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268 Cards in this Set
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pyrroline 5 carboxylate dehydrogenase
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hyperprolinemia type 2; abnormal enzyme sequesters pyridoxal phosphate
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neurological problems; typically febrile seizures followed by afebrile seizures, siezures are caused by pyridoxine deficiency. maps to 1p36; treat with vitamin B6
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fumarylacetoacetate hydrolase
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last step in Phe/Tyr metabolism
Tyrosinemia type 1(hepatorenal) cabbage odor |
presents with RICKETS and FTT; therapy is low protien, low Phe/tyr diet plus NTBC; liver txpt
toxic compoound is succinylacetone; inhibits porphyria pathway, is carcinogenic (liver) toxic to kidneys (impairs nutrient resorbtion |
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succinylacetone
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toxic compound in tyrosinemia type 1 (hepatorenal); best screening tool for this disorder; inhibits porphyrin pathway
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theryapy tyrosinemia type 1 (hepatorenal
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NTBC, low protein, low phe/tyr diet
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presentation tyrosinemia type 1
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rickets and FTT; elevated succinylacetone on NBS; elevated Met lys, arg, tyr, phe (liver amino acids) elevated alpha fetoprotien and delta amino levulinic acid
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presentation hyperprolinemia type 2
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febrile seizures, followed by afebrile seizures (similar to pyridoxine dependant seizures); not identified by NBS
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therapy hyperprolinemia type 2
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vitamin B6 (defective enzyme sequesters pyridoxal phosphate
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cofactor hyperprolinemia type 2
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pyridoxal phosphate (active form, B6)
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tyrosine aminotransferase
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tyrosinemia type 2 (oculocutaneous)
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presentation tyrosinemia type 2
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photophobia, corneal erosions; painful hyperkeratotic plaques on palms and soles ~50% MR; tyrosine very elevated (400-3000)
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therapy tyrosinemia type 2 (oculocutaneous)
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low protein, low phe/tyr diet, may try pyridoxine as well
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cofactor tyrosinemia type 2
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pyridoxine (B6)
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4 OH phenypyruvate dioxygenase
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tyrosinemia type 3; may not be an actual disease, has been noted in children with MR
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presentation of tyrosinemia type 3
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elevated tyrosine on NBS
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transient form of tyrosinemia type 3
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enzyme 4 Oh phenylpyruvate dioxegenase can be immature, treat with vitamin C
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therapy tyrosinemia type 3
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vitamin C, low protein, low phe/tyr diet
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cofactor tyrosinemia type 3
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vitamin C
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causes of elevated tyr in newborn period
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1. TPN 2. impaired lver fnx 3. transient tyrosinemia of newborn 4. high protein diet 5. tyrosinemia type I, 6. tyrosinemia type II, 7. tyrosinemia type III
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4OH phenulpyruvate dioygensase deficiency; DOMINANT
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Hawkinsuria
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Presentation Hawkinsuria
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hawkinsin on UAA; liver dysfunction which improves on diet, metabolic acidosis
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treatment of hawkinsuria
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low protein diet, vitamin C; tends to improve with age
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homogentisic acid oxidase
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alkaptonuria
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presentation alkaptonuria
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arthritis due to accumulation of homogentistic acid in connective tissues, heart valve failure, pigmentation of sclera and ears
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therapy alkaptonuria
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NTBC, low tyr/phe diet; unsure of long term effect of therapy
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branched chain ketoacid dehydrogenase
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maple syrup urine disease
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pathogenesis MSUD
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leucine accumulation leads to brain swelling
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diagnosis MSUD
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elevated leu, val, Ile; alloisoleucine present; UOA's show elevated ketoisocaproate, ketoisovalarate, and 2-OH isovalarate, ketonuria
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therapy MSUD
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low protein, low branched chain amino acid diet, thiamine
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cofactor E1 (branched chain ketoacid dehydrogenase subunit)
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thiamin
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branched chain ketoacid dehydrogenase complex
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made of three catalytic components; E1 and E2 are only part of BCKD, E3 is also part of pyruvate dehydrogenase, alpha ketogulatarate dehydrogenase
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intermediate MSUD
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BCAA continually elevated, neuro impairment, FTT, onset in childhood
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intermittent MSUD
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recurrent episodes of lethargy, ataxia, semicoma triggered by infections or protein consumption; ketoacidosis during episodes only
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E3 deficiency
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combined deficiency of BCKD, pyruvate dehydrogenase, and alpha Ketogltarate dehydrogenase; gycine cleavage system also affected
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presentation of E3 deficiency
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multiple presentations, neonatal, childhood, and isolated liver failure
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neonatal E3 deficiency
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microcephaly and leigh syndrome with severe delays ataxia, hypotonia, hypotonia, lactic acidosis and ketoacidosis
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childhood E3 deficiency
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exertional fatigue between decompensation episodes
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E3 liver deficiency
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coagulopathy, hyperammonemia and increased transaminases
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E3 diagnosis
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UOA lactic acidosis in addtion to branched chain kedto acids and ketoglutarate, elevated alanine is high in plasma mild increase of branched chain ketoacids, may see alloisoleucine
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causes of increased leucine, isoleucine, allo isoleucine, hydroxyproline
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1. MSUD
2. intravenous hyperal 3. hydroxyprolinemia |
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cystathione beta synthase deficiency
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most common cause of homocystinuria
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presentation of cystathione beta synthase deficiency
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asymptomatic at birth developmental delays, MR, lens dislocation, DVT, pectus, marfanoid habitus, osteoporosis in adulthood
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cystathion beta synthase cofactor
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pyridoxal phosphate (active form of B6)
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pathogenesis of homocystinuria
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homocystine interferes with collagen crosslinking, causes MR and interferes with endothelial function causing thrombosis
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diagnosis cystathione beta synthase deficiency
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increased methionine (not always at birth) free homocystine in plasma aa; total plasma homocysteine is very elevated (>100)
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treatment cystathione beta synthase deficiency
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low protein diet with amino acid mixture lacking Met/Cys; may try pruidoxine; also: Folic acid, B12 and betaine (favor homocysteine remethylation)
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other causes of elevated methionine
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1. dietary 2. liver dz. 3. s-adenosylhomocysteine hydrolase deficiency 4. glycine n-methyltransferase deficiency 5. Methionine adenosyltransferase defic
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proline oxidase deficiency
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type 1 hyperprolinemia -- due to insufficiency of a mitochondrial enzyme expressed in kidney, liver, and brain
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diagnosis hyperprolinemia type 1
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elevated proline above 550 micromoles per L; no excretion of the breakdown product of proline 1-pyrroline-5-carboxylate
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methionine adenosyltransferase deficiency presentation
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again, may not be a disease; has very high methionemia, AR, may develop demyelination and neuro sx
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methionine adenosyltransferase deficiency therapy
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low protein diet restricted in sulfur amino acids
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s-adenosulhomocysteine hydrolase deficiency presentation
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hypotonia sluggishness, psychomotor delay, absent DTRs, delayed myelination
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s-adenosylhomocysteine hydrolase deficiency diagnosis
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increased CK, elevated aminotransfirases, elevated plasma AdoHcy, AdoMet; high methionine,
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therapy s-adenosylhomocystein hydrolase
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methionine restriction, creatine and phosphatidylcholine supplementation
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glycine cleavage system
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deficiencies cause glycine encephalopathy (nonketotic hyperglycinemia); made up of P, T, H, and L proteins, most commonly affected is P, no identified L defic.
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glycine encephalopathy pathogenesis
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accum of glycine in brain affects neurotransmission and impairs brain development
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glycine
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made from serine, present in diet; used to make creatine oxalate, purines, porphyrins, etc; removed from the brain by the glycine cleavage system
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presentation -- glycine encephalopathy: neonatal (classic)
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progressive lethargy, hypotonia, myoclonic jerks leading to apnea and death; if survive, profound MR and intractable seizures, Hiccups before and after birth
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presentation -- glycine encephalopathy: atypical forms: infantile
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seizures beyond the neonatal period, mod-profound MR
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presentation -- glycine encephalopathy: atypical forms: mild/episodic
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mild MR, chorea, agitated delirium, vertical gaze palsy
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presentation -- glycine encephalopathy: atypical forms: late-onset
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variable mild spastic paraparesis, optic atrophy, mild MR and choreoathetosis
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presentation -- glycine encephalopathy: transient
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improve spontaneously at 2-8 weeks of age with normalization of glycine levels
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Diagnosis -- glycine encephalopathy
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NOT IDENTIFIED on NBS
plas AA, elevated glycine, UOA normal, plasma acylcarn nl; CSF aa's: high glycine, higher than in plasma (CSF/plasma gly > 0.08 |
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other causes of elevated plasma glycine without ketosis
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1. valproate therapy
2. transient neonatal hyperglycinemia 3. d-glyceric acidemia |
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causes of ketotic hyperglycinemia
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proprionic acidemia
methylmalonic acidemia isovaleric acidemia beta ketothiolase deficiency |
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therapy -- glycine encephalopathy
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glycine reduction, receptor blockade with dextromethorphanm ketamine, felbamate, and lamictal
topiramate (AMPA receptor blocker) diazepam (Gaba activation) AVOID VALPROATE |
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serine
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diet derived also synthesized from glycine or 3-phosphoglycerate. difficult to transport into brain, must be locally synthesized; glycine is synthesized from serine so defects in serine synthesis leade to low lwvels of serine and glycine
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3-phosphoglycerate dehydrogenase deficiency
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a cause of serine deficiency encephalopathy
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3-phosphopyruvate aminotransferase
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a cause of serine deficiency encephalopathy
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serine deficiency encephalopathy -- presentation
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congenital microcephaly and severe psychomotor retardation, intractable seizures
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serine deficiency encephalopathy -- diagnosis
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low serine and glycine in plasma; low serine and glycine in CSF,
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serine deficiency encephalopathy -- therapy
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L-serine and Glycine supplementation
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pyridoxal phosphate
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active form of vitamin B6 (pyridoxine)
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PLP dependent enzymes
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glutamate decarboxylase, aromatic amino acid decarboxylase, glycine cleavage, serine racemase, GABA transaminases, kynureninase (tryptophan catabolism)
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pyridoxine dependent epilepsy -- presentation (classic)
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multiple types of intractable seizures beginning in the first hours of life; responsive only to pyridoxine hydrochloride
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pyridoxine dependent epilepsy -- presentation (variant)
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intractable seizures may onset as late as three years
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alpha aminoadipic semialdehyde dehydrogenase
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causes pyridoxine dependent epilepsy
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pyridoxine dependent epilepsy -- treatment
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life long pyridoxine (B6) supplementation; many will still have delays. treatment cannot reverse pre-existing brain damage
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PNPO (pyridoxamine phosphate oxidase) deficiency
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piridoxal phosphate dependent seizures
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pyridoxal phosphate dependent seizures -- presentation
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neonatal epileptic encephalopathy not responsive to pyridoxine; seizures controlled with pyridoxal phosphate
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kinureninase deficiency
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kinureninase is involved in tryptophan metabolism
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kinureninase deficiency -- cofactor
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pyridoxal phosphate
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kinureninase deficiency -- presentation
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developmental delays and seizures
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methylene tetrahydrofolate reductase
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leads to homocystinemia with LOW methionine; a disorder of homocysteine remethylation
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methylene tetrahydrofolate reductase (MTHFR) cofactor
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cobalamin
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methylene tetrahydrofolate reductase (MTHFR) deficiency presentation
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variable time of presentation (most commonly in infants): developmental delay, apnea, seicures, thrombosis (NO ANEMIA)
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methylene tetrahydrofolate reductase (MTHFR) deficiency -- therapy
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difficult -- betaine is most useful (acts as a methyl donor in making methionine from homocystine; folinic acid, methionine, pyridoxine, cobalamin, and carnitine supplementation can be considered
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betaine mechanism of action
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methyl donor
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variant methylene tetrahydrofolate reductase deficiency
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50% residual activity, leads to intermediate homocystinuria
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variant methylene tetrahydrofolate reductase deficiency -- diagnosis
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mild increase in plasma homocysteine, low normal methionine, no free homocystine
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variant methylene tetrahydrofolate reductase deficiency -- presentation
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thought to be an inherited risk factor for coronary heart disease
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variant methylene tetrahydrofolate reductase deficiency -- therapy
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high dose folic acid -- must exclude B12 deficiency prior to therapy or supplement this as well
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hyperhomocysteinemia
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patients with increased total homocysteine; may include free homocystine; no homocystinuria -- seen in heterozygotes for some of the causes of homocystinuria
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other causes of hyperhomocystinemia
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menopause, renal failure, hypothyroidism, leukemia, psoriasis, methotrexate therapy, nitrous oxide therapy, isoniazid therapy, antiepileptics
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methionine synthase deficiency
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cblG
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methionine synthase reductase deficiency
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cblE
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cobalamin metabolism
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converted to adoCbl in mito; meCbl in cytoplasm
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pathogenesis of cblG and E
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cannot mae MeCbl from Cbl (in cytoplasm)
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presentation cbl G and E
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hyperhomocystinemia, homocystinuria, low methionine, NO MMA; developmental delay, cerebral atrophy, ataxia, seizures, nystagmus, blindness, megaloblastic anemia
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therapy cbl G and E
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hydroxycobalamin
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methionine synthase -- cofactor
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methylcobalamin
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methylmalonyl-CoA mutase cofactor
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adoCbl
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cobalamin
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vitamin B12; ingested from animal dietary sources; converted into two active forms adenosycobalamin (AdoCbl) and methylcobalamin (MeCbl)
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Cbl C& D presentation
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MMA and homocystinuria; CblC is more severe -- failure to thrive, developmental delay, megaloblastic anemia, metabolic acidosis
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Cbl C&D therapy
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high dose hydroxycobalamin in combination with methylfolate and pyridoxine
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CblF deficiency
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cobalamin retained in lysosomes; poor conversion to active cofactors; leads to MMA and homocystinuria -- presentation is similar to C&D
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phenylalanine hydroxylase deficiency
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PKU
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phenylalanine hydroxylase cofactor
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tetrahydrobiopterin
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PKU presentation
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asymptomatic at birth, progressive onset of microcephaly, eczema, developmental delays noted at 6 mo; also have fair skin
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PKU therapy
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low protein/low phe diet, tyrosine supplementation
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pterin - 4a carbinolamy dehydratase
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PKU variant (biopterin defic)
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recessive GTP cylclohydrolase I deficicency
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PKU variant -- biopterin defic
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6-pyruvoyl tetrahydropterin synthase defic (6-PTS, PTPS)
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PKU variant -- biopterin defic
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dihydropteridine reductase defic (DHPR)
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PKU variant -- biopterin defic
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BH4 biosynthesis defects -- mechanism
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poor neurotransmitter synthesis; phenylalanine metabolism
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BH4 biosynthesis defects presentation
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seizures dystonia and parkinsonism with elevated Phe; controlling phe does not modify symptoms
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BH4 deficiency defect -- therapy
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BH4 supplementation, folic acid, L-Dopa, 5-OH-Trp, carbidopa, consider segiline
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GTP cyclohydrolase deficiency heterozygote
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DOPA-responsive dystonia
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carbinolamine dehydratase deficiency
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mild -- transient PKU, resolves with liver maturity and ability to bypass the metabolic block
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BH4 deficiency -- presentation
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truncal hypotonia, hypertonia of extremities, poor balance, dystonia, hypersalivation, difficulty swallowing, oculogyric crises, temperature instability, irritability and myoclonic siezures despite dietary phe control
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GTP cyclohydrolase deficiency
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defect of biopterin synthesis
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sepiapterin reductase
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defect of biopterin synthesis
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liver glycogen synthase
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GSD0
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presentation GSD 0
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morning drowsiness, fatigue, vomiting, occ convulsions with hypoglycemia and hyperketonemia: no hepatomegaly or hyperlipidemia prolonged hyperglycemia and elevated lactate levels after glucose administration; often present after weaning
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treatment GSD 0
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frequent feedings rich in protein and nighttime uncooked cornstarch -- infants do not make enough amylase to use uncooked cornstarch
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muscle glycogen synthase
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Muscle GSD 0
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muscle GSD 0 presentation
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muscle fatigability, hypertrophic cardiomyopathy, abnormal heart rate and BP while exercising, sudden death. NO HYPOGLYCEMIA
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muscle GSD 0 treatment
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exercise avoidance -- actually unknown, prognosis is unknown
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glucose-6-phosphatase
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glycogen storage disease type 1a (Von Gierke disease)
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GSD 1a presentation
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severe hypoglycemia, lactic acidosis, and hyperuricemia
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defective uptake of glucose 6 phosphate by endoplasmic reticulum (transporter defect)
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GSD 1b
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GSD 1b presentation
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severe hypoglycemia, lactic acidosis, hyperuricemia, neutropenia and recurrent infections
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lab abnormalities in GSD1
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increased lactate, lipids, biotinidase; only minimal increase in blood glucose with counterregulatory hormones
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treatment of GSD1
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continuous NG infusion of glucose polymers (vivonex/tolerex)at night and frequent feeds (q2-4hrs) in the first year of life; then conrnstarch 1.5-2.5g/kg perdose) Restrict fructose and galactose as they cannot be converted to free glucose: allopurinol after puberty; monitor for liver cancer
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alpha glucosidase (acid maltase) deficiency
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GSD II (Pompe)
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GSD II (pompe) mechanism
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glycogen accumulates in lysosomes, damaging muscles. No hypoglycemia or metabolic abnormalities.
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GSD II (pompe) presentation -- infantile (classic)
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massive cardiomegaly with cardiac hypertrophy, poor muscle tone delays, resp sx due to heart failure, macroglossia and hepatomegaly (due to heart failure not storage) death in one year
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GSDII (pompe) presentation -- juvenile
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slowly progressive muscle involvement, not cardiac, respiratory failure and death by 20 years of age
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GSD II (pompe) presentation -- adult
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slowly progressive myopathy, may require respiratory support overnight
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differential diagnosis for GSD II (Pompe)
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environmental -- viral infx, vit defic, toxins, drugs, etc
metabolic -- fatty acid oxidation disorders, carnitine deficiency, lysosomal and mitochondrial disorders, barth syndrome, 1p36 deletion |
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therapy GSD II (pompe)
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enzyme replacement therapy effective if started before irreversible muscle damage in CRIM+ individuals -- will try in CRIM - as well
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glycogen debranching enzyme deficiency
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GSD III
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GSD III presentation
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hepatomegaly, hypoglycemia, hyperlipidemia, short stature, variable skeletal myopathy, mild cardiomyopathy. hepatic symptoms improve with age, esp after puberty. muscle symptoms tend to worsen with age.
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GSD IIIa
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involves both liver and muscle
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GSD IIIb
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liver involvement only (about 15% of pts with GSD III)
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GSD III diagnosis
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hypoglycemia, hyperlipidemia, elevated liver transaminases, normal uric and lactic acid, CK typically mildly elevated
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GSD III treatment
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frequent complex carbohydrate meals during daytime with cornstarch overnight, no need to restrict fructose or galactose.
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branching enzyme deficiency
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GSD IV aka amylopectinosis or Andersen disease.
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GSD IV pathogenesis
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glycogen does not have enough branch points, triggers the immune system leading to fibrosis, cirrhosis and death
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GSD IV presentation
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progressive liver cirrhosis; HSM and FTT prior to 18 mo of age; death by age 5
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GSD IV presentation neuromuscular form - neonatal
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neonatal hypotonia, muscle atrophy, neuronal involvement and early death
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GSD IV neuromuscular form -- chilhood
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myopathy or cardiomyopathy in late childhood
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GSD IV neuromuscular form -- adult
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adult onset diffuse central and peripheral nervous system dysfunction accompanied by accumulation polyglycosan bodies in the nervous system
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GSD IV therapy
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liver transplant
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liver phosphorylase deficiency
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GSD VI (Hers disease)
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GSD VI presentation
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hepatomegaly and growth retardation in childhood, +/- mild hypoglycemia, hyperlipidemia and ketosis: normal lactic and uric acid levels. Hepatomegaly and growth problems improve with age and resolve at puberty, no muscle involvement
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liver phosphorylase kinase deficiency
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GSD IX
phosphorylase kinase has four subunits |
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GSD IX presentation
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may involve liver muscle or heart or any combination of these. one form is x-linked; not severe -- some centers do not treat
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myophosphorylase deficiency
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GSD V (McArdle)
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Presentation GSD V (McArdle)
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ATP generation by glycogenolysis limited; exercise intolerance beginning after puberty; muscle cramps with intense or sustained activity; may have "second wind" myoglobinuria may lead to renal failure
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GSD V (McArdle) diagnosis
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elevated CK, elevates further with exercise. Blood ammonia, inosine, hypoxanthine, and uric acid increase with exercise as well. NO INCREASE OF LACTATE AFTER ANEROBIC EXERCISE
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GSD V (McArdle) therapy
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avoidance of strenuous exercise, ingest glucose or fructose prior to exertion, high-protein diet
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muscle phosphofructokinase deficiency
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GSD VII (Tauri disease)
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GSD VII presentation
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similar to type V(McArdle); may present in childhood, may see hemolysis and hyperuricemia, exercise intolerance is worst after eating
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five other muscle glycogenoses
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phophoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, fructose 1,6-bisphosphate aldolase A, and pyruvate kinase
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phosphorylase b kinase deficiency
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multisubunit enzyme with different phenotypes depending on affected subunit
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phosphorylase b kinase deficiency A2
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non-muscle alpha subunit: benign x-linked liver disease of infancy
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phosphorylase b kinase deficiency beta subunit
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autosomal recessive liver and muscle disease
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phosphorylase b kinase deficiency - adult myopathy type
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affects both sexes but predominantly men
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phosphorylase b kinase deficiency -- severe liver
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cirrhosis, severe liver dysfunction, autosomal recessive
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phosphorylase b kinase deficiency G2 (gamma 2 subunit)
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fetal infantile cardiopathy
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carnitine transporter deficiency
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primary carnitine deficiency
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presentation carnitine transporter deficiency
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reye syndrome, sudden early death (i.e. SIDS) cardiomyopathy in later life
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pathogenesis carnitine transporter deficiency
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lose carnitine in urine leads to carnitine deficinecy and impaired fatty acid oxidation
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therapy carnitine transporter deficiency
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carnitine
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diagnosis carnitine transporter deficiency
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very low plasma carnitine, confirmed by fibroblast studies
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CPT1A deficiency (isoform of carnitine palmitoyl transferase 1)
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unable to conjugate fatty acids to carnitine in liver, unable to make ketones
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presentation CPT1A
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hepatic encephalopathy induce by fasting, fever, vomiting; at time of attack will have hypoketotic hypoglycemia
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therapy CPT 1A
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avoid fasting, high carbohydrate low fat diet with greater than one third of fat from medium chain triglycerides that do not require carnitine shuttle for mito entry
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lab findings CPT 1a
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may see ELEVATED carnitine (only time will see this) low long chain acylcarnitines, actually difficult to screen for
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carnitine acylcarnitine translocator (CACT) deficiency
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acylcarnitines cannot enter the mitochondria; long chain fatty acids are arrythmogenic
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carnitine acylcarnitine translocator deficiency (CACT) presentation
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arrythmia, cardiac arrest shortly after birth, hypoketotic hypoglycemia, cardiomyopathy
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carnitine acylcarnitine translocator deficiency (CACT) therapy
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MCT oil, carnitine, essential fatty acids, low fat diet
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CPT-2 deficiency
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cannot use acylcarnitines inside mitochondria, muscles lack energy during exercise, the accumulate acylcarnitines can be toxic
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CPT-2 deficiency presentation -- classic (muscle form)
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episodic myoglobinuria and muscle weakness with exercise, may also be triggered by stress, fasting, cold
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CPT-2 deficiency presentation -- newborn (fatal)
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hypoketotic hypoglycemia, cardiomyopathy, renal dysgenesis, dysmorphism, arrhythmia
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CPT-2 deficiency presentation -- infantile
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fasting hypoglycemia and cardiomyopathy, arrhythmia
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CPT-2 deficiency -- diagnosis
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elevated CPK increased long chain acylcarnitines, carnitine deficiency in plasma and tissue
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CPT-2 deficiency -- therapy
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avoid stressors, MCT oil, carnitine
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MCAD
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most common FAO, cannot metabolize medium chain fatty acids
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MCAD presentations
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1 at birth
2 intercurrent illness 3 stress 4. sleep through night |
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MCAD therapy
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avoidance of fasting, low fat diet, carnitine supplementation, treat acute illness with IV glucose AVOID MCT OIL
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Very long chain aclyCoA dehydrogenase deficiency
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loass of the initial rate limiting step in mitochondrial fatty acid beta oxidation
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VLCAD presentation early onset
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hypertrophic cardiomyopathy biventricular hypertrophy sever morbidity and mortality
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VLCAD presentation - mild
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hypoketotic hypoglycemia increased LFT's and CPK, similar to MCAD
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VLCAD presentation - intermittent
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stress induced rhabdomyolysis -- similar to muscle form of CPT2 defic
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VLCAD therapy
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MCT oil low fat diet, low dose carnitine, avoid fasting
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long chain 3-OH-AcylCoA Dehydrogenase (LCHAD) deficiency
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part of trifunctional protein, fatty acid oxidation disorder
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LCHAD presentation
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fasting induced vomiting and hypoglycemia, hypotonia, cardiomyopathy, liver dysfunction. retinitis pigmentosa, may have neuropathy and recurrent rhabdomyolysis (more common in trifunctional protien defic); mothers may have acute fatty liver of pregnancy or HELLP
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LCHAD diagnosis
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dicarboxylic aciduria 3-OH saturated and unsaturated fatty acids on UOA confirm by enzyme assay or DNA
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LCHAD therapy
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MCT oil, low dose carnitine, low fat diet, essential fatty acids
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Gal-1-P-uidyltransferase deficiency (GALT)
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classic galactosemia
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Galactokinase deficiency
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non-classic galactosemia
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Epimerase deficiency
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non-classic galactosemia
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GALT deficiency presentation
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poor feeding, vomiting, diarrhea, jaundice, lethargy-->coma, hepatomegaly, liver failure, E.coli sepsis, cataracts
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treatment GALT deficiency
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eliminate galactose from diet will reverse growth failure renal and hepatic dysfunction; does not prevent ovarian failure, may stiil have mental retardation speech dyspraxia, ataxia, and learning disabilities
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galactokinase deficiency
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alternate type of galactosemia
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galactokinase deficiency, presentation
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cataracts typically sole manifestation
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galactokinase deficiency, therapy
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galactose restriction before irreversible lens changes
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epimerase deficiency
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nonclassic form of galactosemia there is a benign form limited to RBCs and a severe form
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epimerase deficiency presentation, severe form
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similar to GALT deficiency plaus hypotonia and nerve deafness
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fructose 1,6 bisphosphenate (aldolase B) deficiency
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hereditary fructose intolerance
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hereditary fructose intolerance presentation
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do fine on breastmilk, become ill when exposed to fructose or sucrose -- jaundice, hepatomegaly, vomiting, lethargy, irritability, and convulsions. Older pts c/o recurrent absominal pain and nausea with fructose ingestion; pts die of liver and kidney failure
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hereditary fructose intolerance mechanism
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fructose 1 phosphate accumulates, which is toxic to the liver and also depletes phosphorus which impairs glucose production causing hypoglycemia
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treatment hereditary fructose intolerance
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eliminate all sucrose, fructose, and sorbitol from the diet, tolerance improves with age and long term prognosis is good
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hepatic fructokinase deficiency
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essential fructosuria; benign condition, fructose seen in urine depending on dietary consumption
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fructose 1,6-diphosphatase deficiency
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gluconeogenesis defect
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presentation fructose 1,6 diphosphatase deficiency
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life threatening episodes of severe acidosis triggered by febrile infections and poor po intake. labs show loww glucose low phos high lactate and uric acid, metabolic acidosis, LIVER AND KIDNEY fnx NL
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treatment fructose 1,6 diphosphatase deficiency
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IV glucose and bicarb for attacks, avoid fasting, eliminate fructose and sucrose, consider uncooked cornstarch; pts do not have an aversion to sweets
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proprionyl CoA carboxylase deficiency
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most common cause of proprionic acidemia
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holocarboxylase synthase deficiency
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second cause of proprionic acidemia
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biotinidase deficiency
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third cause of proprionic acidemia
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proponyl-CoA carboxylase cofactor
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biotin
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origin of proprionic acid
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catabolism of valine, isoleucine, methionine and threonine (VOMIT); odd chain fatty acids and cholesterol, thymine and uracil, bacterial also produce proprionate in the gut
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proprionic acidemia pathogenesis
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accumulation of proprionate inhibits Krebs cycle; impairs oxidation of acetyl CoA, leads to ketosis and acidosis: may block glycine cleavage system -- hyperglycinemia
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PPA presentation
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short normal interval after birth (18-96h) followed by acidosis, refusal to feed, vomiting, tachypnea, lethargy-->coma; ketosis, acidosis, dehydration, hyperammonemia, thrombocytopenia, and neutropenia; bone marrow suppression may be very prominent
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PPA complications
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pancreatitis, osteoporosis, hypotonia/hypertonia, older children may be frankly spastic, chronic moniliasis, metabolic stroke, cardiomyopathy, frequent infections,
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PPA treatment
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calories, fluids, bicarb as needed, dialysis, delay protein admin until acidosis and hyperammonemia have corrected.
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biotinidase deficiency
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disorder of biotin recyclinc
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biotinidase deficiency presentation
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seizures, hypotonia, ataxia, breathing problems, hearing loss, optic atrophy, developmental delay, skin rash, and alopecia, conjunctivitis, fugal infections: VARIABLE presentation; onset from several weeks to several years
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biotinidase lab findings
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metabolic ketolactic acidosis and organic aciduria
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biotinidase treatment
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biotin supplementation
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multiple carboxylase deficiency
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impaired activity of four biotin dependent enzymes acetyl CoA carboxylase, priprionly CoA carboxylase, 3 methylcrotonyl CoA carboxylase, and pyruvate carboxylase
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multiple carboxylase deficiency presentation
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feeding and breathing difficulties, hypotonia, seizures, lethargy, may see coma, developmental delay, possible skin rash, alopecia, metabolic acidosis, organic aciduria, hyperammonemia
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multiple carboxylase deficiency therapy
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biotin supplementation
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methyl malonyl CoA mutase deficiency
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methylmalonic acidemia
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methyl malonyl coa mutase cofactor
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adenosyl cobalamin
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presentation methylmalonic acidemia
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brief normal interval followed by refusal of feeding, severe vomiting, tachypnea and lethargy -->coma, ketosis, acidosis, dehydration, hyperammonemia, thrombocytopenia, and neutropenia, hypotonia or spasticity
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dietary treatment of organic acidurias
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special formulas propimex, maxamaid, etc; (free of isoleucine, valine, methionine, threonine), limit protein intake, include protein free foods, avoid fasting, biotin until biotin defic ruled out, hydroxycobalamin in MMA
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isovaleryl coa dehydrogenase deficiency
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isovaleric acidemia
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isovaleric acidemia presentation
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severe metabolic acidosis and hyperammonemia leading to death shortly after birth: milder variants present with vomiting and failure to thrive
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isovaleric acidemia treatment
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low protein diet with amino acid mixture lacking leucine, carnitine and glycine supplements; glycine helps conjugate toxins and allow urinary excretion, similar to carnitine
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3 methylcrotonyl CoA Carboxylase deficiency
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mitochondrial enzyme with two subunits, biotin dependant
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3- MCC cofactor
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biotin
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3-MCC presentation - early
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presents in infancy with neurological involvement and developmental delay
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3-MCC presentation - intermittent
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recurrent attacks of metabolic decompensation with ketoacidosis, hypoglycemia, seizures, hyperammonemia, coma
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3MCC therapy
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fasting avoidance, treat illness with IV fluids with glucose, carnitine, severe cases may need low protein leucine restricted diet
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3-methylglutaconly-CoA Hydratase deficiency
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unknown phenotype, mostly manage fever/infections promptly; may not require therapy
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2-methylbutyryl -CoA dehydrogenase deficiency
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variable organic aciduria most common in the Hmong population
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2-methylbutyryl CoA dehydrogenase deficiency presentation
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highly variable: asymptomatic, muscle weakness, cerebral palsy, developmental delays, lethargy, hypoglycemia, metabolic acidosis
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2-methulnbutyryl CoA dehydrogenase deficiency therapy
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protein restriction, carnitine supplementation, prompt treatment of fasting
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glutaryl coa dehydrogenase deficiency
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glutaric acidemia type 1
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GA1 underlying defect
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defect in lysine tryptophan and hydroxylysine metabolism glutaric acid damages the caudate and putamen
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GA1 presentation
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macrocephaly at birth or develop this, mildy hypotonic; will develop dystonia and spasticity with illness which is irreversible, patients without significant decompensation have normal mentality.
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GA1 therapy
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carnitine supplementation, tx intercurrent illness with fluids glucose and insulin, low lysine and tryptophan diet
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pyruvate dehydrogenase deficiency
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mitochondrial disorder; leading cause of isolated lactic acidosis, may casue Leigh syndrome: multisubunit complex will have elevated lactate, pyruvate, alanine (pyruvate gets converted into lactate and alanine) along with succinic, fumaric and 2-ketoglutaric acids
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presentation pyruvate dehdrogenase deficiency - severe
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overwhelming lactic acidosis at birth
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presentation pyruvate dehydrogenase deficiency - moderate
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moderate lactic acidemia, profound psychomotor retardation, worsening with age, brainstem and basal ganglia damage with death in infancy
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presentation pyruvate dehydrogenase deficiency - male only form
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carbohydrate induced episodic ataxia, mild developmental delay
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pyruvate dehydrogenase deficiency therapy
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ketogenic diet, carbohydrate avoidance,
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E3 dihydrolipoamide dehydrogenase deficiency
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a subunit found in three different enzymes -- branched chain ketoacid dehydrogenase, pyruvate dehydrogenase, and ketoglutarate dehydrogenase
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E3 presentation -- neonatal
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microcephaly and leigh syndrome with severe delays ataxia, hypotonia, lactic acidosis and ketoacidosis
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E3 presentation -- childhood
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exertional fatigue between decompensation episodes
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E3 presentation - liver
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coagulopathy hyperammonemia and increased liver transaminiases
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E3 lab findings
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lactic acidosis, branched chain ketoacids, ketoglutarate, high plasma alanine, elevated branched chain amino acids
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E3 therapy
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lipoic acid, thiamine, protein restriction - improves biochemical testing doesn't do much for the regression
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pyruvate carboxylase deficiency
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essential gluconeogenesis enzyme also necessary for oxaloacetate synthesis (essential Krebs cycle intermediate)
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pyrivate carboxylase presentation simple from
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mild to moderate lactic acidosis in infancy and developmental delay
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pyruvate carboxylase presentation complex form
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presents shortly after birth with severe lactic acidemia, hyper ammonemia, citrullinemia and hyperlysinemia, poor survival
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