Disorders of fatty acid oxidation

The fatty acid oxidation disorders comprise a clinically continuous spectrum, from severe neonatal-onset multiorgan disease to mild late-onset myopathy. Onset ranges from the neonatal period to adulthood, according to the specific enzyme defect and residual activity.

In medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, affected individuals appear typically normal at birth and show symptoms for the first time between two and 24 months of age, although adult presentations are possible.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency can occur in three phenotypes: the severe early-onset form, the early childhood-onset form and a later-onset form.

In general, the following clinical characteristics can occur: hypoketotic hypoglycaemia, hepatomegaly, cardiomyopathy and myopathy with recurrent rhabdomyolysis, triggered by a catabolic state.

Peripheral neuropathy and retinopathy are long-term effects of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and trifunctional protein (TFP, synonym MTP) deficiency. One can distinguish LCHAD from TFP. Whilst LCHAD just shows deficiency of the enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase, for TFP deficiency of all three enzymes occur (long-chain 3-hydroxyacyl-CoA dehydrogenase, long-chain enoyl-CoA hydratase, and long-chain 3-ketoacyl-CoA thiolase.

The clinical spectrum of Multiple acyl-CoA dehydrogenase deficiency (MADD) can be divided into three types: type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies) and, type III (onset from infancy to adulthood, rarely late-onset). Hypoglycemia and hyperammonemia occur as well as Reye syndrome; e.g., muscle weakness and exercise intolerance are common symptoms. Individuals ascertained through newborn screening can be asymptomatic at diagnosis for MCAD or LCHAD deficiency.

Birth prevalence of MCAD deficiency, the most common fatty acid oxidation disorder in populations of European ancestry, ranges from 1/4,900 to 1/25,000 and approximately 1/15,000 worldwide, ranging from 1/4,900 in Europe up to 1/260,000 in Taiwan. Collectively, the fatty acid oxidation disorders (FAOD) affect approximately 1 to 2 per 10,000 births.

This panel analyses seven genes encoding enzymes of mitochondrial fatty acid beta-oxidation, each causing disease through a germline pathogenic variant.

ACADM and ACADVL encode the medium-chain and very long-chain acyl-CoA dehydrogenases, respectively.

HADHA and HADHB encode the mitochondrial trifunctional protein, whose deficiency causes LCHAD deficiency and trifunctional protein deficiency.

ETFA, ETFB and ETFDH encode electron transfer flavoprotein and its dehydrogenase, whose deficiency causes multiple acyl-CoA dehydrogenase deficiency, also termed glutaric acidaemia type II (GA-II).

Each enzyme defect interrupts a distinct step of the beta-oxidation pathway, reducing mitochondrial energy production during fasting and catabolic stress.

All fatty acid oxidation disorders in this panel are inherited in an autosomal recessive manner. For a couple who have had one affected child, the recurrence risk in each future pregnancy is 25%. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Diagnosis is based on the characteristic plasma acylcarnitine profile. Prominent C8-octanoylcarnitine with elevated C8/C2 and C8/C10 ratios indicates MCAD deficiency; elevated long-chain hydroxyacylcarnitines indicate LCHAD and TFP deficiency; and multiple elevated acylcarnitine species indicate MADD deficiency. Urine organic acid and acylglycine analyses provide support, and molecular genetic testing confirms the diagnosis.

Main differential diagnoses include:

• (carnitine uptake defect): Broad clinical spectrum; may present with hypoketotic hypoglycaemia and hepatomegaly similar to the FAODs, but plasma total and free carnitine levels are low; SLC22A5
• Carnitine palmitoyltransferase II (CPT II) deficiency: Adult myopathic and severe infantile hepatocardiomuscular forms; plasma acylcarnitines show elevated C16-OH, C16:1, C18 and C18:1 species; CPT2
• Carnitine-acylcarnitine translocase (CACT) deficiency: May be clinically and biochemically indistinguishable from CPT II deficiency; SLC25A20
• Carnitine palmitoyltransferase 1A (CPT 1A) deficiency: Does not present with cardiomyopathy or skeletal myopathy; increased free carnitine with reduced long-chain acylcarnitines and an increased C0/(C16+C18) ratio; CPT1A
• Short-chain acyl-CoA dehydrogenase (SCAD) deficiency: Now regarded as a clinically benign biochemical phenotype; acylcarnitines show increased C4-butyrylcarnitine; ACADS and others (seven differentials in total).

• Genetic testing confirms the diagnosis where a biochemical or clinical suspicion exists, identifying the causative pathogenic variants at the molecular level.
• Identification of the germline pathogenic variants supports condition-specific monitoring, long-term follow-up and management decisions made by the treating physicians in consultation with the affected individual.
• Once the familial variants are known, testing of at-risk relatives, including apparently unaffected siblings, can clarify their genetic status.

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