Current Management and Future Developments in Metabolic Disease

Current Management and Future Developments in Metabolic Disease APAGBI Annual Scientific Meeting Friday 15 th May 2015 Dr Saikat Santra Birmingham Children s Hospital, UK

Outline Metabolic disorders in general Approaches to treatment of metabolic diseases Common anaesthetic considerations New treatments in development

Inborn Errors of Metabolism Substrate Enzyme Cofactor Product Substrate Enzyme Cofactor Product

Inborn Errors of Metabolism Substrate Enzyme Cofactor Product Substrate Enzyme Cofactor Product

Inborn Errors of Metabolism Substrate Enzyme Cofactor Product Substrate Enzyme Cofactor Product Product Deficiency

Inborn Errors of Metabolism Substrate Enzyme Cofactor Product Substrate Enzyme Cofactor Product Substrate Accumulation Product Deficiency

Inborn Errors of Metabolism Substrate Enzyme Cofactor Product Substrate Enzyme Cofactor Product Substrate Accumulation Product Deficiency Metabolite Accumulation

Inborn Errors of Metabolism Substrate Enzyme Cofactor Product Substrate Enzyme Cofactor Product Substrate Accumulation DISEASE Product Deficiency Metabolite Accumulation

Inborn Errors of Metabolism Product Deficiency Hypoglycaemia Energy Deficiency Lactic acidosis Brain chemicals Neurotransmitters Creatine Folate Cholesterol Accumulating Metabolites Ammonia UCEDs Toxic Amino Acids LYS Glutaric Aciduria I LEU Maple Syrup Urine Dx PHE Late treated PKU HCY Homocystinuria GLY - Glycine Metabolic acidosis Organic Acids Large Molecules MPS, Oligosaccharides

Common Approaches to Management 1. Conditions associated with impaired fasting tolerance / hypoglycaemia

IEM with Impaired Fasting Tolerance Carbohydrate Disorders Glycogen Storage Disorders Type 1a/b 1-2hrs Type III 5-7hrs Type VI/IX Variable Fanconi-Bickel Syndrome Additional hyperglycaemia Gluconeogenic Defects Especially during illness Ketotic Hypoglycaemias Glycogen synthase def Extreme end of normal Fatty Acid Oxidation Defects VLCADD / LCHADD / TFP def Short fasting tolerance Additional risk of rhabdomyolysis MCADD Common 1:10 000 NBS No fasting impairment under regular conditions SCADD Probably not a significant metabolic disorder

Long Term Management Where necessary limit daytime fasting Cornstarch Regular feeds Is overnight fasting safe? Night time cornstarch Continuous overnight NG or gastrostomy feeding Long chain FAOD Supply additional MCT in feed which can be metabolised

Common Surgical Procedures Gastrostomy All conditions requiring long term continuous night time feeding May be reversed in some GSDs in adolescence Dental procedures Need for high CHO intake GSD 1b Neutropenia and frequent infections in GSD1b- abscess drainage a common reason for GA Also investigations for inflammatory bowel disease Liver transplantation Long chain FAOD May develop life-threatening rhabdomyolysis needing dialysis/filtration and vascular access

Anaesthetic Considerations 6hr pre-op starve often unsafe Safest approach is IV 10% dextrose during fasting and during surgery If safe to fast 2-3hrs Could drink glucose polymer (SOS, Maxijul etc) until 2h pre-op Classed as a clear fluid Enables cannulation in theatre and IV dextrose intra- and post-op until feeding

Common Approaches to Management 2. Conditions associated with hyperammonaemia

IEM Causing Hyperammonaemia Urea Cycle Disorders OTC deficiency Citrullinaemia Type 1 Argininosuccinic Aciduria NAGS deficiency CPS deficiency Arginase deficiency Transport defects Lysinuric Protein Intolerance HHH Syndrome Organic Acidaemias Propionic Acidaemia Often also neutropenic Methylmalonic Acidaemia If advanced often have chronic renal failure in addition Isovaleric Acidaemia Biotin-responsive organic acidaemias HCS deficiency Biotinidase deficiency

Long Term Management Protein metabolism disorders Low protein diet 1.5-1.8g/kg/day usually Additional essential amino acids or precursor-free amino acid mixtures Regular medications Ammonia scavengers for UCED Sodium Benzoate, Sodium phenylbutyrate, Arginine or Citrulline Detoxification for Organic acidaemias L-Carnitine for all and L-glycine for IVA Cofactors eg Vit B12 for MMA and Biotin for multiple carboxylase def Avoid catabolism Glucose polymer emergency regimen Overnight NG/Gastrostomy feeding often helpful

Common Surgical Procedures Gastrostomy Most need long term night time feeding poor appetite part of disease Vascular access Frequent hospital admissions with decompensations needing IV Rx & temporary CVL Increasing referrals for TIVADs Transplantation Renal or Liver/Kidney in MMA Liver in PA, UCED

Anaesthetic Considerations Fasting tolerance usually safe If fed overnight Put on emergency regimen until 2h pre-op Medications Give orally pre-op if short surgery May need IV treatment if major surgery Cardiomyopathy not uncommon Esp MMA and PA but increasingly in UCEDs Prolonged QTc is very common in PA Catabolic stress of surgery can precipitate decompensation Do not operate if unwell Perioperative management should be with IMD centre

Common Approaches to Management 3. Conditions associated with amino acid toxicity

Neurotoxic Aminoacidopathies Maple Syrup Urine Disease Glutaric Aciduria Type 1 Branched chain amino acid metabolism disorder Leucine especially toxic Cerebral oedema and metabolic stroke Now part of NBS program Disorder of lysine and tryptophan metabolism Glutaric acid trapping in brain leads to basal ganglia infarction and metabolic stroke Residual dystonia / epilepsy Now part of NBS program

Neurotoxic aminoacidopathies Protein metabolism disorders Low protein diet 1.5-1.8g/kg/day usually Additional amino acid mixtures are an essential component of the diet BCAA free for MSUD Lys-free Low Trp for GA1 Regular medications L-Carnitine in GA1 + often AED/Dystonia Rx Avoid catabolism Glucose polymer emergency regimen Overnight NG/Gastrostomy feeding often helpful especially during illness Amino acid mixtures particularly important during catabolism to keep down toxic amino acid levels

Common Surgical Procedures Gastrostomy Brain MRI scans Vascular access Frequent hospital admissions with decompensations needing IV Rx & temporary CVL Increasing referrals for TIVADs Transplantation Liver in MSUD

Anaesthetic Considerations Fasting tolerance usually safe but if fed overnight Put on emergency regimen until 2h pre-op Amino Acid Mixtures are very important Help keep down Leu / Lys levels BUT are quite gloopy in stomach risk of aspiration Major surgery consider special TPN / NJ feeding Catabolic stress of surgery can precipitate decompensation Do not operate if unwell or recent control poor (MSUD) Perioperative management should be with IMD centre If not NG fed often safest to have NG inserted postop

4. Lysosomal Storage Disorders

Lysosomal Storage Disorders Affecting CNS MPS 1 (Hurler) MPS 2 (severe) MPS 3 MPS 7 MLD Krabbe NCLs Oligosaccharidoses Sphingolipidoses Gaucher II/III Niemann Pick A/C GM1 / GM2 Not affecting CNS MPS 1 (Scheie) MPS 2 (attenuated) MPS 4 MPS 6 Pompe Disease Fabry Disease Gaucher I Niemann Pick B LAL deficiency

Management of LSDs Neurodegenerative Good palliative care and symptom management Enzyme Replacement Therapies Established for MPS 6 / Pompe / Fabry Available for non-cns MPS 1 / MPS 2 / Gaucher In development for MPS 4 / NPB / a-mann / LALD Also Substrate Reduction (NPC, Gaucher) Monitoring for complications Cervical cord compression Cardiomyopathy Lumbar spinal disease Lung Disease Carpal Tunnel Syndrome

Common Surgical Procedures Gastrostomy for slowly degenerative LSDs Brain MRI scans Vascular access if on ERT Transplantation (HSCT) Orthopaedic surgery Knees, hips Cervical spine decompression / fixation Lumbar spinal deformity Carpal Tunnel decompression Hernia repairs ENT Surgery

Anaesthetic Considerations Discussed in earlier talk Risk of very difficult airways anticipate Risk of cervical cord instability/compression Comorbidities (respiratory, cardiac) Likewise Mitochondrial Disorders

www.bimdg.org.uk

Future Developments in the Management of Inherited Metabolic Disorders 1. Increasing Transplantation

Transplantation in IEMs SOLID ORGAN (Liver) HSCT GSDs esp Type 1B Urea Cycle Disorders Recommend at 1yr Homozygous FH Organic Acidaemias Esp MMA, PA, MSUD LSDs affecting CNS MPS 1 MPS 2 if done v early MLD/Krabbe Other LSD To avoid need for lifelong ERT MPS 1 MPS 6

Future Developments in the Management of Inherited Metabolic Disorders 2. New Enzyme Replacement Therapies

Recently licensed New ERTs MPS 4 significant effect on endurance In clinical trials Niemann Pick B significant effect on splenomegaly and interstitial lung disease LAL Deficiency significant effect on survival in Wolman Alpha mannosidosis disease and on hepatosplenomegaly liver inflammation and lipids

Future Developments in the Management of Inherited Metabolic Disorders 3. Treating the CNS

Treating the CNS Clinical trials of Intrathecal/Intraventricular ERT MPS 2 MPS 3A and MPS 3B Cyclodextrin in NPC Clinical trials of Intraventricular Gene Therapy MPS 3A

Anaesthetic Considerations in CNS-targeted trials MRI Brain often a key outcome Typically needed q6-12m under GA Insertion of Intrathecal drug delivery devices High rates of failure in early devices, needing multiple revision surgeries Initial CNS dosing eg in gene therapies Lumbar punctures Where ICP an outcome/safety measure and/or dosing given by regular LP

Summary Patients with IMDs have frequent needs for surgery and anaesthesia Different IMDs pose different challenges for the anaesthetist which can often be predicted and planned for Clinical trials and new treatment options will expose even more patients with IMDs to potentially risky anaesthesia Guidance for perioperative management of IMDs can be obtained from BIMDG Website Local IMD Centre

Thank Youl