Chapter 629

Metabolic Myopathies and Channelopathies

Harvey B. Sarnat

Table 629.1 describes the differential diagnosis of metabolic myopathies.

Table 629.1

Muscle Channelopathies

	MYOTONIA CONGENITA	PARAMYOTONIA CONGENITA	OTHER SODIUM CHANNEL MYOTONIAS	HYPERKALEMIC PERIODIC PARALYSIS	HYPOKALEMIC PERIODIC PARALYSIS	ANDERSEN-TAWIL SYNDROME	THYROTOXIC PERIODIC PARALYSIS	CENTRAL CORE/MALIGNANT HYPERTHERMIA
Gene	CLCN1	SCN4A	SCN4A	SCN4A	CACNA1S, SCN4A	KCNJ2	KCNJ18	RYR1
Chromosome	7q35	17q23	17q23	17q23	1q32, 17q23*	17q24	17†	19q 13
Clinical features	Myotonia	Myotonia, episodic weakness	Myotonia	Episodic weakness, myotonia	Episodic weakness	Episodic weakness, premature ventricular contractions, ventricular tachyarrhythmia	Episodic weakness	Weakness, malignant hyperthermia, and rarely myotonia
Triggers	Cold (some patients)	Cold	Potassium (some patients)	Potassium, rest after exercise	Carbohydrates, rest after exercise	Rest after exercise, carbohydrates (some patients), potassium (some patients)	Thyrotoxicosis	Anesthesia
Acute treatment	n/a	n/a	n/a	Carbohydrate/glucose	Potassium oral, rarely IV	Potassium (if attacks associated with hypokalemia)	Potassium, adrenergic blocking agents	IV fluids, support
Chronic treatment	Mexiletine, phenytoin, procainamide	Mexiletine, phenytoin, procainamide	Mexiletine, phenytoin, procainamide, acetazolamide	Acetazolamide, dichlorphenamide	Potassium, acetazolamide, dichlorphenamide, potassium-sparing diuretic	Potassium (if attacks are associated with hypokalemia), acetazolamide, dichlorphenamide, potassium-sparing diuretic	Treatment of thyrotoxicosis	n/a
Exercise testing	Short exercise test (SET): Postexercise decrement, rapid return to baseline	SET: Postexercise decrement, facilitated by repetition or cold	SET: Often nondiagnostic	Long exercise test (LET): Postexercise decrement	LET: Postexercise decrement	LET: Postexercise decrement	LET: postexercise decrement (when symptomatic)	n/a
Laboratory features	n/a	n/a	n/a	Ictal high potassium‡	Ictal low potassium	Ictal high/low potassium	Ictal low potassium, elevated thyroid hormone	Elevated creatine kinase during malignant hyperthermia
Commercially available genetic testing	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes

^* Calcium channel gene chromosome 1, sodium channel gene chromosome 17.

^† Exact location not determined.

^‡ Case reports of families with mutations associated with hyperkalemic periodic paralysis and normal potassium.

From Statland JM, Barohn RJ: Muscle channelopathies: the nondystrophic myotonias and periodic paralyses, Continuum 19(6):1598-1614, 2013, Table 4.1 .

629.1

Periodic Paralyses and Other Muscle Channelopathies

Harvey B. Sarnat

Episodic, reversible weakness or paralysis, known as periodic paralysis, is associated with transient alterations in serum potassium levels, usually hypokalemia but occasionally hyperkalemia. All familial forms of periodic paralysis are caused by mutations in genes encoding voltage-gated ion channels in muscle: sodium, calcium, and potassium (see Table 629.1 ). Nonhereditary causes of periodic paralysis are caused by a diverse group of disorders that affect potassium balance (Table 629.2 ).

Table 629.2

Secondary Causes of Periodic Paralysis
HYPOKALEMIC
Thyrotoxic Primary hyperaldosteronism (Conn syndrome) Renal tubular acidosis (e.g., Fanconi syndrome) Juxtaglomerular apparatus hyperplasia (Bartter syndrome) Gastrointestinal potassium wastage Villous adenoma Laxative abuse Pancreatic non–insulin-secreting tumors with diarrhea Nontropical sprue Barium intoxication Potassium-depleting diuretics Amphotericin B Licorice Corticosteroids Toluene toxicity p -Aminosalicylic acid Carbenoxolone
HYPERKALEMIC
Addison disease Hypoaldosteronism Excessive potassium supplementation Potassium-sparing diuretics Chronic renal failure

From Chinnery PF: Muscle diseases. In Goldman L, Schafer AI, editors: Goldman's Cecil medicine , ed 24, Philadelphia, 2012, Elsevier, Table 429-8, p. 2415.

During attacks of hypokalemic paralysis, myofibers are electrically unexcitable, although the contractile apparatus can respond normally to calcium. The genetic disorder is inherited as an autosomal dominant trait. It is precipitated in some patients by a heavy carbohydrate meal, insulin, epinephrine including that induced by emotional stress, hyperaldosteronism or hyperthyroidism, administration of amphotericin B, or ingestion of licorice.

Attacks of hypokalemic paralysis often begin in infancy, particularly in the hyperkalemic form, and the disease is nearly always symptomatic by 10 yr of age, affecting both sexes equally. Late childhood or adolescence is the more typical age of onset of the hypokalemic form, Andersen-Tawil syndrome, and paramyotonia congenita. Periodic paralysis is an episodic event; patients are unable to move after awakening and gradually recover muscle strength during the next few minutes or hours. All four extremities are involved. Muscles that remain active in sleep, such as the diaphragm, extraocular muscles (rapid eye movements), and cardiac muscle, are not affected. Patients are normal between attacks, but in adult life the attacks become more frequent, and the disorder causes progressive myopathy with permanent weakness even between attacks. The usual frequency of attacks in childhood is once a week. The differential diagnosis includes thyrotoxic periodic paralysis, myotonia congenita, and paramyotonia congenita. A triad of periodic paralysis, potentially fatal cardiac ventricular ectopy (caused by a defect in Kir2.1 channels for terminal repolarization), and characteristic physical features is known as Andersen-Tawil syndrome.

Alterations in serum potassium levels occur only during acute episodes and are accompanied by T-wave changes in the electrocardiogram. Hypokalemia may be caused by alterations in calcium gradients. The creatine kinase (CK) level may be mildly elevated at those times. Plasma phosphate levels often decrease during symptomatic periods. Muscle biopsy findings are often normal between attacks, but during an attack a vacuolar myopathy is demonstrated. Pathologic changes in the periodic paralyses are similar, whether the disease is the result of a sodium or a potassium channel defect, suggesting that the changes might result from the recurrent paralytic state rather than the specific channelopathy. The vacuoles are dilated sarcoplasmic reticulum and invaginations of the extracellular space into the cytoplasm, and they may be filled with glycogen. Muscle biopsy is not essential to diagnose periodic paralysis, however. Hypoglycemia does not occur. Loci for the majority of periodic paralyses have been demonstrated and the genes at least partially characterized, but many patients with the same clinical phenotype exhibit no mutations in the identified genes.

Treatment

Paralytic attacks of hypokalemic periodic paralysis are best treated by the oral administration of potassium or even fruit juices that contain potassium. A low sodium intake and the administration of acetazolamide, 5 mg/kg/day bid or tid as a starting dose, often is effective in abolishing attacks or at least reducing their frequency and severity. Dichlorphenamide, a carbonic anhydrase inhibitor, is approved for the treatment of primary hypokalemic and hyperkalemic periodic paralysis syndromes in adults. The drug reduced the frequency, with few side effects (paresthesias, confusion, dysgeusia). Acetazolamide has also been used off label for these conditions.

Other Muscle Channelopathies

Disorders of ion channels other than the well-documented potassium channelopathies also are recognized (see Table 629.1 ). A rare, severe neonatal myotonia is secondary to a mutation of the voltage-gated sodium-channel SCN4A gene; it is unrelated to neonatal myotonic dystrophy, myotonia congenita, or infantile myofibrillar myopathies. This same gene also is responsible for severe neonatal episodic laryngospasm. Mexiletine is effective treatment of the myotonia, but the long-term prognosis remains poor, with death by 2 yr of age. Sodium channel blockers, such as carbamazepine, phenytoin, and procainamide, are alternatives.

Neuromyotonia, a continuous muscle activity of neurogenic origin, may be caused by mutations in genes encoding or antibodies against potassium channels, but is rare in childhood. Schwartz-Jampel disease, resulting from an autosomal recessive trait, involves severe muscle stiffness, myotonia, blepharospasm, and chondroplasia. It becomes symptomatic in the first year of life and is slowly progressive until midadolescence, after which it is stable. It is no longer considered a variant of myotonic dystrophy and is caused by a mutation in the HSPG2 gene that encodes perlecan, the major heparin sulphate proteoglycan of basement membranes. Sodium channel blockers may be useful.

Bibliography

Fontaine B. Muscle channelopathies and related diseases. Handb Clin Neurol . 2013;113:1433–1436.

Gay S, Dupuis D, Faivre L, et al. Severe neonatal non-dystrophic myotonia secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) gene. Am J Med Genet A . 2008;146:380–383.

Kullmann DM. Neurological channelopathies. Annu Rev Neurosci . 2010;33:151–171.

Matthews E, Silwal A, Sud R, et al. Skeletal muscle channelopathies: rare disorders with common pediatric symptoms. J Pediatr . 2017;188:181–185.

Nicole S, Davoine CS, Topaloglu H, et al. Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nat Genet . 2000;26:480–483.

Sansone VA, Burge J, McDermott MP, et al. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis. Neurology . 2016;86:1–9.

Statland JM, Barohn RJ. Muscle channelopathies: the nondystrophic myotonias and periodic paralyses. Continuum (N Y) . 2013;19(6):1598–1614.

The Medical Letter. Dichlorphenamide (Keveyis) for periodic paralysis. Med Lett . 2016;58(1492):50.

Venance SL, Cannon SC, Fialho D, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain . 2006;129:8–17.

629.2

Malignant Hyperthermia

Harvey B. Sarnat

Bibliography

Hopkins PM, Rüffert H, Snoeck MM, et al. European malignant hyperthermia group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth . 2015;115:531–539.

Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis . 2015;10:93.

629.3

Glycogenoses

Harvey B. Sarnat

See also Chapter 105.1 and Table 629.3 .

Table 629.3

Metabolic Diseases That Affect Muscle

NAME(S)	ENZYME DEFICIENCY	CLINICAL FEATURES	DIAGNOSTIC TESTING
Glycogen storage disease type II (Pompe disease)	α-1,4-Glucosidase (GAA enzyme)	• Infantile-onset Pompe: poor feeding, motor delay and hypotonia with weakness, respiratory difficulties, cardiac issues (short P-R interval with wide QRS complex, cardiomegaly, LV outflow obstruction, cardiomyopathy) • Late-onset Pompe: limb–girdle pattern of weakness, respiratory insufficiency without clinical heart disease • GAA enzyme replacement therapy available	• Measure α-glucosidase (GAA) enzyme activity on dried blood spot to screen • Confirm via GAA gene sequencing demonstrating biallelic mutations for definitive diagnosis • Baseline elevated CK (~10× normal) in infantile-onset form; baseline CK may be normal in adult-onset form • Muscle biopsy may show vacuoles (lysosomes) and glycogen accumulation with positively staining PAS; 20–30% of patients with adult-onset form may not show specific changes on biopsy
Glycogen storage disease type IIIa (Debrancher deficiency, Cori disease, Forbes disease)	Amylo-1,6-glucosidase	• Ketotic hypoglycemia, hepatomegaly, hyperlipidemia, elevated liver enzymes, cardiomyopathy in childhood, limb–girdle pattern of weakness in 20s–30s	• Baseline elevated CK (2-20× normal) • Triglycerides, cholesterol, and liver enzymes are elevated • AGL gene sequencing demonstrating biallelic mutations for definitive diagnosis
Glycogen storage disease type IV (Brancher deficiency, Andersen disease)	Glycogen branching enzyme (GBE)	• Fatal perinatal neuromuscular subtype: fetal akinesia, polyhydramnios, fetal hydrops • Congenital neuromuscular subtype: hypotonic newborn, respiratory distress, dilated cardiomyopathy, death in infancy • Childhood neuromuscular subtype: chronic progressive myopathy, dilated cardiomyopathy	• Demonstrate deficiency of GBE in the liver, muscle, or skin fibroblasts • GBE1 gene sequencing demonstrating biallelic mutations for definitive diagnosis
Glycogen storage disease type V (McArdle disease)	Myophosphorylase	• Exercise-induced muscle cramps and pain, especially early in exercise, that improve with rest or lower intensity (2nd-wind phenomenon) • Recurrent myoglobinuria +/− rhabdomyolysis	• Baseline elevated CK (>5× normal) • PYGM gene sequencing demonstrating biallelic mutations for definitive diagnosis • Quantitative or qualitative (stain) on muscle biopsy shows virtual absence of enzyme activity • Subsarcolemmal glycogen accumulation on muscle biopsy on LM (either PAS-positive or vacuoles on H&E) and EM
Glycogen storage disease type VII (Tarui disease)	Phosphofructokinase	• Classical form: muscle aching, cramping, exercise intolerance, myoglobinuria, nausea/vomiting after intense exercise, starting in childhood; hemolytic anemia • Late-onset form: cramps, myalgia, mild proximal weakness in adulthood • Infantile form: hypotonia, arthrogryposis, intellectual disability, fatal in infancy	• Baseline elevated CK • PFK gene sequencing demonstrating biallelic mutations for definitive diagnosis
Glycogen storage disease VIII (phosphorylase kinase [PhK] deficiency)	Phosphorylase b kinase	• Exercise intolerance, cramps, myoglobinuria, progressive muscle weakness in childhood to adulthood • Hepatomegaly, growth retardation, fasting ketosis and hypoglycemia	• Baseline elevated CK • PhK enzyme activity reduced in muscle • PHKA1 gene sequencing or/and PHKB gene sequencing demonstrating biallelic mutations for definitive diagnosis
	Phosphorylase a1 kinase	• Same as above but X-linked and very rare
Glycogen storage disease IX (phosphoglycerate kinase deficiency)	Phosphoglycerate kinase	• Myopathic form: muscle weakness, pain, cramping, especially with exercise with myoglobinuria +/− rhabdomyolysis	• Baseline mildly elevated CK • PGK1 gene sequencing demonstrating biallelic mutations for definitive diagnosis
Glycogen storage disease X (Phosphoglycerate mutase deficiency)	Phosphoglycerate mutase	• Strenuous exercise intolerance, cramps, myoglobinuria	• Baseline mildly elevated CK • PGAM2 gene sequencing demonstrating biallelic mutations for definitive diagnosis
Glycogen storage disease XI (lactate dehydrogenase deficiency)	Lactate dehydrogenase	• Exercise intolerance, cramping, recurrent myoglobinuria	• Normal CK between attacks • LDHA gene sequencing demonstrating biallelic mutations for definitive diagnosis
Systemic primary carnitine deficiency	Solute carrier family 22 (sodium-dependent carnitine transporter)	• Childhood myopathic form: hypotonia, dilated cardiomyopathy that could result in death, proximal muscle weakness in early childhood (2–4 yr) • Adult form: fatigability	• Baseline CK elevated • Reduced plasma carnitine levels • Increased lipid deposition on muscle biopsy • SLC22A5 gene sequencing demonstrating biallelic mutations for definitive diagnosis
Carnitine palmitoyltransferase II deficiency	Carnitine palmitoyltransferase II (CPT II)	• Myopathic form: recurrent myalgia and myoglobinuria after prolonged exercise, cold, or fasting; weakness during attacks; onset from childhood to adulthood • Severe infantile form: liver failure, cardiomyopathy, seizures, hypoketotic hypoglycemia, myopathy before 1 yr of age (rare)	• Normal CK between attacks • CPT II gene sequencing demonstrating biallelic mutations for definitive diagnosis • Muscle biopsy can be normal

CK, creatine kinase; EM, electron microscopy; H&E, hematoxylin and eosin; LM, light microscopy; LV, left ventricular; PAS, periodic acid–Schiff.

From Konersman C: Hypotonia, weakness, and stroke. In Kliegman RM, Lye PS, Bordini BJ, et al (eds): Nelson symptom-based diagnosis , Philadelphia, 2018, Elsevier, Table 29.12.

Glycogenosis I (von Gierke disease) is not a true myopathy because the deficient liver enzyme glucose-6-phosphatase is not normally present in muscle. Nevertheless, children with this disease are hypotonic and mildly weak for unknown reasons.

Glycogenosis II (Pompe disease) is an autosomal recessively inherited deficiency of the glycolytic lysosomal enzyme α-glucosidase (formerly known as acid maltase) that cleaves the α-1,4 and α-1,6 glycosidic linkages. Of the 12 known glycogenoses, type II is the only one with a defective lysosomal enzyme. The defective gene is at locus 17q23, with more than 200 distinct mutations identified. Two clinical forms are described. The infantile form is a severe generalized myopathy and cardiomyopathy. Patients have cardiomegaly and hepatomegaly and are diffusely hypotonic and weak. The serum CK level is greatly elevated. A muscle biopsy specimen reveals a vacuolar myopathy with abnormal lysosomal enzymatic activities such as acid and alkaline phosphatases. Evidence of a secondary mitochondrial cytopathy is often demonstrated; it includes electron microscopic demonstration of paracrystallin structures within muscle mitochondria and low concentrations of respiratory chain enzymes. Death in infancy or early childhood is usual; however, enzyme replacement therapy has improved the outcome.

The late childhood or adult form is a much milder myopathy without cardiac or hepatic enlargement. It might not become clinically expressed until later childhood or early adult life but may be symptomatic as myopathic weakness and hypotonia even in early infancy. Even in late adult-onset acid maltase deficiency, > 50% of the patients report difficulties with muscle strength dating from childhood. Ultrastructural evidence of secondary mitochondrial cytopathy also occurs, as with infantile Pompe disease. MRI of muscle may show distinctive changes that differ from other myopathies.

The serum CK level is greatly elevated, and the muscle biopsy findings are diagnostic even in the presymptomatic stage. The diagnosis of glycogenosis II is confirmed by quantitative assay of acid maltase activity in muscle or liver biopsy specimens. An evidence-based review and Canadian guidelines for diagnosis and management were recently published.

A rare variant of the milder form of acid maltase deficiency can show muscle acid maltase activity in the low normal range with only intermittent decreases to subnormal values; the muscle biopsy findings are similar although milder. In another form, Danon disease, transmitted as an X-linked recessive trait at the Xq24 locus, the primary deficiency is lysosomal membrane protein-2 (LAMP2) and results in hypertrophic cardiomyopathy, proximal myopathy, and intellectual disability.

Glycogenosis III (Cori-Forbes disease), a deficiency of debrancher enzyme (amylo-1,6-glucosidase), is more common than is usually diagnosed, and it is generally the least severe. Hypotonia, weakness, hepatomegaly, and fasting hypoglycemia in infancy are common, but these features often resolve spontaneously, and patients become asymptomatic in childhood and adult life. Others experience slowly progressive distal muscle wasting, hepatic cirrhosis, recurrent hypoglycemia, and heart failure. This more serious chronic course is particularly seen in the Inuit population. Minor myopathic findings including vacuolation of muscle fibers are found in the muscle biopsy specimen.

Glycogenosis IV (Andersen disease) is a deficiency of brancher enzyme, resulting in the formation of an abnormal glycogen molecule, amylopectin, in the liver, reticuloendothelial cells, and skeletal and cardiac muscle. Hypotonia, generalized weakness, muscle wasting, and contractures are the usual signs of myopathic involvement. Most patients die before age 4 yr because of hepatic or cardiac failure. A few children without neuromuscular manifestations have been described.

Glycogenosis V (McArdle disease) is caused by muscle glycogen phosphorylase deficiency inherited as an autosomal recessive trait at locus 11q13, encoded by the PMGM gene. Exercise intolerance is the cardinal clinical feature. Physical exertion results in cramps, weakness, and myoglobinuria, but strength is normal between attacks. The serum CK level is elevated only during exercise. A characteristic clinical feature is lack of the normal rise in serum lactate levels during ischemic exercise because of inability to convert pyruvate to lactate under anaerobic conditions in vivo. Myophosphorylase deficiency may be demonstrated histochemically and biochemically in the muscle biopsy tissue. Some patients have a defect in adenosine monophosphate–dependent muscle phosphorylase β-kinase, a phosphorylase enzyme activator. Muscle phosphorylase deficiency was the first neuromuscular disease to be diagnosed by MR spectroscopy, which shows that the intramuscular pH does not decrease with exercise and there is no depletion of adenosine triphosphatase but that the phosphocreatine concentration falls excessively. This noninvasive technique may be useful in some patients if the radiologist is experienced with the disease.

A rare neonatal form of myophosphorylase deficiency causes feeding difficulties in early infancy, may be severe enough to result in neonatal death, or can follow a course of slowly progressive weakness resembling a muscular dystrophy. The long-term prognosis is good. Patients must learn to moderate their physical activities, but they do not develop severe chronic myopathic handicaps or cardiac involvement.

Glycogenosis VII (Tarui disease) is muscle phosphofructokinase deficiency. Although this disease is rarer than glycogenosis V, the symptoms of exercise intolerance, clinical course, and inability to convert pyruvate to lactate are identical. The distinction is made by biochemical study of the muscle biopsy specimen. It is transmitted as an autosomal recessive trait at the 1cenq32 locus, and some mutations are particularly prevalent in the Ashkenazi Jewish population.

Bibliography

Bembi B, Cerini E, Danesino C, et al. Diagnosis of glycogenosis type II; management and treatment of glycogenosis type II. Neurology . 2008;71:S4–S11 [S12–S36].

Dlamini N, Jan W, Norwood F, et al. Muscle MRI findings in siblings with juvenile-onset acid maltase deficiency (pompe disease). Neuromuscul Disord . 2008;18:408–409.

Hagemans MLC, Winkel LPF, Van Doorn PA, et al. Clinical manifestations and natural course of late-onset pompe disease in 54 Dutch patients. Brain . 2005;128:671–677.

Marín-García J, Goldenthal MJ, Sarnat HB. Probing striated muscle mitochondrial phenotype in neuromuscular disorders. Pediatr Neurol . 2003;29:26–33.

Tarnopolsky M, Katzberg H, Petrof B, et al. Pompe disease: diagnosis and management: evidence-based guidelines from a Canadian expert panel. Can J Neurol Sci . 2016;43(4):472–485.

Zimakas PJ, Rodd CJ. Glycogen storage disease type III in inuit children. CMAJ . 2005;172:355–358.

629.4

Mitochondrial Myopathies

Harvey B. Sarnat

See also Chapters 105.4 and 616.2 and Table 629.4 .

Table 629.4

Select Mitochondrial Disorders with Hypotonia Classified by Clinical Phenotypes

CLINICAL PHENOTYPE	ASSOCIATED MUTATIONS	MODE OF INHERITANCE	COMMON CLINICAL FEATURES
MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes)	tRNA point mutations: • m.3243A>G in tRNA ^Leu (~80% of cases) • m.3217T>C in tRNA ^Leu (~7.5% of cases) • m.13513G>A encoding NADH-ubiquinone (<15% of cases) • m.3252A>G in tRNA ^Leu (<5% of cases) • Multiple other mtDNA point mutations	Maternal	• Cardinal: strokelike episodes, intermittent encephalopathy, T2/FLAIR abnormalities on brain MRI that do not respect vascular territory, lactic acidosis • Other: hearing loss, diabetes, short stature, gastrointestinal issues
MERRF syndrome (myoclonic epilepsy with ragged red fibers)	tRNA point mutations: • m.8344A>G in tRNA ^Lys (>80% of cases) • m.8356T>C in tRNA ^Lys • m.8363G>A in tRNA ^Lys • m.8361G>A in tRNA ^Lys • Multiple other mtDNA point mutations	Maternal	• Cardinal: myoclonus, proximal weakness, generalized epilepsy, ataxia • Other: multiple lipomatosis, hearing loss, cognitive impairment, neuropathy
KSS (Kearns–Sayre syndrome)	Single large mtDNA deletion (1.1-10-kb) • m.8470_13446del4977 (deletion of 4977 base pairs; most common) • Multiple other mtDNA deletions	Sporadic	• Cardinal: multisystemic disease with progressive external ophthalmoplegia, pigmentary retinopathy, cardiomyopathy before age 20 yr • Other: short stature, proximal muscle weakness, hearing loss, dementia, ataxia, multiple endocrinopathies (diabetes, hypothyroidism, hypoparathyroidism, hypogonadism)
CPEO (chronic progressive external ophthalmoplegia)	Single large mtDNA deletion (1.1-10 kb)	Sporadic	• Cardinal: skeletal muscle disorder with ptosis, ophthalmoparesis, +/− proximal muscle weakness
	• m.3243A>G in tRNA ^Leu (most common; same as MELAS) • Multiple other mtDNA point mutations	Maternal
	• Multiple mtDNA deletions caused by mutations in the following nuclear genes: SLC25A4 encoding ANT1, C10orf2 encoding twinkle, POLG1 encoding mtDNA polymerase, POLG2, OPA1	Autosomal dominant
Leigh syndrome (subacute necrotizing encephalomyelopathy)	mtDNA mutations: • m.8993T>G or m.8993T>C in MT-ATP6 (~10% of cases) • Multiple other mtDNA point mutations	Maternal	• Hypotonia, spasticity, movement disorders (chorea), cerebellar ataxia, neuropathy, bilateral basal ganglia lesions, seizures, lactic acidosis, psychomotor retardation/regression especially with illness between 3-12 mo of age • Hypertrophic cardiomyopathy
	• m.8470_13446del4977 (deletion of 4977 base pairs; also seen in KSS)	Sporadic
	Nuclear gene mutations resulting in respiratory chain complex deficiencies: • Complex I: NDUFV1, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFA1, NDUFA2, NDUFA10, NDUFA9, NDUFA12, NDUFAF2, NDUFAF5, NDUFAF6, FOXRED1 • Complex II: SDHA, SDHAF1 • Complex III: BCS1L, UQCRQ, TTC19 • Complex IV: SURF1, COX10, COX15, SCO2, NDUFA4, PET100, LRPPRC	Autosomal recessive
NARP (neurogenic muscle weakness, ataxia, retinitis pigmentosa)	• m.8993T>G or m.8993T>C in MT-ATP6 (50% of cases)	Maternal	• Proximal neurogenic muscle weakness, sensory neuropathy, seizures, ataxia, pigmentary retinopathy, learning difficulties, dementia with onset usually in childhood
Mitochondrial DNA depletion syndrome	• Homozygous or compound heterozygous mutations in TK2 (thymidine kinase 2), a mitochondrial deoxyribonuclease, resulting in mitochondrial depletion	Autosomal recessive	• Hypotonia, proximal muscle weakness, axial weakness, respiratory insufficiency, marked clinical variability with death in infancy to early adulthood due to respiratory insufficiency

FLAIR, fluid-attenuated inversion recovery; GI, gastrointestinal; MRI, magnetic resonance imaging; mtDNA, mitochondrial DNA; NADH, nicotinamide adenine dinucleotide, reduced form; tRNA, transfer RNA.

Data from DiMauro S, Hirano M: MERRF, GeneReviews [Internet], June 3, 2003, Seattle: University of Washington; DiMauro S, Hirano M: MELAS, GeneReviews [Internet] February 27, 2001, Seattle: University of Washington; Thorburn DR, Rahman S: Mitochondrial DNA-associated Leigh syndrome and NARP, GeneReviews [Internet], October 30, 2003, Seattle: University of Washington; Liang C, Ahmad K, Sue CM: The broadening spectrum of mitochondrial disease: shifts in the diagnostic paradigm, Biochim Biophys Acta 1840:1360-1367, 2014; Konersman C: Hypotonia, weakness, and stroke. In Kliegman RM, Lye PS, Bordini BJ, et al (eds): Nelson symptom-based diagnosis , Philadelphia, 2018, Elsevier, Table 29.11.

Several diseases involving muscle, brain, and other organs are associated with structural and functional abnormalities of mitochondria, producing defects in aerobic cellular metabolism, the electron transport chain, and the Krebs cycle (Table 629.5 and see Table 629.4 ). Because mitochondria are found in all cells except mature erythrocytes, the term mitochondrial cytopathy is used preferentially to emphasize the multisystemic nature of these diseases. The structural aberrations are best demonstrated by electron microscopy of the muscle biopsy sample, revealing a proliferation of abnormally shaped cristae, including stacked or whorled cristae and paracrystallin structures that occupy the space between cristae and are formed from CK. Muscle biopsies of neonates, infants, and toddlers show more severe involvement of endothelial cells of intramuscular capillaries than of myofibers, unlike the reverse in adults, but endothelial paracrystallin structures are globular rather than brick shaped as in myofibers. The endoplasmic reticulum becomes abnormally adherent to mitochondria. Similar endothelial mitochondrial alterations are seen in the brain in Leigh and other infantile mitochondrial encephalopathies. Histochemical study of the muscle biopsy specimen reveals abnormal clumping of oxidative enzymatic activity and scattered myofibers, with loss of cytochrome-c oxidase activity and with increased neutral lipids within myofibers. Ragged red muscle fibers occur in some mitochondrial myopathies, particularly those with a combination of respiratory chain complexes I and IV deficiencies. Accumulations of this membranous material beneath the muscle fiber membrane are best demonstrated by special stains, such as modified Gomori trichrome.

Table 629.5

Clinical Spectrum of Mitochondrial Disease

NERVOUS SYSTEM

• Hypotonia

• Failure to thrive

• Motor regression

• Stroke (nonvascular)

• Dementia

• Episodic encephalopathy (elevated cerebrospinal fluid lactate)

• Intellectual disability

• Neuropathy (axonal, demyelinating, or sensory ganglionopathy)

• Ophthalmoparesis (slowly progressive)

• Ptosis (slowly progressive; little diurnal variation; asymmetric at onset)

• Optic atrophy

• Retinitis pigmentosa (perimacular; vision usually spared)

• Ataxia

• Central apnea

• Epilepsy (focal or multifocal myoclonus; status epilepticus; triggered by sodium valproate)

• Migraines

• Sensorineural hearing loss (asymmetric; young onset; partial recovery possible)

HEART

• Cardiomyopathy

• Conduction block or arrhythmia

SKELETAL MUSCLE

• Myopathy (proximal, symmetric weakness; myalgia)

• Exercise intolerance

• Episodic rhabdomyolysis

OTHER

• Lactic acidosis

• Recurrent bowel obstruction (pseudoobstruction)

• Short stature

• Diabetes (young onset; nonobese)

Data from Amato A, Russell J: Neuromuscular disorders , 1st ed, New York, 2008, McGraw-Hill; Liang C, Ahmad K, Sue CM: The broadening spectrum of mitochondrial disease: shifts in the diagnostic paradigm, Biochim Biophys Acta 1840:1360-1367, 2014.

These characteristic histochemical and ultrastructural changes are most consistently seen with point mutations in mitochondrial transfer RNA. The large mitochondrial DNA (mtDNA) deletions of 5 or 7.4 kb (the single mitochondrial chromosome has 16.5 kb) are associated with defects in mitochondrial respiratory oxidative enzyme complexes, if as few as 2% of the mitochondria are affected, but minimal or no morphologic or histochemical changes may be noted in the muscle biopsy specimen, even by electron microscopy; hence, quantitative biochemical studies of the muscle tissue are needed to confirm the diagnosis. Because most of the subunits of the respiratory chain complexes are encoded by nuclear DNA (nDNA) rather than mtDNA, mendelian autosomal inheritance is possible, rather than maternal transmission as with pure mtDNA point mutations. Complex II (succinate dehydrogenase) is the only enzyme complex in which all of its subunits are encoded by nDNA; hence, it is histochemically reactive in all mitochondrial diseases with mtDNA point mutations. Serum lactate is elevated in some diseases, and cerebrospinal fluid lactate is more consistently elevated, even if serum concentrations are normal.

Several distinct mitochondrial diseases that primarily affect striated muscle or muscle and brain are identified. These can be divided into the ragged red fiber diseases and non–ragged fiber diseases. The ragged red fiber diseases include Kearns-Sayre, MELAS (m itochondrial e ncephalopathy, l actic a cidosis, and s troke-like episodes) syndrome, MERRF (m yoclonic e pilepsy with r agged r ed f ibers) syndrome, and progressive external ophthalmoplegia syndromes, which are associated with a combined defect in respiratory chain complexes I and IV. The non–ragged fiber diseases include Leigh encephalopathy and Leber hereditary optic atrophy; they involve complex I or IV alone or, in children, the common combination of defective complexes III and V. Kearns-Sayre syndrome is characterized by the triad of progressive external ophthalmoplegia, pigmentary degeneration of the retina, and onset before age 20 yr. Heart block, cerebellar deficits, and a high cerebrospinal fluid protein content are often associated. Visual evoked potentials are abnormal. Patients usually do not experience weakness of the trunk or extremities or dysphagia. Most cases are sporadic.

Chronic progressive external ophthalmoplegia may be isolated or accompanied by limb muscle weakness, dysphagia, and dysarthria. A few patients described as having ophthalmoplegia plus have additional central nervous system involvement. Autosomal dominant inheritance is found in some pedigrees, but most cases are sporadic.

MERRF and MELAS syndromes are other mitochondrial disorders affecting children. The latter is characterized by stunted growth, episodic vomiting, seizures, and recurring cerebral insults causing hemiparesis, hemianopia, or even cortical blindness, and dementia. The disease behaves as a degenerative disorder, and children die within a few years.

Other “degenerative” diseases of the central nervous system that also involve myopathy with mitochondrial abnormalities include Leigh subacute necrotizing encephalopathy (see Chapter 105.4 ) and cerebrohepatorenal (Zellweger) disease, primarily a peroxisomal disease with secondary mitochondrial alterations (see Chapter 104.2 ). Another recognized mitochondrial myopathy is cytochrome-c oxidase deficiency. Oculopharyngeal muscular dystrophy is also fundamentally a mitochondrial myopathy.

Mitochondrial depletion syndrome of early infancy is characterized by severely decreased oxidative enzymatic activities in most or all five of the complexes; in addition to diffuse muscle weakness, neonates and young infants can show multisystemic involvement, and the syndrome occurs in several forms: myopathic; encephalomyopathic; hepatoencephalopathic; and intestinal encephalopathic. Cardiomyopathy and sometimes bullous skin lesions or generalized edema also can occur. Alpers syndrome is genetically homogeneous and is caused by mtDNA depletion and mutations in the POLG1 gene. Several other genes are identified, mostly in later-onset forms; hence, mitochondrial depletion is a syndrome and not a single disease. Barth syndrome is an X-linked recessive mitochondrial disorder characterized by cardiomyopathy, myopathy of striated muscle, growth retardation, neutropenia, and high serum and urinary concentrations of 3-methyl-glutaconic acid.

Many rare diseases with only a few case reports are suspected of being mitochondrial disorders. It is also now recognized that secondary mitochondrial defects occur in a wide range of nonmitochondrial diseases, including inflammatory autoimmune myopathies, Pompe disease, and some cerebral malformations, and also may be induced by certain drugs and toxins, so that interpretation of mitochondrial abnormalities as primary defects must be approached with caution.

mtDNA is distinct from the DNA of the cell nucleus and is inherited exclusively from the mother; mitochondria are present in the cytoplasm of the ovum but not in the head of the sperm, the only part that enters the ovum at fertilization. The rate of mutation of mtDNA is 10 times higher than that of nDNA. The mitochondrial respiratory enzyme complexes each have subunits encoded either in mtDNA or nDNA. Complex II (succinate dehydrogenase, a Krebs cycle enzyme) has four subunits, all encoded in nDNA; complex III (ubiquinol or cytochrome-b oxidase) has nine subunits, only one of which is encoded by mtDNA and eight of which are programmed by nDNA; complex IV (cytochrome-c oxidase) has thirteen subunits, only three of which are encoded by mtDNA. For this reason, mitochondrial diseases of muscle may be transmitted as autosomal recessive traits rather than by strict maternal transmission, even though all mitochondria are inherited from the mother.

In Kearns-Sayre syndrome, a single large mtDNA deletion has been identified, but other genetic variants are known; in MERRF and MELAS syndromes of mitochondrial myopathy, point mutations occur in transfer RNA.

Investigations

Investigation for mitochondrial cytopathies begins with serum lactate. Lactic acid is not increased in all mitochondrial cytopathies, so that a normal result is not necessarily reassuring; cerebrospinal fluid lactate is increased in some cases in which serum lactate is normal, particularly if there are clinical signs of encephalopathy. Serum 3-methyl-glutaconic acid often is increased in mitochondrial cytopathies in general, demonstrated in more than 50 different genetic mutations, and hence is a good screening measurement; it rarely is increased in other metabolic diseases. This product also may be increased in urine. Hepatic enzymes (transaminases) should be measured in blood. Cardiac evaluation often is warranted. Molecular markers in blood for the common diseases with known mtDNA point mutations identify many of the mitochondrial cytopathies presenting in adult life or adolescence, but less frequently in children and least in young infants. MRI of the brain may reveal hyperintense lesions of the basal ganglia and MR spectroscopy can demonstrate an increased lactate peak. The muscle biopsy provides the best evidence of all mitochondrial myopathies and should include histochemistry for oxidative enzymes, electron microscopy, and quantitative biochemical assay of respiratory chain enzyme complexes and coenzyme-Q10; muscle tissue also can be analyzed for mtDNA. Many mitochondrial disorders also can affect the Schwann cells and axons of peripheral nerves and present clinically with neuropathy; hence, motor and sensory nerve conduction velocities can be measured in selected patients; sural nerve biopsy is required only rarely if neuropathy is the predominant finding and the diagnosis is not evident from other studies.

A diagnostic approach is noted in Fig. 629.1 .

Fig. 629.1 Clinical diagnostic algorithm for patients with exercise intolerance in whom a metabolic myopathy is suspected. CK, creatine kinase; COX, cytochrome-c oxidase; CPT, carnitine palmitoyl transferase; cyt b, cytochrome b ; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; PFK, phosphofructokinase; PGAM, phosphoglycerate mutase; PGK, phosphoglycerate kinase; PPL, myophosphorylase; RRF, ragged red fibers; TFP, trifunctional protein deficiency; VLCAD, very-long-chain acyl-coenzyme A dehydrogenase. (From Berardo A, Di Mauro S, Hirano M: A diagnostic algorithm for metabolic myopathies, Curr Neurol Neurosci Rep 10:118-126, 2010, Fig. 1.)

Treatment

There is no effective treatment of mitochondrial cytopathies, but various cocktails are often used empirically to try to overcome the metabolic deficits. These include oral carnitine supplements, riboflavin, coenzyme-Q10, ascorbic acid (vitamin C), vitamin E, and other antioxidants. Although some anecdotal reports are encouraging, no controlled studies that prove efficacy have been published.

Bibliography

Berardo A, Di Mauro S, Hirano M. A diagnostic algorithm for metabolic myopathies. Curr Neurol Neurosci Rep . 2010;10:118–126.

Darin N, Oldfors A, Moslemi A-R, et al. Genotypes and clinical phenotypes in children with cytochrome-c-oxidase deficiency. Neuropediatrics . 2003;34:311–317.

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Jeffries JL. Barth syndrome. Am J Med Genet C Semin Med Genet . 2013;163:198–205.

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Nishino I, Yamamoto A, Sugie K, et al. Danon disease and related disorders. Acta Myol . 2001;20:120.

Sarnat HB, Flores-Sarnat L, Casey R, et al. Endothelial ultrastructural alterations of intramuscular capillaries in infantile mitochondrial cytopathies. Neuropathology . 2012;32:617–627.

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629.5

Lipid Myopathies

Harvey B. Sarnat

See Chapter 104.4 .

Considered as metabolic organs, skeletal muscles are the most important sites in the body for long-chain fatty acid metabolism because of their large mass and their rich density of mitochondria where fatty acids are metabolized. They are the major source of energy for skeletal muscle during sustained exercise or fasting. Hereditary disorders of lipid metabolism that cause progressive myopathy are an important, relatively common, and often treatable group of muscle diseases (Table 629.6 ). Increased lipid within myofibers is seen in the muscle biopsy of some mitochondrial myopathies and is a constant, rather than an unpredictable, feature of specific diseases. Among the ragged red fiber diseases, Kearns-Sayre syndrome always shows increased neutral lipid, whereas MERRF and MELAS syndromes do not, a useful diagnostic marker for the pathologist. Free fatty acids are converted to acyl-coenzyme A by fatty acyl-coenzyme A synthetases; the resulting long-chain fatty acids bind to carnitine and are transported into mitochondria where β-oxidation is carried out. Disorders of lipid fuel utilization and lipid storage disorders can be divided into defects of transport and oxidation of exogenous fatty acids within mitochondria and defects of endogenous triglyceride catabolism.

Table 629.6

Lipid Metabolism Deficiencies
Carnitine palmitoyltransferase* Primary systemic/muscle carnitine deficiency Secondary carnitine deficiency β-Oxidation defects Medications (valproic acid)

^* Deficiency can produce exercise intolerance and myoglobinuria.

From Chinnery PF: Muscle diseases. In Goldman L, Schafer AI, editors: Goldman's Cecil medicine , ed 24, Philadelphia, 2012, Elsevier, Table 429-7, p. 2413.

Muscle carnitine deficiency is an autosomal recessive disease caused by mutations in the SLC22A5 gene, involving deficient transport of dietary carnitine across the intestinal mucosa. Carnitine is acquired from dietary sources but is also synthesized in the liver and kidneys from lysine and methionine; it is the obligatory carrier of long- and medium-chain fatty acids into muscle mitochondria.

The clinical course may be one of sudden exacerbations of weakness or can resemble a progressive muscular dystrophy with generalized proximal myopathy and sometimes facial, pharyngeal, and cardiac involvement. Symptoms usually begin in late childhood or adolescence or may be delayed until adult life. Progression is slow but can end in death.

The serum CK level is mildly elevated. Muscle biopsy material shows vacuoles filled with lipid within muscle fibers in addition to nonspecific changes suggestive of a muscular dystrophy. Mitochondria can appear normal or abnormal. Carnitine measured in muscle biopsy tissue is reduced, but the serum carnitine level is normal.

Treatment stops the progression of the disease and can even restore lost strength if the disease is not too advanced. It consists of special diets low in long-chain fatty acids. Steroids can enhance fatty acid transport. Specific therapy with L -carnitine taken orally in large doses overcomes the intestinal barrier in some patients. Some patients also improve when given supplementary riboflavin, and other patients seem to improve with propranolol.

Systemic carnitine deficiency is a disease of impaired renal and hepatic synthesis of carnitine rather than a primary myopathy. Patients with this autosomal recessive disease experience progressive proximal myopathy and show muscle biopsy changes similar to those of muscle carnitine deficiency; however, the onset of weakness is earlier and may be evident at birth. Endocardial fibroelastosis also can occur. Episodes of acute hepatic encephalopathy resembling Reye syndrome can occur. Hypoglycemia and metabolic acidosis complicate acute episodes. Cardiomyopathy may be the predominating feature in some cases and result in death.

Cerebral infarctions and myopathy occur in children, particularly when accompanied by hypoglycemia. The mean age at presentation is approximately 9 yr. A brain MRI shows distinctive changes related to multiple infarcts of various sizes.

The concentration of carnitine is reduced in serum as well as in muscle and liver. L -Carnitine deficiency can be corrected by oral administration of carnitine on a daily basis.

A similar clinical syndrome may be a complication of renal Fanconi syndrome because of excessive urinary loss of carnitine or loss during chronic hemodialysis.

Treatment with L -carnitine improves the maintenance of blood glucose and serum carnitine levels but does not reverse the ketosis or acidosis or improve the exercise capacity.

Muscle carnitine palmitoyltransferase (CPT) deficiency manifests as episodes of rhabdomyolysis, coma, and elevated serum CK levels. It is the most common identified cause of recurrent myoglobinuria in adults, but myoglobinuria is not a constant feature in all. CPT transfers long-chain fatty acid acyl-coenzyme A residues to carnitine on the outer mitochondrial membrane for transport into the mitochondria. Exercise intolerance and myoglobinuria resemble glycogenoses V and VII. The degree of exercise that triggers an attack varies among individuals, ranging from casual walking to strenuous exercise. Fasting hypoglycemia can occur. Some patients present only in late adolescence or adult life with myalgias. Genetic transmission is autosomal recessive and is caused by a defect on chromosome 1 at the 1p32 locus. Administration of valproic acid can precipitate acute rhabdomyolysis with myoglobinuria in patients with CPT deficiency; it should be avoided in the treatment of seizures or migraine if they occur. Very long-chain acyl-coenzyme A dehydrogenase deficiency has a similar clinical presentation but mainly with adult onset.

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629.6

Vitamin E Deficiency Myopathy

Harvey B. Sarnat

In experimental animals, deficiency of vitamin E (α-tocopherol, an antioxidant also important in mitochondrial superoxide generation) produces a progressive myopathy closely resembling a muscular dystrophy. Myopathy and neuropathy are recognized in humans who lack adequate intake of this antioxidant. Patients with chronic malabsorption, those undergoing long-term dialysis, and premature infants who do not receive vitamin E supplements are particularly vulnerable. Treatment with high doses of vitamin E can reverse the deficiency. Myopathy caused by chronic hypervitaminosis E also occurs.

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