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Metabolic myopathies caused by disorders of lipid and purine metabolism

Metabolic myopathies caused by disorders of lipid and purine metabolism
Author:
Basil T Darras, MD
Section Editor:
Marc C Patterson, MD, FRACP
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Oct 2022. | This topic last updated: Dec 01, 2020.

INTRODUCTION — Patients with metabolic myopathies have underlying deficiencies of energy production in muscle due to a wide variety of defects. These include defects in lipid, glycogen, glucose, adenine nucleotide, and mitochondrial metabolism [1]. This topic will briefly describe fatty acid oxidation disorders (FAODs) (table 1), which are inborn errors of metabolism resulting in failure of mitochondrial beta-oxidation or the carnitine-based transport of fatty acids into mitochondria. This topic will also summarize neutral lipid storage disease and lipin-1 deficiency, two other disorders of lipid metabolism. Myoadenylate deaminase deficiency, which affects purine metabolism, is also reviewed here.

The clinical manifestations of the myopathies resulting from mitochondrial defects and from nonlysosomal and lysosomal glycogenoses are presented elsewhere. (See "Mitochondrial myopathies: Clinical features and diagnosis" and "Overview of inherited disorders of glucose and glycogen metabolism".)

An overview of the clinical manifestations resulting from a metabolic myopathy and the approach to the patient suspected of having a metabolic myopathy is discussed separately. (See "Approach to the metabolic myopathies".)

CARNITINE CYCLE DISORDERS — The carnitine cycle shuttles long-chain fatty acids from the cytosol into the mitochondrial matrix where fatty acid oxidation occurs (figure 1). The presentations of carnitine cycle disorders vary with age; newborns and infants tend to present with more severe multisystemic disease triggered by infection or fasting, often with acute encephalopathy, liver failure, and cardiac involvement, while older children and adults tend to present with exercise-induced myalgias, weakness, and fatigue.

Carnitine transporter deficiency (also called primary systemic carnitine deficiency or carnitine uptake defect) is an autosomal recessive disease caused by mutations in the solute carrier family 22 member 5 (SLC22A5) gene that encodes a high-affinity sodium-ion dependent organic cation transporter protein (OCTN2) expressed in heart muscle, kidney, lymphoblasts, and fibroblasts. Carnitine transporter deficiency is characterized by hypoketotic hypoglycemia, hyperammonemia, liver dysfunction, cardiomyopathy, and skeletal hypotonia. Presentation during the neonatal period is uncommon. Cardiomyopathy may be the presenting sign in children or young adults. Carnitine transporter deficiency is discussed in greater detail separately. (See "Specific fatty acid oxidation disorders", section on 'Carnitine transporter deficiency'.)

Carnitine palmitoyltransferase 1A deficiency is an autosomal recessive disorder caused by mutations in the CPT1A gene, which encodes a liver enzyme involved in fatty acid oxidation (figure 2). The most common phenotype is hepatic encephalopathy in childhood. Adult-onset myopathy is less common and neonatal hypoglycemia is rare. Acute fatty liver of pregnancy can develop in female carriers if the fetus is homozygous for a pathogenic mutation in CPT1A. Carnitine palmitoyltransferase 1A deficiency is discussed in greater detail separately. (See "Specific fatty acid oxidation disorders", section on 'Carnitine palmitoyltransferase 1A deficiency'.)

Carnitine acylcarnitine translocase deficiency is a rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the SLC25A20 gene. The onset of symptoms usually occurs in infancy or early childhood and both heart and skeletal muscle involvement is observed. The initial manifestations usually occur in the neonatal period with acute encephalopathy, severe hypoketotic hypoglycemia, hyperammonemia, and ventricular arrhythmias. Patients may also develop progressive hypertrophic or dilated cardiomyopathy and skeletal muscle involvement. Carnitine acylcarnitine translocase deficiency is discussed in greater detail separately. (See "Specific fatty acid oxidation disorders", section on 'Carnitine-acylcarnitine translocase deficiency'.)

Carnitine palmitoyltransferase type 2 deficiency presents with hypotonia, cardiomyopathy, arrhythmias, seizures, and multiple congenital anomalies (dysmorphic facies, renal cysts, brain malformations) and may result in death during the first days to months of life [2]. However, the majority of affected individuals have a later-onset form that presents in the second or third decade of life with exercise intolerance and attacks of rhabdomyolysis, which can lead to renal failure and death [3]. Carnitine palmitoyltransferase type 2 deficiency is discussed in greater detail separately. (See "Specific fatty acid oxidation disorders", section on 'Carnitine palmitoyltransferase type 2 deficiency'.)

DEFECTS OF BETA-OXIDATION ENZYMES — The intramitochondrial beta-oxidation defects involve the following enzymes [4]:

Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) (see "Specific fatty acid oxidation disorders", section on 'Very-long-chain acyl-CoA dehydrogenase deficiency')

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) and trifunctional protein (see "Specific fatty acid oxidation disorders", section on 'Long-chain 3-hydroxyacyl-CoA dehydrogenase and trifunctional protein deficiency')

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) (see "Specific fatty acid oxidation disorders", section on 'Medium-chain acyl-CoA dehydrogenase deficiency')

Short-chain acyl-coenzyme A dehydrogenase (SCAD) (see "Specific fatty acid oxidation disorders", section on 'Short-chain acyl-CoA dehydrogenase deficiency')

Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD) (see "Specific fatty acid oxidation disorders", section on 'Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency')

Multiple acyl-coenzyme A dehydrogenase (see "Specific fatty acid oxidation disorders", section on 'Multiple acyl-CoA dehydrogenase deficiency'):

Electron transfer flavoprotein dehydrogenase (ETFDH)

Electron transfer flavoprotein (encoded by ETFA and ETFB)

HMG-coenzyme A lyase [5]

Patients with defects in these enzymes may present with failure to thrive or hypotonia in infancy, or with exercise intolerance or weakness in older children and adults [6]. These disorders are discussed in greater detail separately. (See "Specific fatty acid oxidation disorders".)

NEUTRAL LIPID STORAGE DISEASES — Mutations in the genes encoding two triglyceride lipases cause generalized lipid storage myopathy [7,8]:

Chanarin-Dorfman syndrome, also called neutral lipid storage disease with ichthyosis (NLSDI) is caused by mutations in the ABHD5 gene (also called CGI-58) [8]; patients present with congenital ichthyosiform erythroderma, hepatomegaly, lipid droplets in blood granulocytes (known as the Jordan anomaly), and increased levels of serum creatine kinase and liver enzymes. A subset of patients with NLSDI has muscle weakness.

Neutral lipid storage disease with myopathy (NLSDM) presents with juvenile-onset weakness and is caused by mutations in the PNPLA2 gene [9]. In NLSDM, the onset of weakness is usually late (after the first decade) and is typically characterized by marked shoulder girdle weakness, mild pelvic girdle and distal muscle weakness, and elevated serum creatine kinase levels [10]. Multisystem involvement with cardiomyopathy, dyslipidemia, hepatomegaly, and/or diabetes is present in 20 percent or more of cases, though few patients have all these features combined [11]. Case reports have described rare patients with variant phenotypes including one with no weakness despite extensive lipid storage and markedly elevated creatine kinase levels [12], two with a progressive myopathy with rimmed vacuoles [13], and one with multisystem involvement including cognitive impairment [11].

Management is supportive, as there are no established treatments for these disorders [14].

LIPIN-1 DEFICIENCY — Lipin-1 deficiency is an autosomal recessive disorder caused by mutations in LPIN1 gene that usually presents with recurrent rhabdomyolysis and myoglobinuria in young children, mostly in the setting of intercurrent infections with fever and less frequently with fasting or exercise [15-17]. However, adult onset is also reported [16].

Lipin-1 is a muscle-specific phosphatidic acid phosphatase that catalyzes the conversion of phosphatidic acid to diacylglycerol [18]; thus, it is an important enzyme in the pathway of triglyceride and phospholipid biosynthesis. Lipin-1 is also acts as a transcriptional protein that regulates cellular lipid metabolism, including genes involved in fatty acid oxidation and mitochondrial biosynthesis [19]. Lipin-1 deficiency in muscle causes skeletal chronic myopathy in mice associated with abnormal mitochondria and exercise-induced elevation of plasma creatine kinase levels [20].

Creatine kinase levels can be very high (20,000 to 450,000 units/L), but carnitine levels, acylcarnitine profile, urine organic acids, and fatty acid oxidation studies are normal. Lipid content in muscle may be increased. LPIN1 deficiency-related episodes of rhabdomyolysis may be lethal in up to about one-third of patients [15].

The diagnosis of lipin-1 deficiency is confirmed by genetic testing. Management is supportive.

MYOADENYLATE DEAMINASE DEFICIENCY — Myoadenylate deaminase (MADA) deficiency, a disorder of purine metabolism, is considered by some to be the most common metabolic myopathy, but this remains controversial. MADA deficiency is detected in approximately 2 percent of muscle biopsy specimens [21]. This high prevalence of enzyme deficiency in muscle and the documentation of asymptomatic individuals have raised doubts regarding the clinical relevance of MADA deficiency. Nevertheless, the possibility of being pathogenic in certain patients because of the effect of other genetic or epigenetic factors cannot be excluded.

Myoadenylate deaminase converts adenosine monophosphate to inosine monophosphate and ammonia. MADA deficiency results in decreased entry of adenine nucleotides into the purine nucleotide cycle during exercise [22]. This enzyme has three tissue-specific subunits: E (erythrocyte), L (liver), and M (muscle). The gene that encodes for the M subunit (AMPD1) maps to the short arm of chromosome 1 [23]. MADA exists as an M homotetramer in human adult muscle. Pathogenic homozygous or heterozygous mutations have been described [24-27]; the heterozygous state is common and is found in approximately 10 percent of individuals of European or African descent [24,28]. However, many individuals are completely asymptomatic, possibly because of alternative splicing patterns involving exon 2 of AMPD1 [29].

Classic or primary myoadenylate deaminase deficiency is characterized by dynamic symptoms related to exertion, and consists primarily of muscle aches and cramps which are sometimes very mild and poorly defined; it can also present with myoglobinuria [30-32].

Myoadenylate deaminase deficiency has also been noted in patients with other myopathies, such as Duchenne or Becker muscular dystrophy, phosphorylase deficiency, spinal muscular atrophy, or amyotrophic lateral sclerosis. In the latter group of patients, the myoadenylate deaminase deficiency appears to be secondary.

Findings on laboratory examination include:

Resting serum creatine kinase level is usually normal or only slightly elevated

Electromyography is normal in most cases, or may show nonspecific myopathic changes

Muscle biopsy is histologically normal, but MADA deficiency can be detected by immunohistochemistry and muscle biochemistry [33]

The forearm ischemic exercise test shows a normal lactate curve, but no increase in the ammonia level or inosine monophosphate

Molecular genetic testing may reveal homozygosity or compound heterozygosity for AMPD1 mutations [24-27]

There is no specific treatment for symptomatic MADA deficiency.

SUMMARY

Patients with metabolic myopathies have underlying deficiencies of energy production in muscle due to a wide variety of defects, including defects in lipid metabolism (table 1).

Carnitine cycle disorders include:

Carnitine transporter deficiency (See "Specific fatty acid oxidation disorders", section on 'Carnitine transporter deficiency'.)

Carnitine palmitoyltransferase 1A deficiency (see "Specific fatty acid oxidation disorders", section on 'Carnitine palmitoyltransferase 1A deficiency')

Carnitine acylcarnitine translocase deficiency (see "Specific fatty acid oxidation disorders", section on 'Carnitine-acylcarnitine translocase deficiency')

Carnitine palmitoyltransferase 2 deficiency (see "Specific fatty acid oxidation disorders", section on 'Carnitine palmitoyltransferase type 2 deficiency')

These deficiencies disrupt the carnitine cycle, which shuttles long-chain fatty acids from the cytosol into the mitochondrial matrix where fatty acid oxidation occurs (figure 1). The presentations of these conditions vary with age; newborns and infants tend to present with more severe multisystemic disease triggered by infection or fasting, often with acute encephalopathy, liver failure, and cardiac involvement, while older children and adults tend to present with exercise-induced myalgias, weakness, and fatigue. (See 'Carnitine cycle disorders' above.)

The intramitochondrial beta-oxidation defects involve the following enzymes:

Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) (see "Specific fatty acid oxidation disorders", section on 'Very-long-chain acyl-CoA dehydrogenase deficiency')

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) and trifunctional protein (see "Specific fatty acid oxidation disorders", section on 'Long-chain 3-hydroxyacyl-CoA dehydrogenase and trifunctional protein deficiency')

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) (see "Specific fatty acid oxidation disorders", section on 'Medium-chain acyl-CoA dehydrogenase deficiency')

Short-chain acyl-coenzyme A dehydrogenase (SCAD) (see "Specific fatty acid oxidation disorders", section on 'Short-chain acyl-CoA dehydrogenase deficiency')

Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD) (see "Specific fatty acid oxidation disorders", section on 'Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency')

Multiple acyl-coenzyme A dehydrogenase (see "Specific fatty acid oxidation disorders", section on 'Multiple acyl-CoA dehydrogenase deficiency'):

-Electron transfer flavoprotein dehydrogenase (ETFDH)

-Electron transfer flavoprotein (encoded by ETFA and ETFB)

HMG-coenzyme A lyase

Patients with defects in these enzymes can present with metabolic decompensation, failure to thrive, or hypotonia in infancy, while adults can present with exercise intolerance or weakness. Additional manifestations may include cardiomyopathy or transient hepatic dysfunction. (See "Specific fatty acid oxidation disorders", section on 'Beta-oxidation defects' and "Specific fatty acid oxidation disorders", section on 'Medium- and short-chain fatty acid oxidation disorders'.)

Mutations in the genes encoding two triglyceride lipases cause generalized lipid storage myopathy, one associated with ichthyosis (Chanarin-Dorfman syndrome, also called neutral lipid storage disease with ichthyosis), the other presenting with juvenile-onset weakness (neutral lipid storage disease with myopathy). (See 'Neutral lipid storage diseases' above.)

Lipin-1 deficiency is an autosomal recessive disorder caused by mutations in LPIN1 gene that usually presents with recurrent rhabdomyolysis and myoglobinuria in young children, mostly in the setting of intercurrent infections with fever and less frequently with fasting or exercise. (See 'Lipin-1 deficiency' above.)

Classic or primary myoadenylate deaminase (MADA) deficiency is characterized by dynamic symptoms related to exertion, and consists primarily of muscle aches and cramps which are sometimes very mild and poorly defined; it can also present with myoglobinuria. Asymptomatic or secondary myoadenylate deaminase deficiency is common, and thus the pathogenicity of MADA deficiency remains controversial. (See 'Myoadenylate deaminase deficiency' above.)

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