Metabolic Myopathies Flashcards
metabolic myopathy defect classification
*carbohydrates (glycogen storage diseases, GSD)
*lipids (fatty acid transport, fatty acid oxidation, FAO)
*mitochondria (oxidative phosphorylation, OXPHOS)
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
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)
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
GSD type I: Von Gierke disease - labs
*hypoglycemia
*lactic acidosis
*hyperuricemia
*hyperlipidemia
GSD type I: Von Gierke disease - treatment
*diet, strict calories
*avoid hypoglycemia
*avoid fructose and galactose
*uncooked starch
GSD type II: Pompe disease - overview
*alpha-1,4-glucosidase deficiency (acid maltase deficiency)
*results in glycogen accumulation in the heart, liver, and muscles
GSD type II: Pompe disease - infantile presentation
*generalized weakness
*hypotonia (“floppy baby”)
*macroglossia
*cardiomyopathy
*weak/poor feeding
*respiratory failure
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)
GSD type II: Pompe disease - adult presentation
*proximal muscle weakness (similar to polymyositis)
*diaphragm involvement
GSD type II: Pompe disease - labs
*elevated CK
*a-glucosidase activity will be low (usually from dried blood spot test)
*high LFT
*high LDH
GSD type II: Pompe disease - treatment
*enzyme replacement therapy - alglucosidase alfa every 2 weeks
*one of the few that actually has an effective treatment
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)
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
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
GSD type III: Cori-Forbes disease - treatment
*low carb, high protein diet to help prevent fasting hypoglycemia
*uncooked cornstarch at bedtime
GSD type V: McArdle disease - gene/enzyme defect
*myophosphorylase deficiency
*associated with gene PYGM
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
GSD type V: McArdle disease - labs
*excessively high CK levels (50k+), even when patients are not symptomatic
*myoglobinuria
*high LDH
GSD type V: McArdle disease - treatment
*control exercise (warm up)
*diet, sugar load prior to activity
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)
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)
