Errors Of Metabolism

Enzyme Defects NEONATES Usually present with collapse + acidosis Differentials = CHS/Sepsis/IEM Increased risk if: Consanguinity – rare AR disorders FH of unexplained deaths Maternal HELLP / acute fatty liver in pregnancy Previous miscarriage / non-immune hydrops Well period before deterioration – placenta clears most toxins therefore have to build up from birth Encephalopathy +/- seizures Metabolic acidosis + anion gap Increased blood ammonia Low BM Urine ketones Dysmorphism Unusual odours Acute intoxication Organic acidaemias (propionic, methylmalonic, isovaleric) MSUD Urea cycle defects Fatty acid oxidation defects Transient hyperammonaemia of the new-born Encephalopathy with seizures Non-ketotic hyperglycinaemia Neurotransmitter defects Pyridoine defects Urea cycle disorders MSUD Congenital lactic acidosis Neonatal liver disease + multi-organ failure Galactosaemia / tyrosinaemia Neonatal haemachromatosis Fatty acid oxidation defect Mitochondrial / glycogen storage disorder Niemann-Pick C Non immune hydrops +/- dysmorphism Lysosomal storage disorder Disorders of sterol metabolism (Smith-Lemli-Opitz) Peroxisomal Red cell enzyme defects Neurological deterioration +/- energy deficiency Mitochondrial / peroxisomal Investigations Serum ammonia, lactate, acylcarnitines Amino acids CSF – lactate and aa Urine – organic acids, aa + oligo/polysaccharides Treatments STOP FEEDS = eliminates toxic precursors Ensure anabolic state = maintain hydration + simple calories (10% dextrose) Remove toxic metabolites = dialysis / stimulate alternative pathway Supportive treatment = correct low BMs & acidosis. Treat low BP & sepsis Reintroduce feeds – once diagnosis CHILDREN Acute encephalopathy Raised ammonia (late onset urea cycle disorder, organic acidaemia, liver failure) Fatty acid oxidation defects Late/intermediate onset MSUD Porphyria Mitochondrial disorders Anion gap = Na + K – (Cl + HCO3) = Usually 10-15 Osmo Gap = actual osmo – (2 (Na) + Glu + Ur) Ketotic Hypoglycaemia Poorly understood Decreased fasting tolerance Often IUGR/SGA Diagnosis of exclusion Rx: emergency feed regime + prevent prolonged fasting If vomiting à 10% dextrose MCAD (and other fatty acid oxidation defects) Hypoglycaemia = late sign Encephalopathy first Screen by carnitines & acylcarnitines Rx – emergency feed plans Glycogen storage disorders Present at any age (most commonly in the first few months) Low BM, high lactate, high urate + palpable liver Hyper-insulin / ammonia Error of glutamate dehydrogenase Multi organ failure Assoc with tyrosinaemia, glactosaemia, mitochondrial disease Ix for encephalopathy BM, carnitines & acylcarnitines, serum lactate + uric acids, urine for organic acids & aa, 3HB:FFA Dysmorphism Lysosomal storage / peroxisomal / mitochondrial / sterol metabolism errors Ix: Urine GAGs (mucopolysaccharidoses) Urine oligosaccharides (oligosaccharidoses) VLCFAs (peroxisomal disorders) MRI Brain (Grey V white matter) Skeletal survey (dysostosis multiplex) Opthalmology RV (clouding/cherry red spot + retinopathy) Visual evoked potentials – brainstem dysfunction Peroxisomal Many separate disease with similar symptoms Dysmorphism, psychomotor slowing, poor tone, weakness, intractable fits, leukodystrophy, vision & hearing difficulties Lysosomal storage disorders Hyperactivity & poor sleep, skeletal (gibbus & kyphosis), gargoylism or dysmorphic/dysplasia/dwarfism, hepatosplenomegaly, gingival hypertrophy, neurodegeration, corneal clouding, changes in retinal pigment Mucopolysaccharidosis Deficiency of enzymes to degrade GAGs All AR (except Hunters = XL) Oligosaccharidosis Skeletal dysplasia, developmental delay, coarse face, neurological deterioration Sphingolipidoses Component of myelin accumulates in reticuloendothelial system e.g. Gauchers, Fabry’s, Niemann Pick A/B Lipidoses e.g. Niemann Pick C Fast feed cycle During fasting Glycogen à glucose + lipolysis à glucose + fatty acids. Brain & kidney need glucose not fatty acids à gluconeogenesis from protein à ketoacids à liver à ketones / glucose During feeing Glucose à glycogen, ketosis reversed, fatty acids & amino acids re-synthesised Illness results from energy insufficiency. If catabolic process if affects à intoxication with ketoacids / lactic acids & ammonia = fasting stress à decompensation Inborn errors of metabolism Tend to be delayed in diagnosis because: Limited Sx Rare (look for common conditions 1st) Unfamiliar tests (may not send for vital tests / problems in interpretation) SHOULD be considered alongside common conditions THEREFORE – should be tested in ALL children with encephalopathy A Principle of error locations Failure of “A” to enter cells (e.g. Hartnup disease) Deficiency of enzyme “a” à accumulation of A (e.g. galactosaemia = accumulation of galactose-1phosphate) Deficiency of enzyme “a” à build of alternative metabolic products of A (e.g. PKU) Deficiency of end products C (e.g. albinism à deficient melanin) Failure of -ve feedback control (e.g. CAH) Clues Neuro Resp ========= Cell memb. A Enzyme a - B Enzyme b C Fluctuating encephalopathy Changes in muscle tone e.g. normal tone in comatose state / axial hypotonia with limb hypertonia / hypertonia with opistotonus Abnormal movements – e.g. jerky myoclonus / boxing / tongue thrusting / lipsmacking / tonic arm elevation NB: true seizures occur late Tachypnoea – respiratory alkalosis – urea cycle disorder Apnoea / periodic breathing in term infants Hiccoughing – hyperketotic hyperglycaemia Temp GI Unexplained hypothermia Vomiting Jaundice Dehydration + polyuria – methyl-malonic academia / propionic-acidaemia Group I – disturbed synthesis / catabolism of complex molecules Symptoms permanent & progressive therefore RARE in neonates Independent of food intake / intercurrent events E.g. Lysosomal / Peroxisomal disease Group II - Metabolic block à Deficiency (end product) & accumulation (interim product) Clinical Sx after a symptom free period Present in a few neonates – due to variable accumulation of products E.g. organic acidaemias, urea cycle disorders Group III – deficiency in energy production / utilisation Symptoms occur during fasting (surgery / stress / overnight) 2-4% of cot death Commonly present at 2-4 months when children start sleeping through the night E.g. fatty acid oxidation disorders, glycogenolysis errors Management STOP all protein intake (inc TPN) Start glucose infusion (6-8mg/kg/min – to stop protein breakdown) Correct acid-base balance Cover for infection Control dehydration & seizures Then start Ix Ix FH & Past Hx Still-births / Neonatal deaths Cot deaths Smells MSUD = burnt sugar Isovaleric acidaemia = sweaty feet Glutaric aciduria = Fish (can à acute status dystonica) PKU – musty odour (sweat & urine) Screening – only useful if treatment available PKU – by time found clinically, damage would be too severe MCAD – usually naturally presents as death on fasting Urine Basic – smell, ketosticks, reducing substances, pH, sulfitest Advanced – organic acids & amino acids – 15-20 mls frozen Blood Basic – lab glucose, FBC, UE, Gas, LFTs Basic specific – ammonia, uric acids, biotinidase, Advance - lactate, FFA, ketones, amino acids, acylcarnitines, carnitines, galactosaemia, plasma for storage Others Infection screen CSF Cranial US ECHO Post mortem Skin biopsy CSF Liver biopsy Dysmorphism Some metabolic disorders à chemical accumulation à dysmorphism e.g. maternal PKU à microcephaly & cleft palate, cardiac probs e.g. pyruvate dehydrogenase deficiency à bifrontal narrowing, high forehead, similar to fetal alcohol syn. Hypoglycaemia Take bloods while hypoglycaemic including for C-peptide (? Factitious/induced illness) Neonates – commonest cause is hyperinsulinaemia due to islet hyperplasia Toddlers – commonest is idiopathic ketotic hypoglycaemia = diagnosis of exclusion If without ketosis Then? Fat oxidation defects, hyperinsulinism, hypopituitarism If ketosis but no raise in lactate Then? Glycogen storage III / synthase deficiency, organic acidaemia, adrenal insufficiency or hypopituitarism If ketosis + lactic acidosis Then? Glycogen storage disease I, disorders of gluconeogenesis and organic acidaemias No Ketones Hepatomegaly Urine Reducing Substances Raised Lactate Y Y Y Y Hyperinsulinaemia MCAD Glycogen storage disorder Galactosaemia Hereditary fructose intolerance Glycogen storage disorder / mitochondrial 100’s = organic acidaemia Raised Ammonia Y 1000’s = urea cycle disorder Metabolic acidosis In early neonate – need to exclude CHD & renal dysplasia (renal tubular acidosis) In infant – need to exclude sepsis & NEC Commonest is organic acidaemias – present with acidosis, ketoacidosis and encephalopathy More rare than PKU individually but more common when combines Can à fulminating neonatal illness or slowly progressive neuro-degeneration NB – ketones are unusual in neonate even in starvation Propionic – can present late with developmental delay, chorioathetosis and T cell immunodeficiency Methylmalonic – recurrent vomiting, FTT & developmental delay Acute encephalopathy Common with many metabolic disorders 2/3 of cases present after acute illness (flu / D&V etc) Peak age of neuro deterioration is 12m Reye Syndrome Acute, non inflammatory encephalopathy (WCC< 8 in CSF) With increased ammonia (3x uln) or increased transaminases (3x uln) AND no more reasonable explanation for condition Some link to aspirin use, influenza A and varicella Mitochondrial Disease Global delay Microcephally Muscle hypotonia Opthalmoplegia Raised lactate Strongly consider if: • Muscle disease + 2 other systems • CNS disease + 2 other systems • Multisystem disease (3+) and Muscle / CNS involvement Investigation: • Organic acids to exclude organic acidura • MRI – to show degenerative changes • CSF lactate – proves brain involvement • Muscle biopsy to show ragged red fibres = definitive Phenylketonuria (PKU) Enzyme block (in liver) = phenylalanine hydroxylase deficiency preventing phenylalanine à tyrosine AR. Chr 12. 1/10,000 births. Carriers = 1/36. If an affected treated mother meets a carrier = 1/72 chance of affected child Tested on Guthrie Card (infant must be established on milk) Sx – Untreated mum à congenital heart defects, microcephaly and learning difficulties due to teratogenic effects of untreated maternal PKU Untreated child à progressive developmental delay (disinterest by 3-6m, clear delay by 1yr), dry skin / rashes, musty odour (of sweat & urine due to phenylacetate) & seizures Diagnosis – increased phenylalanine, decreased tyrosine, normal biopterin metabolism Rx – Dietary phenylalanine restriction (prevents toxic metabolites, but ensures sufficient essential AAs) Effective but can à behavioural problems Usually until 6-8yrs old (nervous system is then less vulnerable) Should be reintroduced preconception as à Microcephaly, severe handicap & structural probs in fetus Organic Acidaemias Increased carboxylic acids (metabolites of AA, Carbs & Fats) Can affect several pathways e.g. branched chain AA or propionyl CoA Presentation Normal at birth Develop acute encephalopathy within 1st week Metabolic acidosis with raised lactate & ammonia & with anion gap. Dehydration/ shock Low Neuts & plts (marrow suppression) Sweaty odour (isovaleric) Neuro complications – metabolic stroke, Basal ganglia involvement Cardiomyopathy (propionic) Pancreatitis Features – vomiting, hypoglycaemia, hyperammonaemia, ketonuria, neutropenia & thrombocytopenia Diagnosis – Urine organic acids or carnitines Metabolic acidosis with ketosis & raised ammonia Distinct urine organic acid profiles Confirm by enzyme analysis Management Stop feeds, given 10% dextrose Rehydrate Bicarb Dialysis to remove ammonia Remove organic acids – carnitine for propionic/methylmalonic, glycine for isovaleric Metronidazole – decreases gut bacteria à reduces production of propionic acid Co-factor supplementation – some are due to low co-factors e.g. biotin / B12 Long term – low protein diet with oral bicarb, carnitine, metronidazole and cofactors E.g. Maple Syrup Urine Disease (MSUD) Defective decarboxylation of branched chain amino acids Presents after breast feeding established (time for toxic metabolites to build up) Sx Progressive encephalopathy from 3-4 days old (once sufficient protein ingested) Peculiar odour (ketonuria) Later metabolic acidosis Dx – increased plasma AAs (leucine, isoleucine, valine) = neurotoxic Acute Mx = IV dextrose & insulin to stop protein breakdown & encourage anabolism. Manitol, Haemodialysis Long Term Mx = dietary restriction with supplements to provide sufficient leucine Outcome – poor Methylmalonic acidaemia Defects in methymalonic-CoA mutase Prevents methylmalonyl-CoA à Succinyl-CoA Requires vitamin B12 therefore can be temporary if deficiency Propionic acidaemia Defective propionyl CoA carboxylase è Only partial processing of branched AAs (isoleucine, valine, threonine & methionine) è build up of propionic acid è damage to brain, heart, muscles etc è poor feeding, vomiting, dehydration, acidosis, hypotonia & lethargy Can be managed with close dietary monitoring May need hospitalisation during illness Significantly more common in Saudi Arabia & Amish Isovaleric acidaemia Defective isovaleric acid-CoA dehydrogenase = responsible for processing leucine Distinctive odour of sweaty feet (due to build up of isovaleric acid) ½ present as babies – poor feeding, vomiting, seizures, and coma Other ½ have sub-acute presentations in childhood with episodes triggered by infection / protein rich meal Rx – dietary restriction & give glycine during illness (conjugates à isovalerylglycine = harmless) Treatment – Protein restriction & L-carnitine (essential AA) Prognosis – Poor. Liver transplant may help Glycogen storage diseases Differential for recurrent hypoglycaemia, hepatomegally, muscle weakness & CCF Type 1 (G-6-Phosphatase deficiency) aka Von Gierke’s disease Infant onset Hepatomegally, hypoglycaemia, metabolic acidosis (body cannot respond to glucagon) Confirm by liver biopsy Patients unable to tolerate fasts over 2-3 hrs Overnight glucose feeds required Type 2 (Pompe disease) Lysozymal Alpha-glucosidase deficiency Excessive glycogen deposition in liver & muscle with cardiac involvement Present soon after birth with poor feeding, weakness, tachypnoea & cardiac failure due to hypertrophic cardiomyopathy DON’T get hypoglycaemia Treatment is supportive Type 3 (Cori’s / Forbes disease) Debranching enzyme deficiency Hypoglycaemia, hepatomegaly & myopathy Rx – high protein diet Type 4 (Andersen disease) Liver phosphorylase deficiency DON’T get hypoglycaemia Do get hepatomegaly & cirrhosis. + FTT. Death approx 5 years Type 5 (McArdle disease) Muscle glycogen phosphorylase deficiency Exercise induced muscle cramps & myolysis à renal failure Galactosaemia Rare AR Clinitest - +ve if reducing sugars Lactose = glucose + galactose e.g. glucose, lactose, fructose, maltose Deficiency of Gal-1-Put (galactose-1-Phospate uridyl NB false +ve with ascorbic & nalidixic acid transferase) Increased galactose 1 phosphate à accumulates in Clinistix - +ve with glucose only neurones & liver à damage & cataracts Sx – FTT (If unable to metabolise galactose = only ½ +ve clinitest with –ve clinistix = likely of energy from milk available), Jaundice galactosaemia (after milk feeds start), Hepatomegaly, à liver failure, sepsis Lethargy, poor feeding, vomiting, hepatomegaly, mixed hyperbilirubinaemia Renal tubular acidosis, hepatomegaly, hypoglycaemia Oil drop shaped cataracts NB – also assoc. with E.coli septicaemia Ix Positive urine reducing substances (galactose) ( = Clinitest) Gal-1-Put in RBCs (invalid if RBC transfusion in 6/52) Treatment – galactose free diet Prognosis – fatal if appropriate treatment not given. Even with good compliance can have poor neuro function Hereditary Fructose Intolerance Fructose à abdominal pain, nausea, vomiting, hypoglycaemia à hepatomegaly, poor growth & liver failure +ve urine reducing substances Rx – avoid sucrose and fructose in diet Fatty acid oxidation disorders Mitochondria à B-oxidation of fatty acids à energy production Especially important during fasting Present after fasting MCAD Deficiency Medium chain acyl-CoA dehydrogenase deficiency 5/100,000 – commonest of the fatty acid oxidation defects (thought to be linked to unexplained infant mortality) Pathophysiology Mitochondrial defect à affects hepatic metabolism of acetyl CoA and NADH2 (essential for gluconeogenesis & ATP synthesis) Blocks ketone production à aggravates energy depletion for brain & cardiac muscle Sx - Clinical severity varies. Can be asymptomatic even in adults Asymptomatic until stressed à collapse, encephalopathy, hypoglycaemia, abnormal LFT’s (within hours) Presentation (usually 1-3 yrs = when starts sleeping through) Hypoglycaemia with inappropriately low plasma/urine ketones Ix – High plasma FA : 3HB ratio Now tested on neonatal heel prick test. Congenital Lactic Acidosis Encephalopathy with intractable seizures = similar to HIE Dx – lactic acid out of proportion to severity of insult Sx – SGA, subtle dysmorphism, structural brain malformations Ix – Lactate / Pyruvate ratio will be > 25 Urea cycle disorders = total of 6 Ornithine Transcarbamylase deficiency (OTC) Prevalence 1:40,000 X Linked enzyme block – fatal in hemizygous males (during neonatal period) Starts after sufficient protein ingested Mild form à vomiting, fits, (following high protein meals) coma & retardation Characteristic symptoms: – after starvation à catabolism à raised ammonia High ammonia (often >800 umol/L), low urea, high transaminases, high urinary ortic acid – Vomiting, seizures, lethargy & coma – Respiratory alkalosis due to high ammonia à raised RR ** May be misdiagnosed as sepsis Diagnosis – liver biopsy and genetic probes antenatally Rx – STOP FEED, IV glucose, IV sodium benzoate, if ammonia > 500 consider haemodialysis Prevention: restrict protein, supplementary arginine NB: Hyperammonaemia doesn’t = Urea cycle disorder Differentials Urea cycle disorder Sepsis etc NB: Should measure ammonia in any non-injury/non epileptic seizure or decreased conscious Can have focal neurology Treatment Stop protein Treat associated problems e.g. low BM, acidosis, dehydration If ammonia > 150 micromol à sodium benzoate + sodium phenylbutyrate If > 350 à urgent dialysis Longer term Rx Protein restrict (1.5g/kg/day) Sodium benzoate (conjugates glycine to make hippurate) Arginine supplements Liver transplant Prognosis - poor Transient Hyperammoniaemia of the newborn Tachypnoea, raised ammonia Due to patent ductus venosus à blood bypassing liver Neurodevelopmental delay & regression Delay is usually autism Regression / loss of skills needs Ix Lesch-Nyhan syn = X linked, HGPRT deficiency, urate crystals in urine, progressive despite treatment à renal failure Leigh Syndrome = demyelination, necrosis and gliosis Mitochondrial disorder (cytochrome-C-oxidase deficiency) – Mother-daughter transmission OR X linked form affecting pyruvate dehydrogenase – Mother are carriers, affected sons Manifests between 3m and 2y as loss of skills Affecting cells of brain stem most severely Poor outcomes (respiratory infections / direct effects) X-linked Adrenoleukodystrophy Excess VLCFA Progressive damage to myelin Neuro-regression starting 4-10yrs à seizures, ataxia, visual & auditory loss Adrenal failure à Addison’s, raised ACTH à tanned appearance à decerebratation in a few yrs. Macromolecular Catabolism Blocks Disorders of lysosomal function à Structural & functional disruption of tissues (esp. NS à disability & death) Suggestive features – neuro deterioration, hepatosplenomegaly, bone deformity, eye signs & coarsening facies Tay-Sachs (GM2-gangliosodosis) Deficiency of lysosomal hexosaminidase complex A&B à Accumulation of gangliosides in grey matter due to lysosome disorder Common in Ashkenazi Jewish population Developmental recession (from 6-9 months) Exaggerated startle to sound (hyperacusis) Muscle weakness & neuro sx by 3-5 months Developmental delay, macrocephaly Optic atrophy, cherry red spots on maculae, visual inattention, and social unresponsiveness Convulsions & swallowing difficulty à death by 3-5yrs Metachromic Leukodystrophy (lysosomal storage disorder) Deficiency of arylsulphatase A enzyme Involves white matter Obvious in 2nd yr Sulphatides accumulate throughout NS à demyelination à motor deterioration & spasticity à intellectual loss, blindness & convulsions Infantile form = Sx by 4 yrs & death 5 years later Other forms = juvenile, late juvenile and adult If identified while asymptomatic then can give bone marrow transplant Gaucher Disease = Sphingolipidoses =lysosomal storage disorder AR Disorder of lipid metabolism B-glucosidase deficiency à accumulation of glycolipds in phagocytes & CNS Type 1 – non-neuropathic (commoner) Present in childhood / early adulthood with tiredness, organomegally & bone pain (due to deposition of sphingolipids) Hepatosplenomegally, hypersplenism, bone involvement à path # Pingueculae = orange wedges in conjunctiva Yellow / brown discolouration in skin areas exposed to sun Reasonable life span Course improved by glucocere brosidase infusions Type 2 – neuropathic Presents in infancy Feeding problems, stridor, spasticity, hepatosplenomegaly, dead within months Investigations Bone marrow will show glycolipid-laden macrophages Leg Xray will show Erlenmeyer flask deformity US will show organomegally Enzyme studies are diagnostic Treatment = enzyme replacement Niemann-Pick disease Abnormal storage in reticulo-endothelial system. 4 varieties – 2 are neuronopathic Can resemble Tay-Sachs and have cherry red macular spot Foam cells in marrow & liver biopsy Mucopolysaccharidoses Due to abnormal accumulation of glycanamnioglycans (sulphated polysaccharides) in fibroblasts & chondrocytes à Coarsening skin, corneal clouding, skeletal dysplasia, progressive neurodegeneration, hepatosplenomegaly Hurlers – Mucopolysacharidosis I (AR inheritance) all of above features AR, deficiency of alpha -L-isouronidase Excess dermatin & heparin sulphate storage Developmental delay, coarse face, corneal clouding, Hepatosplenomegaly and murmur Thickened skin, frontal bossing, hypertrichosis, claw hands and hepatosplenomegally Enzyme defect – demonstrate by white cell / fibroblast culture. High levels of heparin sulphate in urine. NB: Scheie syndrome = less severe form with normal development & preserved IQ. Can have stiff joints Hunters – Mucopolysacharidosis II Milder than Hurlers (no corneal clouding & milder brain involvement) X-linked. Deficiency of iduronate-2-sulphatase Deficiency of lysosomal enzymes which degrade GAGs à intra-lysosomal accumulation of GAGs à excessive urine excretion of GAGs Variable degree of PROGRESSIVE mental & physical deterioration Skeletal Xrays à dysostosis multiplex Enzyme studies = prove diagnosis Enzyme replacement is available for type 1 & in trials for type 2 Bone marrow transplant can be helpful Sanfillipo – Mucopolysacharidosis III = mild coarsening of face, gradual onset developmental delay/regression + motor disease, increased pain tolerance Moriquio – Mucopolysacharidosis IV skeletal deformity, no brain or systemic involvement Fabrys XLR Manifests in childhood / adolescent Fat storage disorder due to alpha galactosidase deficiency. à accumulation of ceremide trihexoside in damaged viscera Female carries may have cloudy corneas Intermittent burning sensation in hands & feet exacerbated by hot weather / exercise, small purple / red marks to legs Diffuse vascular involvement à hypertension, cardiomegaly, renal failure & thrombotic infarction of viscera Angiokeratomas in periumbilical region Dx: enzyme deficiency in white cells Rx: enzyme replacement à improved function