Clinical Management of Organic Acidemias and OAA Natural History Registry. Kim Chapman MD PhD Children s National Rare Disease Institute

Transcription

1 Clinical Management of Organic Acidemias and OAA Natural History Registry Kim Chapman MD PhD Children s National Rare Disease Institute

2 Disclosure Nothing to disclose concerning this lecture

3 Organic acid? R C O OH R= carbon containing chain

4 Organic aciduria (acidemia) Any disorder which accumulates organic acids in excess in the urine (aciduria) Any disorder which accumulate organic acids in excess in the blood (acidemia) Usually due to abnormal breakdown of amino acids

5 Organic acidemias Systemic Propionic acidemia Methylmalonic aciduria Isovaleric acidemia 3-methylglutaconic acidurias 3-methylcrotonylglycinuria D-2-hydroxyglutaric aciduria 2-methyl-3-hydroxybutyric aciduria HMG-CoA Lyase deficiency Cerebral Glutaric aciduria I L-2-hydroxyglutaric aciduria

6 Clinical findings Presentations No symptoms Neonatal (Vomiting, Lethargy, Decreased intake, Coma, Death) Adolescent (as above, also odd e.g. diabetes only when sick, etc.) Adult (as above, also cardiomyopathies, renal failure, etc.) Laboratories Metabolic acidosis +/- Hyperammonemia Diagnostic organic acids in urine Often elevated Acylcarnitine of note Can become carnitine deficient July 11, 2018

7 Basic Biochemical Disease Typical Reactions A + B C Biochemical Disorder A + B C F E

8 Systemic OA Propionic Acidemia Methylmalonic aciduria +/- total homocystinuria Isovaleric aciduria

9 Propionic Acidemia Metabolic acidosis and hyperammonemia Vomiting, lethargy, coma death. Propionyl CoA Carboxylase deficiency PCCA and PCCB 3-hydroxypropionate, methylcitrate, propionylcarnitine (C3) July 11, 2018

10 Methylmalonic Acidurias Metabolic acidosis and hyperammonemia Vomiting, lethargy, coma, death MUT, MMAA, MMAB Methylmalonic acid, 3- hydroxypropionic acid, methylcitrate, C3, C4DC If caused by cobalamin deficiency, then also elevated total homocysteine MMACHC, MMADHC July 11, 2018

11 Isovaleric Acidemia Can be mild, but decompensations can have hyperammonemia, coma, death Isovaleryl CoA dehydrogenase deficiency Markers are isovalerylglycine, 3-hydroxyisovaleric acid, isovalerylcarnitine (C5) IVD July 11, 2018

12 Cerebral Organic acidurias Glutaric aciduria 1 Macrocephaly, strokes, movement disorders Glutaryl-CoA dehydrogenase (GCDH) Increased glutaric acid, 3- hydroxyglutaric acid, C5DC

13 Current therapeutic recommendations

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15 Therapies for Organic acidemias Reverse Catabolism/avoid catabolism Decrease exposure Scavenge toxins Replace the non-manufactured Co-factors (Research: fix the enzyme function)

16 Therapies for Organic acidemias Reverse catabolism/avoid catabolism Dextrose at 6-10 mg/kg/min ~ D10+electrolytes at 1.5 maintenance Adequate fluids and calories Adequate protein/fat/cho Decrease exposure Decreased amino acid which cannot break down Metabolic diets protein restriction

17 Therapies for Organic acidemias Reverse Catabolism/avoid catabolism Decrease exposure Scavenge toxins Nitrogen scavengers Dialysis/ECMO Levocarnitine Glycine

18 Therapies for Organic acidemias Reverse Catabolism/avoid catabolism Decrease exposure Scavenge toxins Replace the non-manufactured Anaplerotic therapies (bicitra)

19 Therapies for Organic acidemias Reverse Catabolism/avoid catabolism Decrease exposure Scavenge toxins Replace the non-manufactured Co-factors Cobalamin Biotin Thiamine

20 Therapies for Organic acidemias Reverse Catabolism/avoid catabolism Decrease exposure Scavenge toxins Replace the non-manufactured Co-factors (Research: fix the enzyme function) You will hear plenty of this in next talks

21 Therapy for PA* Acute Reverse catabolism D10 electrolytes at 1.5 M Intralipid +/- Hold protein 24h? Scavenge toxins Carnitine ECMO/Dialysis Nitrogen scavengers Cofactor Biotin? Chronic Diet: avoid prolonged fasting, protein restriction with supplemental non-propiogenic amino acid Levocarnitine Nitrogen scavengers (e.g. sodium benzoate) Screening and standard treatments for underlying long term complications Maybe Liver transplant *Every patient is different so there are some variation in specifics

22 Therapy for MMA (without HCU)* Acute Reverse catabolism D10 electrolytes at 1.5 M Intralipid +/- Hold protein 24h? Scavenge toxins Carnitine ECMO/Dialysis Nitrogen scavengers Cofactor Cobalamin (hydroxocobalamin IM/IV) Chronic Diet: avoid prolonged fasting, protein restriction with supplemental non-propiogenic amino acid Levocarnitine Nitrogen scavengers (e.g. sodium benzoate) Hydroxocobalamin (IM, IV, SC) Screening and standard treatments for underlying long term complications Maybe Renal/Liver transplant * Every patient is different so there are some variation in specifics

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24 Therapy for Cobalamin C and D1* Acute Reverse/prevent catabolism: Avoid dehydration Hydroxocobalamin IM/IV +/- Levocarnitine Chronic Hydroxocobalamin (SC/IM/IV) (NDC: ) Betaine No proven benefit for folate/folinic acid, L- carnitine, and methionine Avoid: Nitrous oxide *Every patient is different so there are some variation in specifics

25 IVA

26 Therapy for IVA* Acute Reverse catabolism: rehydration and calories Decrease protein for 24 hours Scavenge: Levocarnitine and glycine Chronic Protein restriction Levocarnitine Glycine *Every patient is different so there are some variation in specifics

27 GA1

28 Therapy for GA1* Acute Aggressive and early (illness, surgery, immunizations) Reverse catabolism: dextrose + electrolyte fluids (1.5 M) Scavenge: levocarnitine Treat fevers Chronic Sequencing is helpful Low lysine diet +/- Metabolic diet with lysine free and +/- low tryptophan formula up to 6 years Levocarnitine Glycine If surgery, a plan *Every patient is different so there are some variation in specifics

29 GA1: what do you need? Know disease Inform/educate local hospital ER letter (with initiation of acute treatment protocol instructions) Plan for holidays Inform you metabolic provider of fevers >38.5C (~101), vomiting, diarrhea, surgery.

30 Why registries? Rare Disorders No one institution has more than a few patients Disease management has been trial and error Understanding of disorder is based on rare/unusual, really frequent and/or severe complications/presentations The above guidelines are mostly based on opinion

31 There are more than one kind of registry Deep dive, few individual patients Less specific, many patients Patient driven

32 Registries help advance treatment

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36 Our registry Sponsored with NORD YOU put in the data (eventually you can invite your medical provider to supplement it) YOU can participate in the maintenance/next steps

37 What can a registry do for us? Can determine Frequency Variability Co-morbid conditions Pre-condense Expertise Patients Care givers July 11, 2018

38 How do we use a registry? Registry in this context allows us to: Identify complications which are seen Identify medications that are used Dietary history Registry may allow us to: Natural History Frequency of disease Timing of complications Genotype/phenotype correlations July 11, 2018

39 What is in our registry? Demographic data Presentation history Admissions data Growth data Developmental data (once/year) Immunization data Medication data Interim health history Dietary data Physical examination data at each visit (min. 6 months) Review of systems at each visit (6 months) July 11, 2018

40 NORD Project Joint project with FDA and NIH Data housed at NORD (Switzerland) Common data elements for natural history and specific disease elements Entry by Patient/Families and medical professionals via web Data ownership by disease organization but can partner and also legacy option if organization fails etc. Common IRB nationally In Pilot phase with 5 rare disease groups Cost is a fraction of RDCRN registry $10-25,000/year compared to > $1,000,000/year for RDCRN model.

41 OAA registry thus far (June 2) Consented: 86 Not started: 37 Started: 49 Completed:44 Updated: 1

42 Future directions Industry is interested in our registry What needs to occur to make this registry most useful to us (aka, how do we use if to improve care)?

43 Resources Gene Reviews Genetics Home Reference

44 Questions My Contact information: Kimberly A Chapman Children s National Rare Disease Institute Washington DC KChapman@childrensnational.org Paging operators Ask for geneticist on call or me specifically

45 Acknowledgements: My Laboratory July 11, 2018