Last Updated: February 28, 2023
Introduction to Lipid Storage Myopathies
The lipid storage myopathies (LSM) represent a heterogeneous group of inherited disorders that, in addition to other pathologies, are all characterized by abnormal lipid accumulation in muscle fiber. The LSM are classified based upon pathological findings which result in large part due to the accumulation of lipid droplets (LD) in muscle but also in other tissues.
Four discernable LSM have been categorized and includes primary carnitine deficiency (carnitine deficiency systemic primary, CDSP), multiple acyl-CoA dehydrogenase deficiency (MADD; also known as glutaric acidemia type II, GAII), and the neutral lipid storage diseases (NLSD) which includes NLSD with myopathy (NLSDM) and NLSD with ichthyosis (NLSDI).
In addition to the four primary forms of LSM, several additional diseases are associated with lipid myopathy including VLCAD, MCAD, and SCAD deficiencies, CPT-2 deficiency, and the mitochondrial trifunctional protein (MTP) deficiencies. Other lipid myopathies have been shown to be the result of lipin 1 (phosphatidic acid phosphatase) deficiency, acyl-CoA dehydrogenase 9 (ACAD9) deficiency, and acetyl-CoA acyltransferase 2 (ACAA2; also known as medium-chain 3-ketoacyl-CoA thiolase, MCKAT) deficiency
Carnitine Deficiency, Systemic Primary
Primary carnitine deficiencies are due to defects in carnitine transport into cells or due to defects in synthesis from lysine, although the latter are very rare with only a few cases identified worldwide. Mutations in the major carnitine transporter, encoded by the SLC22A5 gene (also known as zwitterion/cation transporter 2, OCTN2), are the predominant causes of primary carnitine deficiency. This disorder is most correctly referred to as carnitine deficiency, systemic primary (CDSP).
Multiple Acyl-CoA Dehydrogenase Deficiency: MADD
MADD is a rare autosomal recessive disorder that results from mutations in either of the two genes that encode the protein components of the heterodimeric complex identified as electron transfer flavoprotein (ETF) or the gene (ETFDH) encoding electron transfer flavoprotein dehydrogenase. The ETF is composed of an α-subunit encoded by the ETFA gene and a β-subunit encoded by the ETFB gene. The ETF is localized to the inner mitochondrial membrane where it accepts electrons from the FAD-dependent dehydrogenases of mitochondrial fatty acid β-oxidation as well as several dehydrogenases involved in amino acid metabolism. The function of ETFDH is to transfer the electrons from the ETF to ubiquinone (CoQ10) of the electron transport chain. The ETFDH activity is also referred to as ETFQO. Individuals in China, Japan, and Taiwan represent the majority of identified patients with MADD. Most of the identified patients in these populations harbor mutations in the ETFDH gene.
The ETFA gene is located on chromosome 15q24.2-q24.3 and is compose of 13 exons that generate two alternatively spliced mRNAs encoding proteins of 333 amino acids (isoform a) and 284 amino acids (isoform b).
The ETFB gene is located on chromosome 19q123.41 and is compose of 7 exons that generate two alternatively spliced mRNAs encoding proteins of 255 amino acids (isoform 1) and 346 amino acids (isoform 2).
The ETFDH gene is located on chromosome 4q32.1 and is compose of 14 exons that generate three alternatively spliced mRNAs encoding proteins of 617 amino acids (isoform 1), 570 amino acids (isoform 2), and 556 amino acids (isoform 3).
As indicated above, MADD is also known known as glutaric acidemia type II (GAII). This name stems from the fact that patients excrete large amounts of glutaric acid. Additional metabolites that are excreted at high levels in MADD include lactic acid, ethylmalonic acid, butyric acid, isobutyric acid, 2-methyl-butyric acid, and isovaleric acid. Glutaric aciduria/acidemia type I results from mutations in the gene encoding the mitochondrial matrix enzyme, glutaryl-CoA dehydrogenase (GCDH).
In the process of mitochondrial fatty acid β-oxidation the electrons that are removed from the lipids during their oxidation by the various FAD-dependent acyl-CoA dehydrogenases (e.g. VLCAD, MCAD, and SCAD) ultimately enter the electron transport chain of oxidative phosphorylation via the ETF and ETFDH. Thus, a defect in either of the two protein components of ETF or in ETFDH will affect all of the FAD-dependent dehydrogenases of the mitochondria, hence the name of the disease as multiple acyl-CoA dehydrogenase deficiency (MADD).
The clinical manifestations of MADD are quite heterogeneous. There are three different classifications of MADD based upon the timing and severity of symptoms and are referred to as the neonatal-onset with congenital anomalies (MADD type I), neonatal-onset without congenital anomalies (MADD type II), and the mild- and/or later-onset form (MADD type III). Mutations in the ETFA and ETFB genes tend to be the causes of the neonatal forms of MADD, whereas mutations in the ETFDH gene are found in the later-onset form.
Onset of type I or type II MADD is usually in the neonatal period and symptoms include severe metabolic acidosis, nonketotic hypoglycemia, and hyperammonemia. Many of these affected patients will die in the neonatal period despite metabolic treatment. Infants who survive the neonatal period will suffer from recurrent episodes of metabolic decompensation resembling Reye syndrome. Very often these infants will also develop hypertrophic cardiomyopathy. In type I MADD the congenital anomalies may include dysmorphic facial features and large cystic kidneys. In males, the type I disease is associated with hypospadias, a condition in which the opening of the penis is on the underside rather than the tip.
Type III MADD represents the most common form of MADD. This form of the disorder can manifest over a wide range of time frames from infancy to adulthood. The most common symptoms of type III MADD are muscle weakness, exercise intolerance, and/or muscle pain. Hypertrophic cardiomyopathy has also been seen in several type III MADD patients. In addition to the cardiac involvement these patients exhibit hepatomegaly. Additional symptoms of type III MADD may include encephalopathy, episodic lethargy, vomiting, and hypoglycemia.
Diagnosis of MADD is aided by measurement of plasma carnitine and acylcarnitines, and by examination of urinary organic acid profiles. Serum acyl-carnitines in MADD are highest for medium- and long-chain fatty acids but all chain length acylcarnitines are elevated. Urine organic acids in MADD include C5 to C10 dicarboxylic acids and their acylglycine derivatives.
Although no defined and universal treatment for MADD is available some patients, particularly those with ETFDH mutations, have symptom alleviation with supplemental riboflavin (100–400 mg/day). Supplementation with L-carnitine can be useful when secondary carnitine deficiency is evident. Improvement in muscle weakness in some MADD patients has been observed following CoQ10 supplementation but this appears only to be useful when there is secondary CoQ10 deficiency.
Neutral Lipid Storage Disease with Myopathy (NLSDM)
Neutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder resulting from mutations in the gene (PNPLA2) encoding the triglyceride metabolizing enzyme, adipose triglyceride lipase, ATGL. ATGL hydrolyzes stored triglycerides, primarily in adipose tissue but also in liver and skeletal muscle. The activity of ATGL is regulated through the association with a coactivator protein identified as α/β hydrolase domain-containing 5, lysophosphatidic acid acyltransferase (ABHD5). Mutations in the ABHD5 gene result in the related lipid storage disorder, NLSD with ichthyosis (NLSDI).
The PNPLA2 gene is located on chromosome 11p15.5 and is composed of 10 exons encoding a 504 amino acids protein.
NLSDM is characterized by triglyceride (TG) deposition in numerous tissues including skin, muscle, liver, central nervous system, and white blood cells. Due to the broad tissue accumulation of TG, patients with NLSDM manifest with an array of clinical pathologies. Symptoms of NLSDM include skeletal myopathy, cardiomyopathy, hepatomegaly, neurosensory hearing loss, cataracts, nystagmus, strabismus, intestinal disturbances, short stature, microcephaly, and intellectual impairment.
The myopathy in NLSDM is a slowly progressive myopathy, that can be either proximal- or distal-dominant. The accumulating lipid droplets in muscle tissue of NLSDM patients are larger and of greater number than other LSM such as MADD or carnitine deficiency, systemic primary.
Whereas in the other well-characterized NLSD, NLSD with ichthyosis (NLSDI), there is an associated non-bullous congenital ichthyosiform erythroderma (NCIE), no ichthyosis is observed in NLSDM patients.
Neutral Lipid Storage Disease with Ichthyosis (NLSDI)
Neutral lipid storage disease with ichthyosis (NLSDI) is a rare autosomal recessive disorder resulting from mutations in the gene (ABHD5) encoding α/β hydrolase domain-containing protein 5, lysophosphatidic acid acyltransferase. The ABHD5 encoded protein functions in the regulation of the activity of the triglyceride metabolizing enzyme, adipose triglyceride lipase, ATGL. The ABHD5 gene was originally identified as comparative gene identification-58, CGI-58. The term Comparative Gene Identification relates to the use of computational methods to identify protein sequences highly conserved across various species and CGI-58 was originally discovered in a screen comparing the proteomes of humans and C. elegans.
The ABHD5 gene is located on chromosome 3p21.33 and is composed of 10 exons that generate four alternatively spliced mRNAs that collectively encode three distinct protein isoforms.
NLSDI manifests with a constellation of symptoms that are identical to NLSDM but also with extensive non-bullous congenital ichthyosiform erythroderma (NCIE), hence the name of this form of NLSD. The disorder is also referred to as Chanarin-Dorfman syndrome. There are numerous disorders that are associated with NCIE which includes the autosomal recessive congenital ichthyosis (ARCI) group of disorder. A characteristic of NCIE is fine white, superficial, semi-adherent scales