Inherited metabolic disease Dr Neil W Hopper SRH Areas for discussion • Introduction to IEMs • Presentation • Initial treatment and investigation of IEMs • Hypoglycaemia • Hyperammonaemia • Other presentations • Management of intercurrent illness • Chronic management Inherited Metabolic Diseases • Result from a block to an essential pathway in the body's metabolism. • Huge number of conditions • All rare – very rare (except for one – 1:500) • Presentation can be non-specific so index of suspicion important • Mostly AR inheritance – ask about consanguinity Incidence (W. Midlands) • Amino acid disorders (excluding phenylketonuria) — 18.7 per 100,000 • Phenylketonuria — 8.1 per 100,000 • Organic acidemias — 12.6 per 100,000 • Urea cycle diseases — 4.5 per 100,000 • Glycogen storage diseases — 6.8 per 100,000 • Lysosomal storage diseases — 19.3 per 100,000 • Peroxisomal disorders — 7.4 per 100,000 • Mitochondrial diseases — 20.3 per 100,000 Pathophysiological classification • Disorders that result in toxic accumulation – Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects) – Disorders of carbohydrate intolerance – Lysosomal storage disorders • Disorders of energy production, utilization – Fatty acid oxidation defects – Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) – Mitochondrial disorders – Peroxisomal disorders IMD presentations • ? IMD presentations • Screening – MCAD, PKU • Progressive unexplained neonatal disease esp if after normal pregnancy and birth • Hypoglycaemia • Hyperammonaemia • Deterioration after feeding • Encephalopathy • Recurrent vomiting and lethargy • Neurological impairment, Developmental Problems • Sudden death / SIDS / ALTE • ‘Storage’ phenotype • Cardiomyopathy • Liver disease The metabolic emergency in a neonate • Clue is non-specific illness after an asymptomatic interval – Second day onwards (intoxication type) – Hyperammonaemia can be from day 1 – Condition deteriorates despite usual care • Poor feeding, vomiting, hypotonia, seizures • Family history of neonatal death with ‘sepsis’, ‘SUDI’ Metabolic emergency in older child • Similar to neonatal presentation or – Recurrent vomiting and lethargy – Reduced GCS leading to coma – Hypoglycaemia, metabolic acidosis – Prompted by vomiting, fever or fasting Investigations • Depends on presentation but a good starting point is.... – Blood gas, lactate – NH4, U&E, LFT, Glucose – Blood amino acids – Urine organic acids, dipstick – NEFA, ketone bodies (β-OH butyrate) – Acylcarnitine profile (Guthrie card) Initial management • Stop feeds (protein, fat, galactose, fructose) • Provide substrate to switch off catabolism – oral fluids and Maxijul – IV 10% Dextrose with appropriate electrolytes – 150 ml /kg / day in neonate (may need more in OAurias or urea cycle defects) – May need insulin if hyperglycaemic • Discuss with regional metabolic centre (Manchester) • Refer to BIMDG guidelines • Specific treatments to enable clearance of toxin – Phenylbutyrate / Benzoate / Arginine for UCDs – Dialysis Other presentations- Hypoglycaemia • Definition controversial • Working consensus of <2.6mmol/L • More difficult to define in neonatal period as around 20% well, term babies have BG below this level – likely protective effect of ketones • In reality a continuum – if symptomatic a higher BG of 2.6-3.0 mmol/L may be significant • CBG machines are inaccurate in lower range • Working definition in diabetics <4.0mmol/L Symptoms of hypoglycaemia • Due to autonomic response and neuroglycopenia – Autonomic response • sweating, weakness, tachycardia, tremor, nervousness, hunger • Ameliorated with repeated episodes – hypo unawareness – Neuroglycopenia • lethargy, irritability, confusion, behavior that is out of character, hypothermia, seizure, coma, brain damage and death Diagnostic approach - history • Antenatal history – DM, IUGR • BWt – SGA / Macrosomia • Asphyxia • Relationship to meal – Some diagnoses cause hypo at different times • FHx of sudden infant death • Intercurrent illness • Possibility of ingestion – alcohol, B-blocker, salicylates Diagnostic approach - examination • Height and Weight • Transverse Earlobe creases, Macroglossia, Exomphalos – BWS • Hepatomegaly – GSD – Gluconeogenesis defects – Galactosaemia • Midline defects, micropenis, bilateral undescended testes – Hypopituitarism – Hyperpigmentation – Adrenal failure Diagnostic approach – the critical sample • To be taken at the time of hypoglycaemia before glucose or feeds given • Allows metabolic or endocrine abnormalities to be identified • Can avoid the need for diagnostic fast • Many abnormalities cannot be detected when euglycaemic Interpretation of the critical sample • Insulin – should be suppressed at time of hypoglycaemia. Detectable insulin at time of hypo with absent ketones in blood and urine suggests hyperinsulinaemia • Cortisol – should be >550mmol/L. If lower suggests adrenal failure • GH – if <10-20 mU/L consider pituitary failure • Blood and urine ketones should rise in fasting and hypoglycaemia. If absent, suggests hyperinsulinaemia, defect of fatty acid oxidation (eg MCAD), or defect of ketogenesis • Lactate may be high in many metabolic disorders such as disorders of gluconeogenesis or glycogenolysis • NEFA (=free fatty acids) rise due to lipolysis. Low in hyperinsulinaemia • Acylcarnitine profiles are diagnostic in defects of fatty acid oxidation and various organic acidurias ‘Ketotic hypoglycaemia’ • Common • Typically child aged 18m-5 years – Slim build, sometimes IUGR – Hypoglycaemia with raised ketones and FFAs during intercurrent illness – Metabolic investigations normal – Appropriate cortisol, GH and insulin response – Low alanine (major substrate for gluconeogenesis) • Diagnosis of exclusion • Remits as child becomes older Hypoglycaemia - management • Acutely – Oral glucose / Glucogel – 2-5mls/kg 10% Dextrose IV – 10% dextrose infusion. If more than 10mg/kg/min needed suggests hyperinsulinism – IM Glucagon • Chronic management – Avoid fasting – Cornstarch – Early use of IV Dextrose to prevent catabolism – Emergency care plan – Home Glucose / Ketone testing • Specific treatment – Diazoxide / Chlorthiazide in HI – Carnitine supplements in β oxidation defects Hyperammonaemia • Neonates – Healthy <110µmol/L – Sick <180µmol/L • After neonatal period – Normal <50µmol/L – Suspect IEM >100µmol/L • Haemolysis, enthusiastic tourniquet or no ice can give falsely raised value Hyperammoniaemia - causes • Urea cycle disorders (UCDs) – Commonest cause of severe HA – Resp alkalosis / met alkalosis / met acidosis – Short time to brain damage – emergency! • Organic acidurias (eg Proprionic Aciduria) and long chain fatty acid oxidation defects (e.g. MCAD) – Lactic acidosis – Can’t distinguish from UCDs on NH3 level • Severe liver failure Hyperammonaemia – treatment • Organise all treatment options as soon as HA confirmed • NH3 >500µmol/L will need haemodiafiltration • Principles – Stop protein intake, reduce catabolism – Remove NH3 – drugs, dialysis – Generous fluids (supports excretion) – Replenish urea cycle with Arginine Hyperammonaemia – treatment • IV 10% Dextrose 2ml/kg stat – Then 120ml/kg/day. Insulin if needed. • NH3 scavengers – provide alternative routes of nitrogen excretion by conjugating glycine and glutamine • Sodium Benzoate • Sodium Phenylbutyrate – Both 250mg/kg loading over 90 mins – Then 500mg/kg day continuous infusion • Arginine infusion Other presentations – Developmental disorder • Many IEMs cause brain damage • May be progressive – regression • Severe behavioural problems • Investigation is directed by clinical features, MRI findings etc • Consider lysosomal disoreders and remember VLCFAs in boys with new onset behavioural problems Other presentations - SUDI • Sudden, unexpected death in previously well child with no abnormality on PM – Extremely likely to be an IEM • Clues – developmental problems, seizures, hepatomegaly, hypotonia, precipitated by gastroenteritis • Basic PM tests – Urine OA, serum AA, blood Acylcarnitines • Store frozen serum, EDTA, CSF and urine, skin biopsy if features suggest IEM Intercurrent illness management Age % Glucose polymer Daily volume (Maxijul / Vitajul / SOS) 0-1 y 10 150-200 ml/kg 1-2 15 100 ml/kg 2-6 20 1200-1500 ml 6-10 20 1500-2000 ml >10 y 25 2000 ml Divide total volume by 12 and give 2 hourly Stop feeds IV fluid if not winning 10% Dextrose with appropriate electrolytes 100-150 ml/kg/day Specific treatments – e.g. hyperammonaemia Chronic management • Condition specific • Often involves dietary manipulation • Specialist dietician input • Management of intercurrent illness • HSCT for lysosomal and peroxisomal storage disorders References and help • http://www.bimdg.org.uk • RMCH 0161 276 1234 • www.climb.org.uk – Patient support Questions? Urine clues to IEMs Potential disorder Urine color Black (upon standing/oxidation) Homogentisic aciduria (alkaptonuria) Blue Tryptophan malabsorption Pink Disorders with hematuria, kidney stone formation Port wine (upon standing/oxidation) Porphyrias Yellow-orange Disorders with increased uric acid Urine odor* Acrid, sweaty feet Glutaric acidemia II Cabbage Tyrosinemia Fishy Trimethlylaminuria, dimethylglycinuria Maple syrup, curry Maple syrup urine disease Mousy Phenylketonuria Sweaty feet Isovaleric acidemia Sweet Beta-ketothiolase deficiency Swimming pool Hawkinsinuria Urine colour and IEMs Alkaptonuria Acute Intermittent Porphyria Eye signs of IEMs Finding/Age of onset Related