Metabolic Myopathies Flashcards by Kyra Porter

metabolic myopathy defect classification

*carbohydrates (glycogen storage diseases, GSD)
*lipids (fatty acid transport, fatty acid oxidation, FAO)
*mitochondria (oxidative phosphorylation, OXPHOS)

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metabolic myopathy classification - static vs dynamic clinical presentation

*static: fixed weakness, progressive; systemic involvement (heart, liver, brain, kidneys); more in newborns and infants
*dynamic: related to exercise (cramping, myalgia, intolerance, myoglobinuria); more in juveniles and adults

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glycogen storage diseases (GSD or glycogenoses)

*most are autosomal recessive
*carbs are predominantly in liver and muscle tissues
*glucose is not being released and therefore cannot be used as an energy source (unable to create ATP)

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GSD type I: Von Gierke disease

*glucose-6-phasophate deficiency
*CANNOT GET GLUCOSE OUT OF LIVER
*2nd most common form of GSD
*G6P only found in the liver, so no significant weakness
*pts present early in life with hepatomegaly, renal disease, growth restriction and typical facial features
*patients often have developmental delays

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GSD type I: Von Gierke disease - labs

*hypoglycemia
*lactic acidosis
*hyperuricemia
*hyperlipidemia

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GSD type I: Von Gierke disease - treatment

*diet, strict calories
*avoid hypoglycemia
*avoid fructose and galactose
*uncooked starch

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GSD type II: Pompe disease - overview

*alpha-1,4-glucosidase deficiency (acid maltase deficiency)
*results in glycogen accumulation in the heart, liver, and muscles

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GSD type II: Pompe disease - infantile presentation

*generalized weakness
*hypotonia (“floppy baby”)
*macroglossia
*cardiomyopathy
*weak/poor feeding
*respiratory failure

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GSD type II: Pompe disease - juvenile presentation

*onset within first decade of life
*proximal muscles and calf hypertrophy
*Gower’s sign (Duchenne muscular dystrophy is most common cause of gower’s though)

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GSD type II: Pompe disease - adult presentation

*proximal muscle weakness (similar to polymyositis)
*diaphragm involvement

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GSD type II: Pompe disease - labs

*elevated CK
*a-glucosidase activity will be low (usually from dried blood spot test)
*high LFT
*high LDH

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GSD type II: Pompe disease - treatment

*enzyme replacement therapy - alglucosidase alfa every 2 weeks
*one of the few that actually has an effective treatment

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GSD type III: Cori-Forbes disease - overview

*debranching enzyme deficiency
*debranching enzyme has 2 functions:
1) glucanotransferase fxn
2) a-1,6-glucosidase fxn
*subtypes of disease based on enzyme deficiency location and specific activity (a-d)

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GSD type III: Cori-Forbes disease - clinical features

*weakness noted in 3rd to 4th decade; 50% in DISTAL muscle groups in lower extremities
*ultimately, ventilatory muscles are involved
*can have associated cardiomyopathy

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GSD type III: Cori-Forbes disease - labs

*reduced enzyme function of muscle, fibroblasts or lymphocytes
*elevated CK levels
*high liver function tests (LFTs)
*muscle biopsy: PAS positive vacuoles

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GSD type III: Cori-Forbes disease - treatment

*low carb, high protein diet to help prevent fasting hypoglycemia
*uncooked cornstarch at bedtime

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GSD type V: McArdle disease - gene/enzyme defect

*myophosphorylase deficiency
*associated with gene PYGM

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GSD type V: McArdle disease - clinical presentation

*typically seen in childhood or young adults
*exercise intolerance with strenuous activity (weight lifting) or prolonged exercise (jogging, swimming)
*exertional muscle pain, cramping with “second wind” phenomenon

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GSD type V: McArdle disease - labs

*excessively high CK levels (50k+), even when patients are not symptomatic
*myoglobinuria
*high LDH

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GSD type V: McArdle disease - treatment

*control exercise (warm up)
*diet, sugar load prior to activity

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GSD type VII: Tauri disease

*very similar to type V (McArdle): exercise-induced myalgia, cramping, jaundice
*typically is associated with fewer myoglobinuria and rhabdomyolysis
*due to lack of PFK in erythrocytes, can lead to hemolysis
*NO SECOND WIND phenomenon, but “out of wind” phenomenon (giving a sucrose load gives no benefit or makes symptoms worse)

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disorders of lipid metabolism

*fatty acids are main source of energy for muscles at rest and following intense exercise or physical activity
*in normal lipid metabolism, fatty acid chains must move from cytoplasm to inner matrix of mitochondria
*long-chain fatty acids need help moving across the membranes
*once within the inner matrix, beta oxidation can occur, ultimately leading to ATP production

carnitine transporter deficiency - etiology

*defects in OCTN2 (sodium dependent carnitine transporter protein)
*result: carnitine is not able to enter cells/cytoplasm and therefore cannot move fatty acids

carnitine transporter deficiency - clinical features

*reduced feeding
*hepatosplenomegaly
*AMS (altered mental status)
*cardiomyopathy
*“hypoketotic hypoglycemia” when fasting

carnitine transporter deficiency - labs

*low carnitine *low ketones *low glucose *high NH4 *high CK

carnitine transporter deficiency - treament

*L-carnitine *avoid fasting *low fat diet

CPT1A deficiency - pathophysiology

*CPT1A = carnitine palmitoryltransferase 1 *pathology associated with type A isoform, which is found in the liver

CPT1A deficiency - clinical features

*altered mental status (AMS) *hepatomegaly *no muscle symptoms *often triggered by viral illness or fasting

CPT1A deficiency - lab findings

*high carnitine *low acylcarnitine *low ketones *low glucose *mild NH4

CPT1A deficiency - treatment

*avoid fasting *low fat diet *MCFA

CACT deficiency - clinical presentation

*typically seen in neonates (up to 18 months) *cardiac arrhythmias *seizures *severe muscle weakness *hepatic dysfunction *apneic episodes *often triggered by infection, stress, fasting

CACT deficiency - labs

*low carnitine *high acylcarnitine *low ketones *low glucose *high NH4 *high CK

CACT deficiency - treatment

*low fat diet *avoid fasting *higher carbs *controlled exercise

CPT2 deficiency - overview

*most common cause of recurrent myoglobinuria/metabolic myopathy in adults

CPT2 deficiency - clinical presentation

*usually in 2nd or 3rd decade of life *intense muscle pain following prolonged fasting, infection, or intense prolonged exertion *neonatal = death

CPT2 deficiency - labs

*low carnitine *high acylcarnitine *low ketones *low glucose *high NH4 and CK

CPT2 deficiency - treatment

*avoid fasting *low fat diet *high carbs *controlled exercise

disorders of fatty acid oxidation

*categorized based on the length of the fatty acid chain *clinical presentations ranging from mild hypotonia in adults to sudden death in infants with hypoketonic hypoglycemia *muscle biopsy often shows excess lipid within fibers *treatment directed at high-carb diets

examples of fatty acid oxidation disorders

*VLCAD (VLCA-CoA dehydrogenase deficiency) *LCAD (LCA-CoA dehydrogenase deficiency) *MCAD (MCA-CoA dehydrogenase deficiency) *SCAD (SCA-CoA dehydrogenase deficeincy)

clinical features of fatty acid oxidation disorders

*hypoglycemia *hepatomegaly *myopathy

labs of fatty acid oxidation disorders

*NORMAL CK other variable

mitochondrial myopathies

*related to deletions or depletions of mtDNA and/or nDNA *results in disruptions of oxidative phosphorylation, impaired ATP production *only passed down maternally *muscle biopsy can show ragged red fibers (RRF)

Kearns-Sayre Syndrome and Progressive External Ophthalmoplegia (KSS/PEO) - genetics/defect

*single large deletion in mtDNA

KSS/PEO - clinical features

*ophthalmoplegia *proximal weakness *respiratory muscle weakness *sensorineural hearing loss *endocrinopathy

KSS/PEO - labs

*normal CK *high lactate *biopsy with RRF, COX negative fibers

KSS/PEO - treatment

*creatine supplement *surgery (ptosis) *CV support

myoclonic epilepsy and ragged red fibers (MERFF) - genetics/defect

*MTTK/ mtDNA point mutation

MERFF - clinical features

*epilepsy *proximal weakness *sensorineural hearing loss *optic atrophy

MERFF - labs

*normal CK *high lactate *pyruvate *abnormal EEG *red ragged fibers on muscle biopsy

MERFF - treatment

*creatine supplementation *AED drugs (tx seizures)

mitochondrial myopathy, lactic acidosis and stroke-like episodes (MELAS) - genetics/defect

*MTTL1, MtDNA point mutation

MELAS - clinical features

*proximal weakness *stroke-like episodes *migraine headaches, nausea, vomiting, hemiparesis, hemianopsia, cortical blindness *can have seizures/myoclonus *rare eye findings

MELAS - labs

*normal or high CK *very high lactate in serum and/or CSF *MRI findings (not localized to a vascular territory)

MELAS - treatment

*L-arginine and citrulline *AED drugs (tx seizures)