Infant with cardiomyopathy: When to suspect inborn errors of metabolism?

Table 1 Red flags for inborn errors of metabolism associated with cardiomyopathy

Disorder	Pathognomonic biochemical abnormalities	Red flags
Mitochondrial disease	Elevated plasma lactate, elevated plasma alanine, proline	Hypotonia, developmental delays/regression, other organ involvement
Barth syndrome	Urinary excretion of 3-Methylglutaconic acid
VLCAD deficiency	Elevation of C14:1 acylcarnitine species	Hypoglycemia, elevated creatine kinase, liver dysfunction, metabolic decompensation with illness
LCHAD deficiency	Elevation of hydroxy compounds C14-OH, C16-OH, C18-OH
Systemic primary carnitine deficiency	Very low plasma carnitine and elevated urinary carnitine extraction
CPT2 deficiency	Elevation of C12 to C18 acylcarnitines, notably of C16 and C18:1
GSD deficiency II (Pompe)	Decreased acid alpha-glucosidase enzyme activity	Hypotonia, enlarged tongue
MPS1 (Hurler, Hurler-Scheie, Scheie)	Elevated urine GAGs, decreased alpha-L-iduronidase enzyme activity	Dysmorphic features (coarse features), hepatomegaly, hernia, hearing loss, corneal clouding (MPS1) developmental delays/regression
MPS2 (Hunter)	Elevated urine GAGs, decreased iduronate-2-sulphatase enzyme activity
Propionic aciduria	Urine organic acids: 3- hydroxypropionate, Methylcitrate, Tyglylglycine, Propionyl Glycine Plasma acylcarnitines: Elevated C3 (propionylcarnitine)	Hypotonia, high anion gap acidosis, hyperammonemia, metabolic decompensation with illness
Malonic aciduria	Plasma acylcarnitines: Elevated C3-DC (Malonyl carnitine). Urine organic acids: elevated malonic acid	Developmental delay/regression, hypotonia, hypoglycemia
Congenital disorders of glycosylation	Abnormal carbohydrate deficient transferrin, abnormal N- and O-glycosylation profiles (qualitative and/or quantitative)	Hypotonia, developmental delays/regression hypoglycemia, liver dysfunction

VLCAD: Very long-chain acyl-CoA dehydrogenase; GAGs: Glycosaminoglycan; CPT2: Carnitine-palmitoyl transferase deficiency; LCHAD: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; GSD II: Glycogen storage disease type 2; MPS1: Mucopolysaccharidosis type 1.

Table 2 Biochemical testing recommendations for metabolic evaluation

Tier 1

Creatine kinase

Plasma acylcarnitine profile

Urine organic acids

Plasma lactate/pyruvate

Plasma amino acids

Enzyme analysis1

Tier 2

Carbohydrate deficient transferrin analysis

Urine glycosaminoglycans

Lysosomal storage disease enzyme panel (large panels are available through many laboratories)

Tier 3

Specific gene sequencing

¹If there is a high suspicion for a single metabolic disease, for example Pompe disease.