Differential Diagnosis in Neurology

Topic 12. Muscle Disease

12.8. Metabolic Muscle Disease

Metabolic muscle disease presents as exercise intolerance, cramps and myoglobinuria with or after strenuous exercise or as progressive weakness. The type and duration of specific exercise offers insight into the metabolic deficiency causing specific clinical symptoms. Burst muscle activity such as sprinting utilizes anaerobic metabolism and Type II muscle fibers. Prolonged less than maximal intensity exercise (measured by oxygen utilization) requires glucose derived from glycogen stores as the primary energy source. Prolonged exercise, such as distance running, free fatty acids (FFA) are utilized for ATP production. Many mitochondrial myopathies suffer weakness and exercise intolerance with minimal activity. Exhaustion of glycogen is correlated with fatigue and myoglobinuria which is seen with energy failure and muscle breakdown from any cause of failure to produce adequate ATP.

Free Fatty Acids (FFA)

Metabolic Disorders of Muscle

  • General Features:
    • Exercise intolerance
    • Cramps with exercise
    • Myoglobinuria with exercise
    • Second wind phenomena (same entities)
  • Weakness of muscle:
    • Episodic:
      • Phosphorylase deficiency
      • Phospho fructose kinase deficiency
      • Carnitine palmityl transferase deficiency
      • Acid maltase deficiency
      • Debrancher deficiency
      • Brancher deficiency

General Categories of Defects in Metabolic Muscle Disease

Disorders of Glycogen Metabolism

  • Type II – Acid maltase deficiency
  • Type III – Amylase 1, 6 glycosidase deficiency (debrancher)
  • Type IV – Amylase 1, 4 to 1, 6 transglycosylase deficiency (brancher)
  • Type V – Myophosphorylase deficiency (McArdle's disease)
  • Type VII – Phosphofructose kinase deficiency (PFK)
  • Type IX – Phosphoglycerate kinase deficiency (PGK)
  • Type X – Phosphoglycerate mutase deficiency (PGM)
  • Type XI – Lactate dehydrogenase deficiency (LDH)

Disorders of Lipid Metabolism

  • Carnitine deficiency
  • Carnitine palmityl transferase deficiency (CPT)
  • Lipid storage myopathies

Disorders of Adenine Nucleotide Metabolism

  • Adenylate deaminase deficiency (AMPD)

Mitochondrial Dysfunction

  • Exercise intolerance:
    • Luft's disease
    • NADH-CO Q reductase deficiency
    • Cytochrome b deficiency
  • Mitochondrial dysfunction with progressive weakness:
    • Kearns–Sayre syndrome
    • ATPase deficiency
    • Cytochrome-c-Oxidase deficiency
    • MERRF (mitochondrial encephalomyopathy with ragged red fibers)
    • MELAS (mitochondrial encephalomyopathy with lactic acid and stroke)
    • PEO (progressive external ophthalmoplegia)

Phosphorylase Deficiency (Type V McArdle's Disease)

  • Genetics:
    • AR; male to female 2.39:1
    • Chromosome 11
    • 16 different mutations; most common is a cytosine to thymine substitution codon in 49 of exon 1; may be analyzed in leukocytes
    • Stored glycogen accumulates at the subsarcolemma areas of muscle fibers (subsarcolemmal vacuoles)
  • Clinical Presentation:
    • Exercise intolerance:
      • Myalgia and early fatigue; weakness of the exercised muscle; easy fatigability in childhood; isometric exercise and sustained dynamic exercise precipitate symptoms
      • Relieved by rest
      • Any muscle may be affected; includes masseters and throat muscles
      • Exercise (isometric or sustained) may precipitate symptoms; the amount of exercise required for symptoms may vary day to day
      • Second wind phenomenon:
        • Rest at first sign of myalgia; then patients are capable of further exercise
      • Painful cramps with muscle swelling if exercise tolerance is exceeded; true cramps
      • Muscle necrosis and myoglobinuria after severe exercise
      • Few patients recognize impending myoglobinuria attacks
      • Renal failure occurs in 25% of patients with myoglobinuria
      • Muscle pain; stiffness, weakness with exercise relieved by rest as the patient enters adulthood
    • Permanent weakness:
      • Usually mild
      • Proximal greater than distal muscles in 1/3 of patients
      • Weakness increases with age
      • Wasting is uncommon; when it is severe it occurs in older patients
      • Exercise intolerance occurs in childhood
      • Increase of seizures greater than in the general population
  • Heterogeneity:
    • Excessive tiredness or fatigue rather than cramps or myoglobinuria as the major complaint
    • Progressive weakness rather than cramps or myalgia
    • Several elderly patients have demonstrated proximal weakness wasting and ptosis
    • Late onset myopathy with weakness
    • A few children have weakness at or soon after birth; respiratory insufficiency; death in infancy
    • Recurrent myoglobinuria in adults
    • Late onset asymmetric arm weakness (one patient)
  • Laboratory evaluation:
    • CK variably increased (92%)
    • EMG (abnormal in 40%):
      • Normal between attacks of myoglobinuria
      • Increased insertional activity
      • Increased polyphasic potentials
      • Increased muscle irritability-fibrillation, myotonic discharges and positive sharp waves
      • No electrical activity during the cramp
    • EKG:
      • Minor abnormalities that are non-specific have been reported in a few patients; abnormal increase of heart rate with exercise
    • EEG:
      • Spike and slow waves are noted in some patients with seizures
    • Positive forearm ischemic exercise test:
      • No rise of lactate and pyruvate with exercise
      • In normal patients there is usually a 3–5 fold increase of pyruvate and lactate at 1 and 3 minutes after exercise
    • Pathology:
      • Subsarcolemmal deposits of PAS positive glycogen, and vacuoles

Phosphofructokinase Deficiency (Tarui's Disease) Glycogenosis Type VII

  • Genetics:
    • AR:
      • Chromosome 1 – encodes muscle (M) subunit
      • Chromosome 2 – encodes the liver (L) subunit
      • Chromosome 10 – encodes platelet enzyme
  • Group I:
    • M subunit of muscle is defective
    • Major symptom complex is myopathy and hemolysis
    • Clinical features:
      • Adults at diagnosis, noted exercise intolerance in childhood
      • Exercise intolerance or cramps:
        • Isometric exercise induces cramps
        • Phasic activity induces cramp and myoglobinuria
        • Intermittent degrees of exercise intolerance
        • Process starts in childhood
        • Patients are nauseated with exercise that induces cramps
        • Permanent weakness may occur after a childhood illness
        • Glucose decreases exercise capacity
        • Fixed weakness in later life in a few patients
      • Myoglobinuria:
        • Myoglobinuria and renal failure are less common than in myophosphorylase deficiency
      • Second wind phenomena occurs
      • Rare seizure
      • Gout
      • Exercise of moderate intensity is better tolerated
    • Laboratory evaluation:
      • CK is increased
      • Ischemic exercise test is positive
      • Decreased RBC, PFK in 50% of patients
      • Hemolysis with elevated reticulocyte count:
        • Some patients are mildly jaundiced
        • Cholecystectomy for gall stones is necessary in some adolescent patients
      • High serum urate
      • Muscle biopsy:
        • PAS positive vacuoles
  • Group II:
    • Hemolysis without myopathy
    • L-subunit disorder; unstable unit
    • PFK is normal in muscle; 60% of normal in RBCs
    • No muscle symptoms
    • Clinical characteristics:
    • Jaundice
      • Jaundice
      • Hemolysis
  • Group III - infantile myopathy:
    • PFK-M normal
    • Delayed motor development
    • No hemolysis
    • Congenital joint deformities
  • Laboratory evaluation:
    • Normal or myopathies features
    • Muscle irritability; fibrillation potentials, pseudomyotonia, positive sharp waves
    • No EMG activity during a cramp
  • Ischemic exercise test:
    • No rise in venous lactate
    • MR spectroscopy, no increase in lactate
  • Muscle biopsy:
    • Same pattern as noted in phosphorylase deficiency
  • Physiology of Phosphofructokinase Deficiency
    • Abnormal Polysaccharide in 2–10% of muscle fibers instead of glycogen
    • High levels of adenosine diphosphate
    • Increased production of ammonia and myogenically induced uric acid
    • Exaggerated sympathetic neural response to exercise:
      • Enhanced mobilization of extra muscular substrate
      • Increased heart rate
      • Increased cardiac output and blood flow in relation to muscle oxygen consumption
    • Glucose diminishes exercise tolerance:
      • lowers the level of circulating FFA and ketones (the alternate substrate for metabolism)
      • opposite of myophosphorylase

Phosphoglycerate Kinase Deficiency (Glycogenosis Type IX)

  • Genetics:
    • X-linked recessive; X q 13
  • Clinical characteristics:
    • Nonspherocytic hemolytic anemia
    • CNS dysfunction; one child with myopathy and mental retardation
    • Exercise intolerance
    • Cramps
    • Primary myopathy
    • Myoglobinuria
    • Prolonged exercise of modulate intensity can be accomplished
  • Hemizygous males:
    • Severe hemolytic anemia after births; hemolytic crisis precipitated by infections
    • Mental retardation, delayed language acquisition, behavioral aberrations and seizures
  • Laboratory evaluation:
    • Anemia
    • Severe reticulocytosis
    • Erythroid hyperplasia of the bone marrow
    • Residual muscle enzyme activity of 5% due to mutant enzyme

Phosphoglycerate Mutase Deficiency (Glycogenosis X)

  • Genetics:
    • AR; chromosome 7
    • Muscle specific M subunits; brain specific B subunits
  • Clinical manifestations (PGAM):
    • Myalgia
    • Cramps
    • Myoglobinuria (recurrent)
    • Intense exercise is the precipitant
    • Childhood onset
  • Laboratory evaluation:
    • Ischemic exercise test:
      • Positive lactate elevation greater than two times above pre-exercise level
      • Elevated CK
      • EMG/NCV - normal
    • Muscle biopsy:
      • Increased PAS positive granules
      • Subsarcolemmal pools of glycogen
      • Tubular aggregates in type II B muscle fibers
      • Decrease in the activity of PGAM to 5–6% of normal activity

Lactate Dehydrogenase Deficiency (glycogenosis Type XI)

  • Genetics: muscle component gene on chromosome II
  • LDH: tetrameric enzyme composed of a:
    • Muscle specific subunit (LDH-A); encoded by gene or chromosome II
    • Cardiac subunit (LDH-B)
  • Clinical features:
    • Pigmenturia following intense exercise
    • A few patients have had dystonia during childbirth
    • Dermatologic abnormalities
  • Laboratory evaluation:
    • Decreased rise in lactate; abnormal rise in pyruvate
    • High CK
    • The amount of residual enzyme activity in muscle is approximately 5% of normal
    • Muscle:
      • 5% of normal enzyme activity in muscle

Differential Diagnosis of Myophosphorylase Deficiency

The major myopathies that comprise the differential diagnosis are other metabolic myopathies terminal glycogenases. These include:

  • PFK (phospho fructokinase)
  • PGK (phospho glycerokinase)
  • PGAM (phosphoglyceromutase)
  • LDH (lactate dehydrogenase)

Patients with PFK differ from those with McArdle's disease (myophosphorylase deficiency) in that they have:

  • Less of a second wind phenomena; glucose may be deleterious for them
  • Severe nausea and vomiting occurs during exercise induced cramps
  • Less myoglobinuria
  • Increased bilirubin in the serum
  • An increased reticulocyte count

Patients with terminal glycogenosis, PGAM, PGK, and LDH, have an abnormally low lactate rise during the ischemic exercise test, but it is not absent. LDH deficiency demonstrates a low lactate and high pyruvate under ischemic stress.

Carnitine palmityl transferase deficiency Type II is the most common cause of recurrent adult myoglobinuria. This occurs not only with exercise, but also with fasting without exertion. The ischemic exercise test is negative in CPT II deficiency. In myophosphorylase deficiency the myoglobinuria occurs with and following intense exercise. Exercise induced myoglobinuria may also occur with DMD, BMD and malignant hyperthermia. The AR recessive genetics pattern, interval CK and clinical presentation rule out the dystrophinopathies. Malignant hyperthermia is AD and there is often a family history of death or unexpected anesthetic complication. Undue fatigue with exercise and without myoglobinuria occurs with terminal glycogenoses as well as with adenylate deaminase deficiency (AMPD). In this myopathy the ischemic exercise test demonstrates a normal rise in lactate, but no increase in ammonia.

Acid Maltase Deficiency

  • Genetics:
    • AR; chromosome 7
    • Acid maltase:
      • Lysosomal L-glucosidase
      • Releases glucose from maltase, oligosaccharides and glycogen
  • Clinical features:
    • Infantile, childhood and adult variants
  • The spectrum of disease:
    • The onset can be in infancy but the patient may survive into the second decade
    • May present during the first few years of life and the patient succumbs near the end of the second decade
    • May present in the 7th decade

Infantile Acid Maltase Deficiency (Pompe's Disease; Glycogenosis Type II)

  • Genetics:
    • AR
    • Long arm of chromosome 17
  • Clinical features:
    • Onset is in the first few months of life; the clinical course is rapidly progressive
    • Progressive weakness and hypotonia
    • Respiratory failure
    • Feeding difficulties
    • Cardiorespiratory failure by age 2; cardiomegaly
    • Macrogenesis
  • Laboratory evaluation:
    • Response of blood glucose to epinephrine or glycogen is normal
    • EMG; myopathic; irritatives features
    • EKG:
      • Short PR interval
      • Thickening of the interventricular septum
      • High QRS voltage
      • Left ventricular hypertrophy
    • CK – increased
    • Chest X-ray: congestive heart failure; massive heart enlargement
  • Pathology:
    • Glycogen accumulates in the liver, heart and skeletal muscle
    • Microscopic examination reveals glycogen in:
      • Smooth muscle
      • Endothelial cells
      • Lymphocytes
      • Cellular components of the eye
      • Neurons of the brain and spinal cord; anterior horn cells and brainstem nuclei
      • Schwamm cells of peripheral nerves

Childhood Acid Maltase Deficiency

  • Genetics: AR
  • Compound heterozygosis
  • Clinical features:
    • Onset in infancy or early childhood
    • Primarily myopathic; no cardiomegaly
    • Delay of motor milestones
    • Weakness is proximal greater than distal
    • Respiratory muscles are affected early
    • Calf enlargement occurs
    • Death from respiratory failure is usual; rarely there is survival past the second decade
    • Enlargement of the liver, heart and tongue is rare
  • Laboratory evaluation:
    • Serum CK: increased
  • EMG:
    • Myopathic with irritative features
  • Pathology:
    • Less marked glycogen in muscle than in the infantile from
    • Acid maltase in muscle
    • Little glycogen in heart, liver, skin and the nervous system

Acid Maltase Deficiency in Adulthood (Glycogenosis Type II)

  • Genetics: 
    • AR; chromosome 17 mutations
  • Clinical features:
    • Slowly progressive myopathy; proximal greater than distal; lower extremity greater than the upper extremity; usually starts in 3rd or 4th decade; some patients onset in sixth or seventh decade
    • Respiratory failure occurs
    • Weakness affects the torso; may involve individual muscles or parts of muscles selectively
    • Loss of reflexes occurs late in the illness
    • 1/3 of patients present with respiratory failure
    • Atrophy is proportionate to weakness
    • Cardiac dysfunction is rare in adults
    • Massive headaches and exertional dyspnea (CO2 retention and diaphragm involvement)
    • No visceromegaly; glycogen in cerebral vessels may cause aneurysms
  • Laboratory evaluation:
    • Serum CK: may be normal or slightly elevated
    • EMG:
      • Myopathic
      • Increased muscle irritability
      • Myotonic discharges (paraspinal and abdominal muscles)
      • Fibrillations, positive sharp waves, repetitive discharges at rest and myotonia
    • Urine:
      • Decreased acid maltase
    • Pulmonary function studies demonstrates restrictive ventilatory deficit with respiratory muscle fatigue
    • Acid and neutral maltase activity in lymphocytes is decreased
  • Pathology:
    • Vacuolar myopathy:
      • All fibers are affected in severe patients
      • Vacuoles contain glycogen; acid phosphatase positive
      • Longitudinal fiber splitting in adult patients
      • Lysosomal and sarcoplasmic glycogen deposits: Type I > II fibers
      • Decreased acid maltase in muscle; biopsy from clinically unaffected muscles may be normal

Differential Diagnosis of Acid Maltase Deficiency

The infantile from of the disease presents with severe weakness and hypotonia. The differential diagnosis includes Werdnig Hoffmann's disease (SMAI) and the other congenital metabolic or myopathic diseases. The major differential feature is severe congestive heart failure and macroglossia. Mitochondrial disorders such as COX deficiency may involve proximal muscles and the heart, but not to the same degree. Macroglossia is not a feature of mitochondrial disease.

Debrancher deficiency presents with massive hepatomegaly and hypoglycemia. There is no rise of blood glucose to epinephrine or glycogen. Phosphorylase kinase deficiency may present with severe cardiomegaly in infancy, but lacks muscle weakness. Duchenne dystrophy has clear X-linked genetics more prominent calf hypertrophy and the EMG does not demonstrate irritative features. Carnitine deficiency does not have the same degree of cardiac dysfunction or macroglossia.

Congential myopathies occasionally present with similar body habitus and include myotubular myopathy, central core disease and nemaline myopathy. Thinness, high arched palate, long facies are characteristic of nemaline myopathy while bilateral symmetrical ptosis is present in myotubular myopathy. Muscle biopsy clearly differentiates these congenital myopathies.

Adult acid maltase deficiency is frequently misdiagnosed as limb girdle muscular dystrophy or polymyositis. The early respiratory muscle involvement as well as paraspinal myotonic discharges and complex repetitive action potentials differentiate the entities.

Two adult variants of autophagic vacuolar myopathy occur with a similar phenotype. One with cardiomyopathy and mental retardation due to a mutation of the gene for lysosome associated membrane protein-2 (LAMP-2 gene) and the other with myopathy and multiorgan involvement. Muscle biopsy differentiates the vacuoles from PFK and acid maltase in the urine and the irritative EMG establishes in the diagnosis of AMD. Glycogen positive acid phosphatase containing vacuoles in AMD (acid maltase disease) distinguishes this entity from chloroquine vacuolar myopathy. This entity may have concomitant macular retinopathy.

Debrancher Enzyme Deficiency (Cori–Forbes Disease): Glycogen Storage Disease Type III

  • Genetics: AR; chromosome 1p21
  • Debranching enzyme catalyses two reactions:
    • Oligo-11,4-1,4-glucantrousferase
    • Amylo-1,6-glucosidase
  • Biochemical variants of the disease:
    • Type IIIa – common deficiency of both enzyme activities in muscle and liver
    • Type IIIb – less common; mutations in exon 3
    • Type IIId – rare; deficiency of oligo-1,4-1,4-glucantransferase
  • Clinical features – infantile form:
    • Hepatomegaly
    • Hypoglycemia
    • Hypotonia (floppy baby)
    • Enlarged tongue with fibrillations
    • Congestive heart failure
    • Growth failure
    • Hypotonia and myopathy increase with age
    • Disease may improve after puberty
    • No exercise intolerance
    • Muscle weakness occurs after disappearance of liver symptoms
  • Clinical features – adult from:
    • Usually had been less active than normal children
    • Onset of weakness in the third or fourth decade
    • Myopathy may be more distal than proximal
    • Wasting of leg muscles and intrinsic hand muscles
    • No exercise intolerance and myoglobinuria
    • Some patients have a preference for a high protein and low carbohydrate diet
  • Laboratory evaluation:
    • Elevated CK
    • EMG:
      • Mixed myopathic and neuropathic picture
      • Some patients have slowed nerve conduction velocities
    • No or minimal increase of lactate in the ischemic exercise test
    • Muscle biopsy:
      • Subsarcolemmal collection of glycogen
      • Increased glycogen between and within fibrils
      • No glycogen excess in muscle
      • No glucose rise after epinephrine or glycogen stimulation
      • Subsarcolemmal PAS positive deposits
      • Vacuoles in Type II fibers

Brancher Enzyme Deficiency (GSD IV; Anderson's Disease)

  • Genetics:
    • AR; gene is on chromosome 3; primarily Jewish patients
    • Spectrum of clinical phenotypes
    • Defect can be silent; alternatively there may be dysfunction in the liver, heart, brain or skeletal muscles
    • Brancher deficiency reported only in Ashkenazi Jewish patients
  • Clinical features – infantile form:
    • Failure to thrive
    • Hypotonia
    • Muscle atrophy
    • In a few older children the predominant problem is cardiomyopathy
    • Progressive cirrhosis with chronic hepatic failure
  • Clinical features – adult form:
    • Distal muscle wasting (intrinsic hand muscles)
    • Enlarged liver
    • Cardiac myopathy
    • Brain involvement (adult polyglucosan body disease) late onset upper and lower motor neuron death, sensory loss, sphincter problems and dementia
  • Laboratory evaluation:
    • Serum CK is normal
    • Flat ischemic exercise test
    • EMG is myopathic
    • Muscle biopsy:
      • Increased glycogen on EM
      • Type II fibers contain PAS + vacuoles
      • Subsarcolemma deposition is amylopectin

Aldolase A Deficiency (Glycogenosis Type XII)

  • Genetics: enzyme is in erythrocytes and skeletal muscle
  • Clinical features:
    • May have isolated non-spherocytic hemolytic anemia
    • Proximal myopathy
    • Exercise intolerance and weakness after febrile illness

Carnitine Deficiency and Lipid Storage Myopathy

Carnitine Deficiency State

  • There is insufficient intracellular carnitine for:
    • Transport of long-chain fatty acids into mitochondria
    • Modulation of intramitochondrial coenzyme A (CoA-acyl CoA)
  • Most carnitine deficiencies syndrome:
    • Secondary to inborn errors of metabolism
    • Suffer metabolic crisis triggered by the carnitine deficiency
    • Lipid storage myopathies:
      • Definition:
        • Abnormal amounts of lipid accumulate in muscle
        • The abnormal lipid accumulation is the predominant pathological process
      • Lipid accumulation correlates with the oxidative capacity of muscle fibers
        • Type I > 2A > 2B fibers
        • Mitochondrial abnormalities may occur concomitantly:
          • Increase in the number and size of mitochondria
          • Intra mitochondrial inclusions
          • Altered morphology of mitochondrial cristae
        • Abnormal lipid deposits are primarily triglycerides

General Characteristics of Lipid Storage Syndrome

  • Some defects of lipid metabolism, principally carnitine palmityl transferase, do not have lipid storage myopathy
  • Muscle fiber lipid content can vary:
    • From patient to patient with the same disorder
    • In different lipid metabolic disorders
    • During the course of the disease
  • Defects in other metabolic pathways:
    • Fatty acid oxidation
    • Utilization of long chain fatty acids
  • Ischemia and obesity increase lipid muscle fiber content

Systemic Carnitine Deficiency

  • Genetics: 
    • AR
    • Chromosome 5q:
      • Encodes organic cation transporter in kidney intestine, muscle, heart and fibroblasts
      • No gender difference
      • 50% of described patients have had siblings who died suddenly or who had cardiomyopathy
  • Clinical features:
    • Onset one month to seven years of age
    • Heterogeneity of clinical presentation
    • Progressive cardiomyopathy is most common:
      • Dilated cardiomyopathy
      • Peaked T waves
      • Ventricular hypertrophy
      • Poor response to diuretics or digitalis
      • Endomyocardial biopsy demonstrates massive lipid storage
      • Carnitine concentration is less than 5% in the myocardium
    • Infant presentation:
      • Acute encephalopathy
      • Hypoketotic hypoglycemia
      • Hepatomegaly
      • Myopathy is associated with cardiomyopathy or encephalopathy
      • Motor delay and hypotonia
      • Crisis resemble those of Reye's syndrome in greater than 75% of patients
    • Adolescent and adult presentation
      • Low levels of free carnitine in plasma, liver and other tissues
  • Clinical presentation:
    • Myopathic weakness may follow an episode of recurrent hepatic encephalopathy. They have preceded or have been noted concomitantly with attacks
    • Hepatic encephalopathy attacks characterized by:
      • Nausea and vomiting
      • Somnolence
      • Mental confusion
      • Hepatomegaly
      • Increased liver enzymes
      • Increased serum ammonia
      • Hypoglycemia (some patients)
      • Metabolic acidosis
      • Increased urinary excretion of dicarboxylic acids
    • Encephalopathy triggered by:
      • Fasting
      • Intermittent infection
        • May remit spontaneously
      • Death due to cardiorespiratory failure
      • Weakness:
        • Proximal greater than distal
        • Eyelids, face and neck may be involved
        • Begins abruptly
        • Fluctuates
        • May rapidly progress during pregnancy or post partum
        • After anesthesia
        • Prolonged fast
      • Heart and peripheral nerves are affected in some patients
  • Laboratory evaluation:
    • Serum:
      • Increased CK
      • Serum carnitine is decreased in most patients
      • All patients have decreased liver, muscle and heart carnitine
    • EMG:
      • Myopathy
    • Pathology:
      • Lipid accumulation in muscle and liver greater than heart and kidney

Primary Muscle Carnitine Deficiency

  • Free carnitine levels less than 25% of normal in muscles; normal or slightly low in other tissues or plasma
  • Clinical presentation:
    • Slowly progressive myopathy in childhood or adolescence
    • Late onset patients well documented
    • Weakness; usual onset 2nd – 3rd decade:
      • Proximal greater than distal muscles
      • Trunks is involved
      • Rarely face, pharyngeal and neck muscle involvement
    • Weakness may fluctuate or progress rapidly
    • Exercise intolerance may develop prior to weakness
    • Cardiomyopathy is rare
  • Laboratory evaluation:
    • Serum: decreased muscle carnitine (less than 20% of normal) with normal serum carnitine
    • Pathology: accumulations of triglycerides in Type I fibers greater than Type II fibers

Mixed Carnitine Deficiency

  • Clinical features of an overlap syndrome:
    • Signs and symptoms of systemic carnitine deficiency
    • Normal serum carnitine
  • Clinical picture of myopathic carnitine deficiency:
    • Normal liver function
    • Decreased serum carnitine
  • Carnitine deficiency is noted in:
    • Chronic hemodialysis
    • Cirrhosis and cachexia
    • Severe and chronic myopathies (muscle)
    • Kwashiorkor (serum)
    • Idiopathic Reye's Syndrome
    • Myxedema
    • Hypopituitarism
    • Adrenal insufficiency
    • Pregnancy
    • Pyruvate treatment
    • Renal Fanconi syndrome
    • Diphtheria
    • Total parenteral nutrition in infants

Metabolic Defects in Association with Carnitine Deficiency

  • Acyl-CoA dehydrogenase defects
  • Coupling of acyl-CoA dehydrogenase to the respiratory chain
  • Defects in enzymes of organic acid metabolism
  • Defects in the respiratory chain
  • Defects in oxidative-phosphorylation coupling
  • Folate metabolism defects
  • Renal Fanconi syndrome
  • Medium chain carnitine acyltransferase defects

Secondary Carnitine Deficiency Syndrome

  • Acyl-CoA dehydrogenase deficiencies:
    • Short chain acyl-CoA enzyme synthetase dehydrogenase deficiency
      • substrate is butyl CoA
    • Medium chain acyl-CoA synthetase dehydrogenase deficiency
      • Substrate is C6-C10 acyl CoA
    • Long chain-acyl CoA – synthetase – dehydrogenase deficiency
      • Substrate is C14-C22 acyl Ca A
  • Short-chain Acyl Coenzyme A Synthetase Dehydrogenase Deficiency (SCAD)
    • Clinical presentation:
      • Onset in infancy
      • Poor feeding, vomiting, failure to thrive
      • Seizures
      • Psychomotor retardation
      • Hyperactivity
    • Childhood from: (1 patient)
      • Myopathy
        • Congenital muscles affected: neck and facial muscles
        • Later axial limb and respiratory muscle involvement
        • Ptosis and progressive external ophthalmoplegia
        • Cataracts
        • Proximal asymmetric muscle weakness
    • Laboratory evaluation:
      • Normal CK
      • Lactic acidemia with minimal exercise
    • 36 hour fast:
      • No hypoglycemia
      • Increased ketone body formation
    • Muscle biopsy:
      • Type I fiber predominance
      • Hypotrophy; multicores
      • Muscle carnitine 30% of normal
    • Urinary excretion of methylmalonic acid (30× normal) increased excretion of methyl succinic acid
  • Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD):
    • Genetics:
      • Chromosome 1p31; K304E mutation is present in more than 90% of patients
    • Clinical presentation:
      • Onset in some patients 5–25 months; others later in childhood
      • An episodic illness resembling Reye's syndrome
      • Less severe than long chain acyl-CoA dehydrogenase deficiency
      • Causes hypoketotic-hypoglycemic coma:
        • Precipitants:
          • Fasting
          • Stress
          • Viral illness
      • Lethargy and vomiting followed by altered consciousness or coma
      • Mild hyper ammonemia during attacks
      • Muscle weakness appears or worsens during attacks:
        • Resolves slowly
        • Proximal greater than distal distribution
        • Patients are easily fatigued between attacks:
          • Seizures
          • Apnea
          • Cardiac arrest
          • Sudden death
    • Laboratory evaluation:
      • Serum:
        • Mild hyperammonemia during attacks
        • Increased liver enzymes
        • Mild hypo prothrombinemia
        • Moderate increase of CK
        • Decreased serum carnitine between attacks
        • Fractions of serum carnitine may increase during crisis or fasting
      • Urine:
        • Increased excretion of dicarboxylic acids in the urine; increases during the crisis:
          • Increased excretion of hexanoyl glycine and sulfur glycine during attacks is characteristic
          • Octanol carnitine is always present in the urine
      • Muscle biopsy:
        • Increased lipid storage in muscle
  • Long chain Acyl-CoA Dehydrogenase Deficiency (LC-ACD):
    • Genetics: probable AR
    • Clinical presentation
      • Onset neonatal or first three months of life
      • Failure to thrive
      • Post prandial vomiting with or without diarrhea
      • A ketotic hypoglycemic encephalopathic crisis
      • Hepatomegaly
      • Hypertrophic cardiomyopathy
      • Hypotonia
    • Laboratory evaluation:
      • Urine: Dicarboxylic aciduria during fasting or crisis
      • Serum: low total serum carnitine
      • Muscle: LC-Acyl-CoA dehydrogenase 10% of normal

Multiple Acyl-CoA Dehydrogenase Deficiency (Glutaric Aciduria Type II); MUL-ACD

  • Electron transfer flavoprotein deficiency (ETF) and ETF CoQ10 oxidoreductase deficiency result in multiple acyl-CoA dehydrogenase deficiencies that cause:
    • An inability of reducing equivalents from the acyl-CoA dehydrogenase to be accepted by an electron transferring flavoprotein (ETF)
    • Failure of oxidized ETF: ubiquinone oxidoreductase (complex I of the mitochondrial chain)
    • Flavin adenine dinucleotide (FAD) is a cofactor for:
      • Three acyl-CoA dehydrogenase enzymes
      • ETF
      • ETF: Q10

Clinical Presentations of MUL-ACD Deficiency

  • Congenital form :
    • Premature birth
    • Polycystic kidneys, facial dysmorphism, abdominal wall and genital anomalies
    • Hypoglycemia and acidosis
    • Death during the first weak
    • Lipid storage in muscle, heart, and kidney
  • Similar congenital form :
    • No associated anomalies
    • Cardiomyopathy (some patients)
  • Late onset variant:
    • AR
    • Onset: first few months of life to the second decade
    • Clinical Characteristics:
      • Intermittent episodes:
        • Vomiting
        • Hypoglycemia
        • Acidosis
        • Mild hyperammonia
        • Increased liver enzymes
        • Protein intolerance
    • Precipitating features:
      • Fasting
      • Pregnancy
      • Infection
    • MUL-ACD: may become symptomatic in heterozygotes during pregnancy
    • Carnitine deficiency occurs: increased levels of esterified to free carnitine in the serum
    • A riboflavin responsive from of glutaric aciduria Type II occurs in adults:
      • Improvement of wasting and weakness within weeks of treatment

Organic Acidurias with secondary Carnitine Deficiency

Enzyme Deficiencies

  • Isovaleric Co-A dehydrogenase
  • Propionyl Co-A carboxylase
  • Methylmalonic Co-A mutase
  • B-hydroxy-G-Methyl glutaric Co-A hydrolase

Clinical Characteristics

  • Hypoglycemia
  • Ketoacidosis
  • Hyperammonia
  • Encephalopathic crisis
  • muscle weakness between attacks; excretion of methylmalonic acids

General Characteristics of Defects in the Mitochondrial Respiratory Chain or in Oxidative Phosphorylation

  • NADH – ubiquinone reductase and succinyl cytochrome c-reductase
  • Maternal transmission
  • Clinical features:
    • Fatigue of muscle on exertion
    • Lactic academia
    • Marked lipid deposition in muscle (rare)
    • Muscle weakness is proximal greater than distal
    • Carnitine depletion in muscle
    • Associated neurological deficits depend on the specific entity
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