Table 1

Differential diagnosis of lipid-storage myopathies

	Primary carnitine deficiency	Neutral lipid storage disease*	MADD	SCADD	MTPD	VLCAD/LCADD	CPT2 deficiency†	LIPIN1 deficiency
Phenotype	Infantile: attacks of vomiting, altered mental status, hypoglycaemia, hepatomegaly (resembling Reye’s syndrome). Childhood/early adult (more frequent phenotype ): myopathy and hypertrophic/dilated cardiomyopathy. Others: rhabdomyolysis and respiratory muscle weakness can also occur.	NLSD-Myopathy ( NLSDM ):slowly progressive proximal and distal myopathy, and dilated cardiomyopathy. NLSD-ichthyosis ( NLSDI ): non-bullous congenital ichthyosiform erythroderma, proximal myopathy (60%) and hepatomegaly.	Neonatal: congenital anomalies, multisystem involvement, death within neonate period. Childhood: hypoglycaemia, encephalopathy, myopathy, cardiomyopathy. Adult: progressive proximal myopathy (or rarely exercise intolerance and myoglobinuria). Others: cardiac, gastrointestinal, hepatomegaly, respiratory failure, dropped-head syndrome, bent-spine syndrome, and sensory axonal polyneuropathy.	Neonatal: Dysmorphic facies, failure to thrive, metabolic acidosis, seizures, myopathy. Infantile/early adult life: exercise intolerance, myalgias or progressive proximal weakness. Others: ptosis, progressive external ophthalmoplegia, respiratory muscle weakness, and cardiomyopathy.	Infancy/early childhood: vomiting, altered mental status, hypoketotic hypoglycaemia, hepatopathy, and cardiomyopathy (mortality 50%). Childhood: progressive weakness and recurrent episodes of myoglobinuria following exercise, illness or fasting. Others: cardiomyopathy sensorimotor polyneuropathy, and pigmentary retinopathy.	Neonatal: hypertrophic cardiomyopathy and liver failure. High mortality rate (50%–75%). Infantile: hypoketotic hypoglycaemia as the main feature. Juvenile/early adult life: e pisodes of myoglobinuria following intense and prolonged exertion, infection, cold or fasting (similar to the adult form of CPT2 deficiency).	Neonatal: encephalopathy, congenital malformations, hepatomegaly and cardiomegaly resulting in death. Infantile: recurrent attacks of acute liver failure, hypoketotic hypoglycaemia and seizures Juvenile/ e arly adult life : e pisodes of muscle pain and myoglobinuria following intense and prolonged exertion, infection, cold or fasting.	Recurrent episodes of myoglobinuria in the setting of febrile illness in children.
Creatine kinase	1–15×ULN	>5×ULN	1–20×ULN	Normal	↑ (Intra-episode)
Free carnitine	↓↓↓	Normal	Normal or slightly reduced (secondary carnitine deficiency)					Normal
AC	↓↓↓	Normal	↑ Long-chain, medium-chain and short-chain acylcarnitines	↑ Short-chain acylcarnitines	↑ Long-chain acylcarnitines (often intra-episode)			Normal
Urine organic acids	Normal	Normal	↑ 2-Hydroxyglutaric acid	↑ Ethylmalonic acid	Normal (or non-specific abnormalities)
Muscle biopsy	Massive accumulation of lipids in muscle fibres			Moderate lipidosis/multi-mini-core	Normal (or very mild lipidosis in muscle fibres)
Gene‡	OCTN2	PNPLA2 (NLSDM) ABHD5 (NLSDI)	ETFDH ETFA, ETFB	ACADS	HADHA, HADHB	ACADVL	CPT2	LPN1
Treatment	PO l-carnitine (100–300 mg/kg/day) for life Intravenous carnitine 100–400 mg/kg/day during life-threatening events	…	Riboflavin (100–400 mg/day) for life CoQ10 supplementation is advised	…	…	Supplementation with medium-chain triglycerides in children (controversial in adults) Triheptanoin Agonists of peroxisome proliferator-activated receptors (PPARs)		…

Of note, medium-chain acyl-CoA deficiency (MCAD) is the most common disease of the mitochondrial fatty acid oxidation; however, its myopathic form is extremely rare and therefore it has not been included in this table.
*The presence of lipid-containing vacuoles in leucocytes (Jordan’s anomaly) on blood smear is a pathognomonic finding of neutral lipid storage disease (NLSD).
†CPT2 deficiency is the most common recognised cause of recurrent rhabdomyolysis in adults.
‡All lipid-storage myopathies shown have an autosomal recessive inheritance pattern.
CPT2, carnitine palmitoyl transferase II; LCADD, long-chain acyl-CoA dehydrogenase deficiency; LIPIN, or phosphatidic acid phosphatase deficiency; MADD, multiple acyl-CoA dehydrogenase deficiency; MTPD, mitochondrial trifunctional protein deficiency/long-chain HAD deficiency; NLSD, neutral lipid storage disease; SCADD, short-chain acyl-CoA dehydrogenase deficiency; ULN, upper limit of normal; VLCAD, very-long-chain acyl-CoA dehydrogenase deficiency.