46
Inborn errors of metabolism

Inborn errors of metabolism are individually rare (Table 46.1) but almost 100 may present in the neonatal period (Table 46.2). Delay in diagnosis can result in irreversible neurologic sequelae or death. In the US, tandem mass spectrometry on blood screening spots is used to identify a wide range of disorders; in the UK, metabolic screening is currently limited to phenylketonuria (PKU), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), maple syrup urine disease (MSUD), isovaleric aciduria (IVA), glutaric aciduria type I (GA1) and homocysteinuria (HCU).

Table 46.1 Examples of inborn errors of metabolism that may present in the neonatal period with incidence.

Amino acid disorders	Urea cycle – ornithine transcarbamylase
	Maple syrup urine disease (MSUD)
Carbohydrate disorders	Galactosemia
	Glycogen storage disease
Organic acidemias	Propionic acidemia (PA)
	Methylmalonic acidemia (MMA)
Fatty acid oxidation defects	LCAD (long-chain acyl-CoA dehydrogenase deficiency)
	MCAD (medium-chain acyl-CoA dehydrogenase deficiency)
Energy defects	Lactic acidosis (LA)

Table 46.2 Incidence of some inborn errors of metabolism.

Disorder	Incidence
Phenylketonuria	1 in 10 000–20 000
Homocystinuria	1 in 200 000–335 000
Galactosemia	1 in 30 000–60 000
Maple syrup urine disease	1 in 185 000
If screened with tandem mass spectrometry:
Amino acid disorders	1 in 4800
Fatty acid oxidation defects	1 in 14 000
Organic acid disorders	1 in 20 000

Age of presentation

Inborn errors can present at any age to adulthood, including in utero as hydrops fetalis. Presentation is often non-specific with a wide differential diagnosis (see below). A characteristic presentation is with acute deterioration or sudden death in the first 3−7 days of life when a previously well term infant who is feeding accumulates toxic metabolites of intermediary metabolism that were previously removed by the placenta. However, feeding is not an obligatory trigger, except for galactosemia.

When to suspect an inborn error of metabolism

Clinical features

Neurologic:
- poor feeding, vomiting
- apnea, tachypnea (secondary to central respiratory stimulation by hyperammonemia or acidosis)
- irritability, progressive lethargy, hypotonia, seizures, encephalopathy, coma.
Acid–base abnormality:
- persistent, unexplained metabolic acidosis or lactic acidosis
- respiratory alkalosis secondary to hyperammonemia
- respiratory distress (from metabolic acidosis).
Hypoglycemia – severe and persistent.
Acute liver disease:
- conjugated hyperbilirubinemia, coagulopathy, hepatomegaly or hepatosplenomegaly.
Cardiac disease:
- cardiac failure or arrest from arrhythmias or cardiomyopathy.
Dysmorphic features.
Failure to gain weight.
Abnormal body or urine odor.

Suggestive clues

Positive family history.
Parental consanguinity.
Sibling or family members with unexplained severe illness, recurrent miscarriages or neonatal death.
Maternal fatty liver of pregnancy (in fetal fatty acid oxidation defects).
Sudden onset of symptoms in previously well term infant.
Progressive deterioration or death despite supportive treatment.

Differential diagnosis

Sepsis – ill with non-specific features.
Congenital heart disease – heart failure, low oxygen saturation.
CNS disease – seizures, encephalopathy, infection (herpes simplex virus), intracranial hemorrhage, non-accidental injury.
Gastrointestinal – vomiting from obstruction, liver disease.
Endocrine – hyperinsulinism, hypopituitarism, adrenal insufficiency.
Hypoxic–ischemic encephalopathy (HIE) – seizures and encephalopathy.

Investigations (Tables 46.3 and 46.4, Fig. 46.1)

Table 46.3 First-line investigations when inborn error of metabolism is suspected.

Investigation	Abnormality	Possible disorder
Blood gas	Metabolic acidosis	Organic acidemia, disorders of carbohydrate metabolism, mitochondrial disorder
	Respiratory alkalosis (due to hyperammonemia)	Urea cycle disorder
Glucose	Hypoglycemia with ketosis	Organic acidemias; glycogen storage
	Hypoglycemia without ketosis	Fatty acid oxidation, hyperinsulinism
Ammonia	Hyperammonemia (Fig. 46.1)	See Fig 46.1
Lactate	High	Respiratory chain defects, pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, hypoxia
Blood urea nitrogen (urea)	Low	Urea cycle
Electrolytes	Raised anion gap	Lactic acidosis, organic acidemia
Liver transaminases	High	Tyrosinemia, galactosemia
Complete blood count	Neutropenia Thrombocytopenia	Organic acidemias
Coagulation	Prolonged	Liver disease, galactosemia, tyrosinemia
Urine	Abnormal odor	Organic acidemia, PKU, MSUD
Urine reducing substances	Negative for glucose	Galactosemia
Urine ketones	Positive	Organic acidemias including MSUD
	Low/negative	Fatty acid oxidation disorders

(MSUD – maple syrup urine disease, PKU – phenylketonuria.)

Management

Early intervention (Table 46.5) is imperative to prevent neurologic sequelae or death. Families will need genetic counseling, which may include screening siblings.

Table 46.5 Approach to management.

Basic support	Cardiorespiratory support, treat sepsis, anticonvulsants as required
Nutrition	Stop protein-containing feeds Stop galactose-containing feed if galactosemia possible. Avoid catabolism – give intravenous dextrose (minimum 10%) to ensure normoglycemia Consider insulin to control blood glucose and to promote anabolism, rather than reduce glucose intake Consider use of vitamin therapies, Table 46.6
Fluids	Consider bicarbonate to correct acidosis
Toxin removal	Ammonia scavenging medications (sodium benzoate, sodium phenylbutyrate or carglumic acid) Substrate support with arginine and/or carnitine Consider hemodialysis or hemodiafiltration

Table 46.6 Examples of vitamins used to treat IEM.

Carnitine

Pyridoxine and pyridoxal phosphate for seizure control

Vitamin B₁₂

Biotin (for biotinidase deficiency)

Hydroxycobalamin (for vitamin B₁₂-responsive methylmalonic acid)

Riboflavin (for glutaric aciduria type II)

Thiamin for pyruvate dehydrogenase deficiency

Also coenzyme Q for respiratory chain support, sodium benzoate, biopterin