Inborn errors of metabolism:

emergency management

Classification of inborn errors of metabolism: (IEM)• I: Intoxication disorders

• II: energy metabolism disorders

• III: complex molecules disorders

Presenting features

Acute presentation• Vomiting• Dehydration• Lethargy• Coma• Rhabdomyolysis• Heart failure• Liver failure • ALTE• Respiratory failure (as complication)

Chronic presentation • FTT• Hepatomegaly• Cardiomyopathy• Developmental delay• Developmental regression

Triggers for decompensation

Increased catabolism Increased consumption

• Fasting• Surgery• Trauma• infection

• Increased protein consumption

Metabolic Causes of acute decompensation

Neurology---------------

MSUDMMAPAIVAMCDUCDFAORCD

SEIZURE--------------

B6 responsiveMCDFolonic acid disordersGlucose up-take

Liver failure-----------------

GALACTOSEMIATyrosinemiaBile acid synthesisRCDGSD

Cardiac failure &Cardiac beat, ALTE---------------

Carnitine disordersFAOStorage diseases

Neurology decompensation(acute encephalopathy)Definitions:

• Consciousness: a state of general wakefulness and responsiveness to environment

• Coma: A state of deep, unarousable, in which the person shows no meaningful response to environment

consciousness sleep lethargy stupor coma

Background physiology

Consciousness requires two components:

1- Arousal or wakefulness, dependent on the function of Reticular Activating System (RAS), a network of neurons located in the brainstem extending from pons to thalamus

2- Awareness, mediated through cerebral neurons

• Awareness requires wakefulness and not vice versa

structural Metabolic-toxictrauma Hypoxia-ischemia

neoplasm Metabolic disordersHypoglycemia, hepatic,

electrolytes, DKA, uremiaVascular

Infarction, haemorrhage, vasculitis

infection

Focal infectionAbscess, cerebritis

Paroxysmal disordersEpilepsy, migraine

hydrocephalus

Classification of causes of acute encephalopathy

Patient assessment

• Primary survey:

A B C DISABILITY – Glascow Coma Scale , useful objective tool for the quantification of the consciousness-coma continuum

• Secondary survey:

Glascoma scoreEyes open spontaneously +4

Eye opening to verbal command +3

Eye opening to pain +2

Eye opening to pain +1

Not assessable 0

Best Verbal Response

Oriented +5Confused +4Inappropriate words +3Incomprehensible sounds +2No verbal response +1Intubated 0Best Motor Response

Obeys commands +6Localizes pain +5Withdrawal from pain +4Flexion to pain +3Extension to pain +2No motor response +1

Investigations of encephalopathy patient

Laboratory investigations• CBC• Electrolytes• LFT• Coagulation profiles• BUN, Cr, Ca, Mg, PO4• Ammonia• Lactate• CPK• Glucose• ABG

Imaging studies• CT/MRI• MRI

HYPOGLYCEMIA

acidemia No acidemia

LA KETONESI

G6PDF1,6P

NormalKetotic hypoglycemiaDebrancher enzymeGH dCortisol d

I FFA

ketones

FAO

FFA

ketones

hyperinsulinism

HYPERAMONEMIA

Bedside differential diagnosis of inborn errors of metabolism presenting with hyperammonemiaParameter Condition

UCDs Organic acidurias

β-Oxidation defects

Hyperinsulinism-

hyperammonemia

syndrome

Pyruvate carboxylase deficiencyg

Acidosis +/– + e +/– – +Ketonuriaa – + – – ++Hypoglycemiab – +/– + + +

↑ Lactic acidc – + +/– – +↑ AST & ALT (+)d – + – +/–↑ CPK – – + – –↑ Uric acid – + + – –↓ WBC/RBC/Plt – + – – –

Weight loss – +f – – +

In addition to the conditions indicated in the table, mitochondrial oxidative phosphorylation defects, citrin deficiency, lysinuric protein intolerance or

findings MSUD OA UCD DCM FAO MD PD LSDMetabolic acidosis

+-

++ - +-

+-

+-

- -

Respiratory alkalosis

- - + - - - - -

Hyperammonemia

+-

+ +++ - +-

+-

- -

Hypoglycemia +-

+-

- + - +-

- -

Ketones A/H H A A/H A/L A/H A ALactic acidosis =

-+-

- + +-

++ - -

DISTINGUISHING BIOCHEMICAL FINDINGS OF IEM

Emergency treatment

• Ventilator support• Fluid resuscitation with saline• Hypoglycemia: 7-10 mg/kg/min, keep blood sugar more than 5.5mmol/l• Hyperammonemia: glucose 10mg/kg/min over 2 hours: Arginine 360mg/kg Na benzoate & or phenylacetate 250mg/kg (max 500/kg) carnitine 100mg/kg maintains: as above Carbaglu in organic academia and UCD 100-200/kg stat, then 100 mg/kg/d

• Metabolic acidosis: PH (more than 7.3) 4-6 meq/kg/d PH (less than 7.3) 1-2 meq/kg/hr to be tapered accordingly

DisorderDistinctive Features

Ketosis Acidosis Other cofactor

Maple syrup urine disease (MSUD) 1

X Maple syrup odor thiamine

Propionic academia 2 X X Neutropenia biotin

Methylmalonic acidemia (MMA) X X Neutropenia B12

Methylmalonic aciduria and homocystinuria, cblC type

Rare RareVomiting, poor feeding, neurologic symptoms

B12, pyrodoxin

Isovaleric academia 1 X Sweaty feet odor

Biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiency

X Hypoglycemia

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency

Reye syndrome, hypoglycemia

Ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase deficiency)

X X Hypoglycemia

Glutaricacidemia type I (GA I)

Basal ganglia injury with movement disorder

riboflavin

Clinical Findings in Organic Academia's Caused by Abnormal Amino Acid Catabolism

Acute management of newborn with suspected organic acidemia1) The patient is kept nil per orally and intravenous glucose is provided.2) Supportive care: hydration, treatment of sepsis, seizures, ventilation.3) Carnitine: 100 mg/kg/day IV or oral.4) Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr)5) Start Biotin 10 mg/day orally.6) Start Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms ofmethylmalonic acidemias)7) Start Thiamine 300 mg/day (useful in thiamine-responsive variants of MSUD).8) If hyperammonemia is present, treat as explained above.

Discontinue all feeds. Provide adequate calories by intravenous glucose andlipids. Maintain glucose infusion rate 8-10 mg/kg/min. Start intravenous lipid 0.5g/kg/day (up to 3g/kg/day). After stabilization gradually add protein 0.25 g/kg till1.5 g/kg/day.2) Dialysis is the only means for rapid removal of ammonia, and hemodialysis ismore effective and faster than peritoneal dialysis, however peritoneal dialysis maybe more widely available and feasible. Exchange transfusion is not useful.3) Alternative pathways for nitrogen excretion-:Sodium benzoate (IV or oral)- loading dose 250 mg/kg then 250-400 mg/kg/dayin 4 divided doses. (Intravenous preparation not available in India).Sodium phenylbutyrate (not available in India)-loading dose 250 mg/kg followedby 250-500 mg/kg/day.L-arginine (oral or IV)- 300 mg/kg/day (Intravenous preparation not available inIndia)L-carnitine (oral or IV)- 200 mg/kg/day4) Supportive care: treatment of sepsis, seizures, ventilation. Avoid sodiumvalproate.

Treatment of hyperammonemia

Supportive care: hydration, treatment of sepsis, seizures, ventilation. Avoidsodium valproate.2) Treat acidosis: sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr)3) Thiamine: up to 300 mg/day in 4 divided doses. Riboflavin: 100 mg/day in 4 divided doses.5) Add co-enzyme Q: 5-15 mg/kg/day6) L-carnitine: 50-100 mg/kg orally.7) Biotin 10 mg/day. (Biotin responsive Multiple carboxylase deficiency maypresent with unexplained lactic acidosis)12