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 disorders

Cataract

Birth Lowe syndrome, peroxisomal biogenesis defects, Cockayne syndrome, sorbitol dehydrogenase deficiency 1 week to 1 month Galactosemia, peripheral epimerase deficiency, 3-phosphoglycerate dehydrogenase deficiency, congenital defects of glycosylation 1 month to 1 year Galactokinase deficiency, galactitol or sorbitol accumulation, sialidosis, mitochondrial disorders, mevalonic aciduria 1 to 15 years Dominant hyperferritinemia, disease, lysinuric protein intolerance

Corneal opacity

3 to 12 months Tyrosinosis type II, cystinosis, I-cell disease, mucopolysaccharidosis type I, type VI, steroid sulfatase deficiency 1 to 6 years Mucopolysaccharidosis type IV, alpha mannosidosis, Tangier disease

>6 years Fabry disease, galactosialidosis, disease

Cherry red spot

Neonates GM1 gangliosidosis, galactosialidosis (early infantile form), Niemann-Pick disease type IA 3 to 12 months Galactosialidosis (late infantile form), Tay-Sachs disease, Sandhoff disease >6 years Sialidosis type I, galactosialidosis (juvenile form)

Retinitis pigmentosa Abetalipoproteinemia, ceroid lipofuscinosis, peroxisomal disorders, congenital defects of glycosylation, mitochondrial disorders Dislocated lens Homocystinuria, sulfite oxidase deficiency, molybdenum cofactor deficiency Amino acid High in plasma Low in plasma High in urine Alanine Disorders of pyruvate metabolism, urea Untreated Maple syrup urine disease Disorders of pyruvate cycle disorders, mitochondrial metabolism, urea cycle disorders, disorders mitochondrial disorders Alloisoleucine Maple syrup urine disease - Maple syrup urine disease Arginine Argininemia Argininosuccinic aciduria, citrullinemia, Argininemia, cystinuria, lysinuric ornitine transcarbamylase deficiency, protein intolerance carbamylphosphatase deficiency, inadequate diet Argininosuccinate Argininosuccinic aciduria - Argininosuccinic aciduria Aspartate - - - Citrulline Citrullinemia, citrin deficiency, Ornitine transcarbamylase deficiency, Citrullinemia, citrin deficiency, argininosuccinic aciduria carbamylphosphatase deficiency, argininosuccinic aciduria inadequate diet Cystine - - Cystinuria Glutamate Improper sample handling - - Glutamine Urea cycle disorders/hyperammonemia Improper sample handling - Glycine Glycine encephalopathy, organic - Glycine encephalopathy, organic acidemias acidemias Histidine Histidinemia (benign condition) - Histidinemia (benign condition) Homocystine Homocystinuria, disorders of vitamin - Cystathionine beta-synthetase (free) B12 transport & synthesis deficiency, disorders of vitamin B12 transport & synthesis Isoleucine Maple syrup urine disease, recent meal Fasting Maple syrup urine disease, recent meal Leucine Maple syrup urine disease, recent meal Fasting Maple syrup urine disease, recent meal Lysine Recent meal, citrin deficiency, Fasting Cystinuria, lysinuric protein hyperlysinemia (benign) intolerance Methionine Homocystinuria, citrin deficiency, liver Disorders of vitamin B12 transport & Cystathionine beta-synthetase dysfunction synthesis deficiency, liver dysfunction Ornithine Ornitine aminotransferase deficiency, - Cystinuria, lysinuric protein HHH syndrome intolerance, ornithine aminotransferase deficiency Phenylalanine Phenylketonuria - Phenylketonuria Proline Hyperprolinemia - Hyperprolinemia Serine Recent meal - - Threonine Recent meal, citrin deficiency Fasting - Tryptophan - - - Tyrosine Tyrosinemia types I & II, hepatic Phenylketonuria Tyrosinemia types I & II, hepatic dysfunction dysfunction Valine Maple syrup urine disease, recent meal Fasting Maple syrup urine disease, recent meal Corneal Opacity Cherry Red Macula