable outcome: CblE/G: haematological abn corrected Neonatal MTHFR-deficient patients treated from birth: (almost) «normal» development & clinical status Unsloved issues: Betaine efficiency during the first months of life? Liver immaturity? L-Methionine: should it be tried in every remethylation deficient patient? Is Methionine toxic? Is it possible to / should we correct CH3-THF CNS deficiency? Acknowledgements Odile Rigal Odile Fenneteau Bogdana Tilea Stéphane Giraudier Nenad Blau PARIS DIDEROT PARIS 7 université Best (& probably the most challenging) option in order to improve outcome= decreasing the number of undiagnosed (untreated) patients?