Biochemical Genetics 1 Flashcards

Question

What are the molecular features associated with FAH

Answer 1

Targeted analysis for the p. Pro261Leu variant accounts for >99% in AJs c.1062+5G>a (IV612+5 G>A) accounts for 88% of variants in the French Canadian pop Pseudodeficiency alleles exist- leads to decreased FAH enzyme activity but adequate FAH mRNA PVs (missense, nonsense, and splice site variants) result in LOF of FAH activity leading to cellular damage + apoptosis

Answer 2

Tyrosinemia type 2: defect in tyrosine aminotransferase (TAT) with high levels of ONLY tyr; associated with painful, nonpruritic, and hyperkeratotic plaques on the soles and palms, ophthalmologic involvement, and DD Tyrosinemia type 3: very rare and ill defined; deficiency of P-hydroxyphenylpyruvic acid dizoygenase; ID/ataxia, NO LIVER INVOLVEMENT, skin and ocular changes Homocystinuria Acute intermittent porphyria

Answer 3

Respiratory support, fluid management, and blood products for bleeding in liver failure Nitisinone (Orfadin): blocks the second step of the tyrosine degradation pathway and prevents FAA accumulation that would turn into succinylacetone Low tyr diet: nitisinone increases blood concentrations of tyr, which can lead to tyr crystals forming in the cornea Measure carnitine levels due to skeletal muscle weakness from renal tubular Fanconi anemia Osteoporosis and rickets tx with 25-hydroxy-vitamin D, Ca++. and phosphate

Answer 4

Those with severe liver failure at presentation and don't respond to nitisinone tx Have documented evidence of malignant changes in hepatic tissue

Answer 5

Gene reversion can occur (explains clinical variability in families/those w same genotype) in which the spontaneous self correction of a germline PV to the normal sequence occurs in somatic cell division The "normal" cells have a selective growth advantage bc they are no longer at risk for apoptosis from the accumulation of FAA

Answer 6

Based on quantification of the ratios of (leu +isoleu) to ala and phe on dry blood spots positive screen requires follow-up w quantitative plasma aa and alloisoleucine analyses NEONATES WITH ISOLATED HYDROXYPROLINEMIA WILL SCREEN + BUT CONFIRMATORY AA ANALYSIS WILL ONLY SHOW INCREASED HYDROXYPROLINE

Answer 7

Immediately after positive NBS either by quantification of aa ratios or plasma AA/ alloisoleucine levels

Answer 8

Identification of biallelic PVs in BCKDHA, BCKDHB, or DBT Use of a multigene panel w/ del/dup is recommended

Answer 9

Maple syrup odor in cerumen (earwax) after birth (~12hrs) and in urine @5-7do; acute metabolic intoxication (leucinosis) with risk for cerebral edema and death, and neurologic deterioration from net protein degradation by infection, sx, injury, psychological stress, iatrogenic essential aa deficiency, recurrent thrush infections 83-100% chance of anxiety, depression, or panic disorder by 35yo; 50% chance for ADHD

Answer 10

increased levels of BCAAs and alloisoleucine; urinary excretion of BCKDs and BCKAs in infants >48-72hrs old; ketonuria, absence of hypoglycemia/hyperammonemia

Answer 11

nausea, anorexia, altered consciousness, acute dystonia, ataxia

Answer 12

cognitive impairment, hyperactivity, sleep disturbances, hallucinations, mood swings, focal dystonia, choreoathetosis, and ataxia

Answer 13

Prolonged neonatal encephalopathy (lethargy, intermittent apnea, opisthotonus, "fencing and bicycling" movement) between 4/5do

Answer 14

Anemia, hair loss, growth failure, due to chronic deficiency of leucine, isoleucine, and valine

Answer 15

may have maple syrup smell in neonatal period and abnormal labs present with feeding issues, poor growth, DD in infancy or later with apparent nonsyndromic ID (majority are caught on NBS) tolerate more leucine and require less nutritional support

Answer 16

tolerate normal leucine intake, typically normal or mildly elevated BCAAs MAY ESCAPE DETECTION ON NBS During infections/physiological stress, can develop all features of classic MSUD

Answer 17

caused by decreased activity of BCKD, a multi-enzyme complex in the mitochondria skeletal muscle is the major site of transamination and oxidation of BCAAs BCKD is expressed in the brain mechanism of dz is decreased function or LOF

Answer 18

BCKDHA has PV missense in 3'UTR; DBT has PV missense in 3'UTR which are higher than expected Notable PVs include c.548G>C in BCKDHB a founder variant in the AJ pop; c.1196C>G in DBT a founder variant in the Malay pop BCKDHA accounts for 45% of PVs, BCKDHB accounts for 35% of PVs; DBT accounts for 20% of PVs

Answer 19

Need to exclude: birth asphyxia, hypoglycemia, status epilepticus (seizures >5min), meningitis, and encephalitis Urea cycle defects Hyperketosis syndromes Glycine encephalopathy Propionic acidemia/isolated methylmalonic acidemia

Answer 20

Unique for odor and + urine dinitrophenylhydrazine test

Answer 21

requires supervision of metabolic dietitian (age appropriate tolerance of leu, iso, val, AND avoiding deficiencies of essential aas, fatty acids, and micronutrients) Dietary indiscretion causes elevated BCAAs but RARELY results in encephalopathy and acute decompensation (lethargy, encephalopathy, seizures, or progressive coma should be managed with generous caloric support in a hospital) Orthotopic liver transplants Plasma levels should be: Leu 150-300umol/L Iso ~= to Leu Val at LEAST 2X >Leu

Answer 22

IMMEDIATELY

Answer 23

metabolic "cure" for classic MSUD does not reverse cognitive disability but may arrest progression of neurocognitive impairment

Answer 24

Pregnancy possible for pts with classic MSUD Increased Leu in pregnant person likely teratogenic Keep mat levels of BCAAs b/wn 150-300umol/L for safe delivery Postpartum is dangerous for mom -- refer to metabolic center

Answer 25

Isolated elevation of levels of glycine in plasma and CSF (obtained simultaneously) by quantitative aa analysis abnormal CSF to glycine ratio (elevation of CSF glycine is more important than the ratio) Urine organic acid profile is expected to be normal

Answer 26

most consistent abnormalities noted on diffusion weighted imaging in the first 3mo of life ALL INFANTS with diffuse restriction of white matter that can recede after 3mo but can be recognized elsewhere between 3-14mo The corpus callosum can be thin and shortened but is NOT absent Small group of infants develop hydrocephalus Atrophy present in older individuals with severe NKH

Answer 27

Biallelic PVs in GLDC, AMT, and (proposed to be involved) GCSH A multigene panel including the above that also includes del/dup analysis is recommended

Answer 28

requires analysis of a liver bx, usually obtained by sx endoscopy as a wedge bx or at autopsy Vast majority have no detectable GCS activity Those w defects in AMT tend to have GCS activity up to 25% of normal values

Answer 29

No developmental progress and intractable epilepsy Never make developmental gains, some will regain few skills Spontaneous bottle feeding, looking, and smiling when tx with benzoate (around 3-4mo they can lose these skills) Before 6mo, develop progressive spasticity and cortical blindness increasingly difficult to tx seizures in the 1st yr; EEG with multifocal spikes scoliosis/hip dislocation; occasionally can have cleft palate, clubfeet, secondary microcephaly Recurrent and long episodes of unexplained severe crying

Answer 30

Inborn error of metabolism resulting in accumulation of large quantities of glycine in all body tissues including the brain Typically will pass away within the first few weeks of life, but can live up to 3-5yo

Answer 31

variable developmental progress with treatable or no epilepsy (relatively easy to tx with benzoate or dextromethorphan alone) Hyperactivity common, can be severe Many have choreic movements Intermittent episodes of lethargy triggered by fever and infection Can have poor, intermediate, or good outcomes

Answer 32

developmental quotient <20 with epilepsy Manifestations between attenuated and severe forms Learn how to grasp objects, usually able to sit, have limited interaction with some signs

Answer 33

developmental quotient 20-50 with easily treatable or no epilepsy walk and communicate with some speech and sign language grasp items and eat independently choreatic movements and pronounced ADHD

Answer 34

Developmental Quotient >50 with no epilepsy make substantial developmental progress half do not present with symptoms until after 3mo have ADHD; episodes of severe lethargy with infections

Answer 35

defined as greater than 2 weeks 50%; 50%

Answer 36

defined as onset >3mo all have attenuated NKH

Answer 37

progressive lethargy into profound coma and marked hypotonia in the first hours to days of life 80% of infants ventilatory drive slows, leading to prolonged apnea and often death (20% maintain spontaneous ventilation) Majority of infants regain spontaneous respiration within the first three wks of life, some show spontaneous improvement in alertness in the first mo of life Myoclonic jerks and hiccups are often a sign of epilepsy initial EEG often shows a burst suppression pattern

Answer 38

hx of hypotonia early one, present with DD and infantile-onset seizures that can be mild or increasingly difficult to tx

Answer 39

rare, associated with the attenuated form, involves DD and possible mild seizures

Answer 40

No, the phenotype of severe vs attenuated NKH is consistent within families

Answer 41

presence of a very thin and shortened corpus callosum Presence of hydrocephalus development of clear pyramidal tract signs (hyperreflexia, weakness, spasticity, and a Babinski sign) before 6mo cleft palate and clubfeet when present persistent burst suppression pattern

Answer 42

glycine/creatine ratio is higher in severe than in attenuated NKH presence of choreatic movements

Answer 43

GCS cofactor deficiencies (pyridoxine dependent epilepsy) Abnormal regulation of GCS (intracellular cobalamin metabolism) Glycine transport defects (GLYT1 encephalopathy) Inhibition of GCS activity (organic acidemias- will have abnormal urine organic acids)

Answer 44

MRI of the brain in neonates (brain atrophy in severe form) EEG Developmental assessment Neurologic assessment Orthopedic eval Pulmonary eval Ophthalmologic assessment GI eval

Answer 45

Glycine-lowering therapy is not effective in improving the affected individuals development, even when initiated at birth (does however decrease frequency and severity of seizures) Improves attentiveness and resolves neonatal apnea

Answer 46

Reduction of plasma concentration of glycine tx with sodium benzoate (improves alertness, reduces or eliminates episodic lethargy, and may also improve behavior) and blockade of NMDA receptors Early, aggressive tx of children with PVs associated with residual GCS activity who are likely to develop attenuated NKH resulted in improved neurodevelopmental outcome and reduced propensity for epilepsy

Answer 47

contribution of dietary glycine is small compared to the excess in endogenous glycine synthesis versus endogenous catabolism of glycine been associated with protein malnutrition

Answer 48

Valproate- it raises blood and CSF glycine concentrations and may increase seizure frequency Vigabatrin resulted in rapid loss of function of the glycine cleavage enzyme system

Answer 49

Loss of function. Residual enzyme activity correlates with the outcome of the dz

Answer 50

GLDC analysis is complicated by the presence of a processed full-length pseudogene with 98% homology to the true gene 20% of pathogenic GLDC variants are large deletions as a result of nonallelic homologous recombination of Alu repeats

Answer 51

total homocysteine levels above 100 umol/L when accompanied by high or borderline high methionine makes the dx very likely ENZYME ACTIVITY TESITNG IS NO LONGER AVAILABLE IN THE US

Answer 52

Detected in SOME affected individuals screens for hyperMETHIONINEMIA using tandem mass spec If initial result exceeds cutoff of methionine, follow up testing is required: 1. repeat dried blood specimen OR 2. quantitative plasma aa analysis and analysis of plasma total homocysteine (dependent on screening program recommendation) Since NBS is for methionine and not homocysteine, other causes of elevated total homocysteine may not be detected bc the methionine level in these disorders is reduced or normal

Answer 53

Ectopia lentis and/or severe myopia Skeletal abnormalities (excessive height, long narrow limbs (dolichostenomelia), scoliosis, pectus excavatum) Thromboembolism (vascular abnormalities) DD/ID NO JOINT HYPERMOBILITY (SPECIFIC TO MARFAN)

Answer 54

Sequence analysis of CBS FIRST then gene-targeted del/dup analysis if only one or no PVs is found Targeted analysis is performed only in the Qatari pop in which a single PV (p.Arg336Cys, c.1006C>T) is present in 93% of the pop

Answer 55

Pyridoxine (B6) challenge test Affected individual (in the neonate or beyond) is given 100mg of pyridoxine daily for two consecutive days, concentrations of plasma total homocysteine and aas are measured in 48hrs after the first dose Reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B6 responsiveness

Answer 56

B6-responsive pts typically have milder presentations than non-responsive individuals (BUT NOT ALWAYS) Myopia followed by ectopia lentis (after one yo but before 8yo) Tall and slender, marfanoid habitus, prone to osteoporosis Scoliosis, high-arched palate, arachnodactyly, pes cavus, pectus excavatum or carinatum, genu valgum (knock knees) Thromboembolism is the major cause of morbidity and early death (problems typically appear in young adults) DD is often the first abnormal sign in individuals with homocystinuria Seizures in 21% of individuals Psychiatric problems (personality disorder, anxiety, depression, OCD, psychotic episodes Hypopigmentation of the hair and skin, malar flush, livedo reticularis (skin to appear reddish-violet and blotchy, forming a net-like pattern), and pancreatitis

Answer 57

presence of a single p.Gly307Ser allele predicts B6 non-responsiveness presence of a single p.Ile278Thr allele usually predicts B6 responsiveness

Answer 58

1. Qatar 2. Norway 3. Germany 4. Ireland

Answer 59

Marfan Tyrosinemia type 1 or galactosemia (secondary hypermethioninemia)

Answer 60

methionine restricted diet continued indefinitely. A methionine free aa formula supplying the other aas is provided Folate and vitamin B12 optimize the conversion of homocysteine to methionine by methionine synthase, thus helping to decrease the plasma homocysteine concentration Tx with betaine provides an alternate remethylation pathway to covert excess homocysteine and methionine may help to prevent thrombosis

Answer 61

Infants should be monitored monthly for the fist six months of life and bimonthly until age 1yr, then every 3mo until age 3yrs Semiannual monitoring through the remainder of childhood and annual monitoring in adolescence and adulthood are indicated Regular ophthalmology assessments DXA scans should be performed q3-5yrs to monitor for osteoporosis

Answer 62

Oral contraceptives increase coagulability and should be avoided in females Sx should also be avoided if possible bc increase in plasma homocysteine concentrations elevates the risk of a thromboembolic event

Answer 63

Prophylactic anticoagulation in the third tri and post partum recommended (low molecular weight heparin), low dose aspirin does NOT appear to have teratogenic effects on a fetus

Answer 64

It is possible (though unlikely) that a parent has classic homocystinuria but has remained asymptomatic (high clinical variability of the condition), it is appropriate to perform an exam and plasma homocysteine and aa analysis in both parents (affected women at increased risk for thromboembolic events during pregnancy

Answer 65

Most often missense variants, some nonsense; the rest are various in/dels, and splice variants

Answer 66

p.Gly307Ser and p.Ile278Thr are found in exon 8 p.Gly307Ser is the leading cause of homocystinuria in Ireland (71% of PVs) p.Arg336Cys is present in 93% of affected individuals in the Qatari pop

Answer 67

group of rare disorder affected the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine failure to break down nitrogen results in the abnormal accumulation of nitrogen (in the form of ammonia) in the blood

Answer 68

refusal to eat and poor feeding habits, progressive lethargy, recurrent vomiting, diarrhea, irritability, and hepatosplenomegaly Seizures, confusion, respiratory distress, and cerebral edema in some cases, may progress to coma due to high levels of ammonia in the blood (resulting in neurological abnormalities including DD, learning disabilities, ID)

Answer 69

failure to thrive, poor growth, avoidance of protein from diet, ataxia, lethargy, vomiting, hypotonia Can still experience hyperammonemic coma and life threatening complications

Answer 70

occur within 24-72hrs after birth caused by accumulation of ammonia in the blood (nitrogen is a waste product of protein metabolism)

Answer 71

Occurs later in infancy or childhood or even adulthood in some cases

Answer 72

biallelic mutations in NAGS NAGS is an activator of another enzyme of the urea cycle (carbamyl phosphate synthetase (CPS))

Answer 73

Other urea cycle disorders Reye syndrome: liver failure, encephalopathy, hypoglycemia, hyperammonia, occurs following a viral infection Organic acidemias (affect the urea cycle as a secondary phenomenon)

Answer 74

lack of appetite, vomiting, drowsiness, seizures, and/or coma hepatosplenomegaly in some cases in severe cases, life threatening complications may result

Answer 75

hypotonia, poor feeding, lethargy, vomiting, and seizures can progress to coma and life-threatening complications

Answer 76

excessive amounts of ammonia in the blood (can also indicate other disorders like organic acidemias, congenital lactic acidosis, and fatty acid oxidation disorders) URINARY ORGANIC ACIDS SHOULD BE NORMAL

Answer 77

prevent excessive ammonia during a hyperammonemic episode Carbaglu (carbamylglutamate) tablets to reduce blood ammonia levels Dietary restrictions (limit the amount of protein intake) and receive supplemental arginine Sodium phenylacetate and sodium benzoate (nitrogen scavengers, allow an alternate route for the metabolism of nitrogen) Hemodialysis may be nexessary if there is no improvement/hyperammonemic coma develops PROMPT TX IF A PT HAS EXTREMELY HIGH AMMONIA LEVELS TO AVOID HYPERAMMONEMIC COMA

Answer 78

administer carbaglu periodic blood tests to determine the levels of ammonia in the blood receive periodic tests to measure the amount of aas such as glutamine in the blood (elevated levels of glutamine often precede the development of hyperammonemia by weeks-days)

Answer 79

healthy at birth but after a few days begin to manifest with lethargy and unwillingness to feed Severe hyperammonemia with vomiting, hypothermia, hypotonia, seizures, coma, which can lead to death

Answer 80

CPS1, in the hepatocytes, controls the first step of the urea cycle where the ammonia is converted into carbamoyl phosphate but excess nitrogen is NOT converted to urea for excretion by the kidneys

Answer 81

severe hyperammonemia very low plasma levels of citrulline and arginine high plasma levels of glutamine Increased transaminases Low/normal levels of orotic acid in the urine

Answer 82

life-long diet low in natural protein, supplements of essential aa's, citrulline and arginine as needed, sodium benzoate and/or sodium or glycerol phenylbutyrate Nutritional support to avoid catabolic stress early liver transplantation for those with neonatal onset CPS1 deficiency can correct metabolic abnormalities, does not reverse neurological complications

Answer 83

plasma ammonia levels must be lowered (by hemodialysis or hemofiltration), ammonia scavenger therapy, catabolism reversed (glucose and lipid infusions), special care to reduce the risk of neurological damage

Answer 84

Valproic acid

Answer 85

considered bleak episodes of hyperammonemic coma of long duration are associated with a poor neurological outcome

Answer 86

Primarily based on the quantification of citrulline on dried blood spots Values outside the range are considered positive and require follow-up biochemical testing (plasma ammonia, plasma aa profile, urine organic acid profile, urine orotic acid quantification) Current NBS methods for OTC vary greatly in sensitivity/specificity

Answer 87

Normal at birth, development of reduced oral intake w poor latching/suck, acute neonatal encephalopathy (lethargy, drowsy) with hyperventilation and hypothermia

Answer 88

Encephalopathic/psychotic episodes (erratic behavior, clouded consciousness, delirium) Recent stressor Hx of recurrent vomiting Migranes Reye-like syndrome (swelling in the brain and liver damage) True protein avoidance Unexplained "cerebral palsy"

Answer 89

elevated plasma ammonia concentration abnormal plasma amino acid analysis (high glutamine and a VERY low citrulline level) Elevated orotic acid on urine analysis Blood gas findings suggestive of respiratory alkalosis in an individual who is hyperventilating Unexpectedly low blood urea nitrogen (may suggest reduced urea production)

Answer 90

Hemizygous PV in OTC Markedly abnormal increase of orotic acid excretion Decreased OTC enzyme activity in the liver

Answer 91

Heterozygous PV in OTC Markedly abnormal increased of orotic acid excretion LIVER BX IS NOT RECOMMENDED IN FEMALES DUE TO THE POSIBILITY OF FALSE NEGATIVE RESULTS

Answer 92

Sequence analysis is performed first to detect missense, nonsense, and splice site variants and small intragenic indels Deep intronic PVs have been reported Therefore, sequencing methods that can detect splice donor and acceptor variants should be included

Answer 93

to determine the amount of orotic acid over a 24hr period OTC

Answer 94

when an OTC PV is not found in a male with a high clinical suspicion for OTC deficiency or if an allopurinol challenge is inconclusive FOR FEMALES: bx may not represent the true total OTC activity bc of the X chromosome inactivation pattern

Answer 95

ASYMPTOMATIC AT BIRTH Become symptomatic in the first week of life (2-3do) with poor suck, reduced intake, and hypotonia followed by lethargy progressing to lethargy and extreme fatigue Hyperventilate and may have subclinical/electroencephalographic seizures

Answer 96

typically catastrophically ill with low body temp (hypothermia), severe encephalopathy, and respiratory alkalosis

Answer 97

Can easily become hyperammonemic again despite low protein diet and tx with oral ammonia scavenger. Even on max ammonia scavenger therapy a neonate may only tolerate the bare minimum protein intake needed to grow Typically liver transplant is required to prevent life threatening hyperammonemic episodes

Answer 98

become symptomatic in infancy when switched from breast milk to formula/whole milk show episodic vomiting, lethargy, irritability, FTT, DD Show true protein avoidance Become encephalopathic (erratic behavior, combativeness, and delirium)

Answer 99

Range from asymptomatic to significant symptoms with recurrent hyperammonia and neurologic compromise depending on X inactivation in her liver cells

Answer 100

ADHD; half are described as withdrawn, depressed, and/or anxious Impulsivity and immaturity can lead to inappropriate behaviors During hyperammonemic coma, EEG shows low voltage with slow waves and may include a burst suppression pattern Seizures are common Neonates who survive after prolonged coma may have ventriculomegaly, diffuse brain atrophy, and low density white matter defects

Answer 101

Liver enzymes are typically moderately elevated and PT and PTT may be prolonged Severe elevations of liver enzyme and coagulopathy consistent with acute liver failure Risk of developing progressive growth failure over time

Answer 102

PVs that are missense that affect residues for catalysis, substrate binding and folding severely impair or completely abolish OTC activity and result in the neonatal onset form of the dz Nonsense, in/dels, that cause frameshift or ORF and SNVs in intronic splice sites result in complete absence of functional OTC and neonatal onset form of dz AA substitutions that decrease OTC enzyme activity or stability may result in a post-neonatal onset phenotype

Answer 103

Late onset NAGS, CPS1, ASS, ASL deficiencies Generalized liver dysfunction resulting in hyperammonemia

Answer 104

Consultation with metabolic physician/biochemical geneticist and specialist metabolic dietician Lab testing Developmental assessment Neurologist Consultation with psychologist and/or social worker Genetic counseling

Answer 105

Renal replacement therapy, nitrogen scavenger therapy, and supplemental citrulline to address hyperammonemia Provide calories from glucose and fat to decrease protein catabolism EEG surveillance to tx seizures and assess risk for neurologic damage

Answer 106

Protein intake restricted to amt necessary for growth and prevention of catabolism; use of an aa medical food (high glutamine concentrations are interpreted as evidence of poor metabolic control) Nitrogen scavengers to provide alternative routes for nitrogen disposal and allow more protein intake Consider liver transplant (removes risk for hyperammonemic episodes) Tx with ASM as directed by neurologist for seizure disorder

Answer 107

No matter how mild, stressors can precipitate a hyperammonemic crisis that becomes life-threatening Remains the most effective means of preventing further hyperammonemic crises and neurodevelopmental deterioration typically performed by 6mo Considered when an affected individual is unstable and has frequent hyperammonemic episodes

Answer 108

valproate, haloperidol, fasting, stress, systemic corticosteroids bc they cause catabolism

Answer 109

heterozygous females are at risk of becoming catabolic during pregnancy and especially in the postpartum period Caution should also be taken for those who are asymptomatic since they can deteriorate due to stress in the peripartum or postpartum periods

Answer 110

Germline mosaicism has been reported De novo rate of 26% in males Spontaneous mutation rate of 67% in females

Answer 111

Prospective tx as soon as the child is born and improved rescue therapy followed by liver transplant now allow some males to reach reproductive age and reproduce

Answer 112

Catalyzes formation of citrulline from ornithine and carbamylphosphate in the liver and small intestine Loss of function

Answer 113

Quantification of citrulline on dried blood spots (high values are considered positive) F/u includes biochemical testing for plasma ammonia concentration (high), plasma quantitative aa analysis (citrulline- high, argininosuccinic acid- absent, arginine and ornithine- low to normal, lysine, glutamine, and alanine- increased) Urinary organic acid analysis may show elevated orotic acid

Answer 114

Evaluate neonate for GI involvement (poor feeding, vomiting, signs of liver dz), respiratory distress, neurologic involvement Initiate management- protein restriction, nitrogen scavengers, arginine supplementation

Answer 115

Sequence analysis of ASS1 to detect missense, nonsense, splice variants, and small indels. F/u w gene-targeted del/dup analysis for exon and whole gene deletions or duplications Urea cycle disorders/hyperammonemia multigene panel Sequence analysis identifies 96% of PVs

Answer 116

Predominantly expressed in the liver (and some in the kidneys) Clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the dx

Answer 117

infant appears normal at birth one to a few days, infant becomes progressively more lethargic, feeds poorly, may vomit, develops signs of liver failure, cerebral edema Longest one can live without tx is 17days Significant neurologic deficits in a manner corresponding to prior # and degree of exposures to elevated ammonia levels Gross motor skills tend to be less well developed than expressive language skills

Answer 118

Neurologic findings may be more subtle bc of the older age of the affected individuals intense headaches, scotomas (blind spot in eye), migraine-like episodes, ataxia, slurred speech, lethargy respiratory alkalosis and tachypnea Without intervention, intracranial pressure increases, increased neuromuscular tone, spasticity, ankle clonus seizures, loss of consciousness, and death

Answer 119

Hyperammonemic coma shortly after birth Implicated in postpartum psychosis

Answer 120

severe classic form typically results from 22 PVs; PV in exon 15, p.Gly390Arg, remains the most prevalent mild form is associated with 12 PVs

Answer 121

Citrullinemia type 2 (citrin deficiency), ASL deficiency Secondary hyperammonemia caused by an organic acidemia

Answer 122

Consultation with metabolic specialist and specialist metabolic dietician Metabolic control (plasma ammonia levels, blood gases, electrolytes, plasma aas) consultation with neurologist developmental assessment consultation w psychologist and/or social worker consultation with PT, OT, and speech

Answer 123

Liver transplant, eliminates need for dietary restriction

Answer 124

protein restriction nitrogen scavenger meds arginine supplementation secondary carnitine deficiency- supplement with carnitine

Answer 125

withhold all protein intake for 24-48hrs Pharmacologic nitrogen scavenger therapy dialysis most effective means of decreasing plasma ammonia rapidly Administer high energy fluids, consider carnitine supplementation, address electrolytes and pH imbalances Control intracranial pressure

Answer 126

excess protein intake prolonged fasting obvious exposure to communicable diseases

Answer 127

the long term prognosis is correlated with initial and peak plasma ammonia concentration

Answer 128

catalyzes an essential rx in the biosynthesis of urea, causing the condensation of citrulline and aspartate to argininosuccinic acid in the cytosol. Transcription starts near the 5' end of exon 3; At least 14 ASS pseduogenes are known Loss of function

Answer 129

Based on quantification of the analyte citrulline on dried blood spots confirmation of the dx requires f/u testing to detect elevated plasma or urine concentration of argininosuccinic acid or its anhydride compounds

Answer 130

elevated citrulline, argininosuccinic acid, and ammonia low to normal arginine normal to high glycine, glutamine, alanine, and orotic acid

Answer 131

Single gene testing: detects small indels and missense, nonsense, and splice site variants. PERFORM SEQUENCE ANALYSIS FIRST, then perform gene-targeted deldup analysis Most appropriate when the dx is made based on results of biochemical testing For this disorder a multigene panel that also includes del/dup analysis is recommended Multigene panel may be considered when the presentation is with hyperammonemia and confirmatory biochemical dx has not been performed/is unavailable

Answer 132

hyperammonemia within the first few days after birth but healthy for the first 24hrs vomiting, lethargy, and refusal to accept feeds; tachypnea and respiratory alkalosis are early findings; seizures, coma, and death hepatomegaly and trichorrhexis nodosa

Answer 133

range from episodic hyperammonemia to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia SYMPTOMS ARE UNRELATED TO THE SEVERITY OR DURATION OF HYPERAMMONEMIC EPISODES

Answer 134

higher incidence of DD and neurologic abnormalities than did those with OTC deficiency increased incidence of ADHD, ID, behavioral abnormalities, and/or learning disability, seizures compared to those with other UCDs many individuals who are tx with protein restriction and supplemental arginine have normal cognition and development

Answer 135

severe neonatal: shares the phenotype of the typical acute neonatal hyperammonemia Late onset: similar to late-onset OTC, late onset citrullinemia type 1 (elevation of argininosuccinate is characteristic

Answer 136

consult with metabolic physician and specialist metabolic dietician neurocognitive assessment baseline eval for evidence of hepatic involvement (hepatomegaly, hepatitis, and signs of liver failure) plotting of systolic and diastolic BP on centile charts based on age and stature

Answer 137

discontinue oral protein intake supplemental IV lipids, glucose, and insulin if needed to promote anabolism IV nitrogen-scavenging therapy. L-arginine prompt institution of hemodialysis if ammonia levels are not decreasing

Answer 138

dietary restriction of protein, arginine supplementation, oral nitrogen-scavenging therapy, orthotopic liver transplant. salt restriction and use of antihypertensives (for HTN). potassium supplementation for hypokalemia, special ed services as needed

Answer 139

excess protein intake, large boluses of protein or aas, less than recommended intake of protein, prolonged fasting or starvation, obvious exposure to commmunicable dz's, valproic acid, IV steroids, and hepatotoxic drugs in those with hepatic involvement

Answer 140

Sources of arginine are exogenous from the diet and endogenous from the breakdown of proteins and synthesis from citrulline Its main role in the urea cycle is conversion of argininosuccinate into arginine and fumarate occurs through loss of ASL enzyme function. Residual activity may be present

Answer 141

Complicated by a pseudogene abnormal ASL alleles typically found in affected individuals with late-onset ASL deficiency had either high residual ASL enzyme activity or two mutated alleles that exhibited complementation

Answer 142

Based on quantification of arginine on dried blood spots Some infants with arginase deficiency may have f/u arginine levels in the normal range, and thus infants who continue to have elevated arginine-to-ornithine ratios and arginine toward the upper limit or normal should undergo additional diagnostic testing

Answer 143

Elevated plasma arginine three to fourfold the upper limit of normal Intermittent elevation of ammonia; acute hyperammonemia is uncommon Urinary orotic acid is elevated

Answer 144

Perform sequence analysis first (identifies >98% of variants) then do de/dup analysis to detect intragenic del/dups In individuals in the French Canadian populations, the c.57+1G>A founder variant may be tested for first

Answer 145

most affected individuals have no detectable (<1%) enzyme activity in RBC extracts Liver and RBC arginase activity correlate well- it is not necessary to perform liver bx when enzyme activity can be measured from a blood sample

Answer 146

age 1-3, linear growth slows (children demonstrate growth deficiency; microcephaly is common; feeding issues may develop age 1-3, normal cognitive development slows or stops, lose developmental milestones; if untx, progresses to severe ID with neurologic findings Progressive neurological signs typically include the development of severe spasticity with loss of ambulation and complete loss of bowel and bladder control; between 2-4, often misdx with cerebral palsy; can have joint contractures and lordosis; seizures in 60-75% (mostly generalized tonic-clonic); cortical atrophy hyperammonemia is rarely severe enough to be life threatening Hepatic dysfunction if present is usually mild (some have developed hepatocellular carcinoma Vast majority appear to survive and live long handicapped lives

Answer 147

Severe dz associated with: Homozygosity/compound heterozygosity for LOF variants like c. 466-2A>G, c.77delA, c.263_266delAGAA, and c.647_648ins32 Missense changes such as p.Ile8Lys or p.Gly106Arg when homozygous or in combo with another severe allele

Answer 148

French Canadian pop* Turkey Brazil China

Answer 149

Other causes of hyperammonemia from a UCD Cerebral palsy (static spastic diplegia)

Answer 150

obtain plasma ammonia, aa profile, guanidinoacetate, and liver function tests gastro/nutrition/feeding team eval developmental assessment neurologic eval musculoskeletal eval

Answer 151

Less prone to episodes of hyperammonemia and when present, more likely to respond to conservative management like IV fluid administration Arginine supplement obviously contraindicated Restriction of dietary protein Administration of oral nitrogen scavenging drugs seizures- standard ASM depending on seizure type spasticity- orthotics, wheelchairs, walkers, etc. hepatic fibrosis and cirrhosis- liver transplant joint contractures- PT

Answer 152

mild to moderate: increase protein free caloric intake severe: same as above plus nitrogen scavengers; dialysis is rarely needed

Answer 153

arginine valproic acid (exacerbates hyperammonemia)

Answer 154

generally continue dietary protein restriction and ammonia-scavenging meds based on clinical course before pregnancy (protein restriction is challenging given the complications like nausea and vomiting in pregnancy) no well controlled studies of the fetal effects of nitrogen scavengers (sodium benzoate, phenylacetate, phenylbutyrate); however generally advised against since animal studies have shown teratogenic effects

Answer 155

May be possible to measure arginase enzyme activity in fetal RBCs from percutaneous umbilical blood sampling after 18wks gestation Amniocytes and CV cells do not have arginase activity naturally, and therefore cannot be used for testing

Answer 156

deficiency in the mitochondrial multimeric enzyme propionyl-CoA carboxylase; enzyme is composed of 6 alpha subunits and 6 beta subunits encoded by PCCA and PCCB respectively

Answer 157

Acylcarnitine analysis by tandem mass spec on dried blood spots -- elevated propionylcarnitine (C3) methionine, C3/C2 ratios, and C3/C16 ratios increase dx accuracy

Answer 158

Elevated propionylcarnitine (C3) on PLASMA ACYLCARNITINE PROFILE On URINE ORGANIC ACIDS: elevated 3-hydroxypropionate, presence of methylcitrate, tiglyglycine, propionylglycine, and lactic acid on PLASMA AAs: elevated glycine

Answer 159

High anion gap metabolic acidosis Lactic acidosis Elevated plasma and urinary ketones Low to normal blood glucose concentration Hyperammonemia Neutropenia, anemia, and thrombocytopenia

Answer 160

Identification of biallelic PVs in PCCA or PCCB Neither gene is more common and there are no characteristic findings to distinguish between PCCA or PCCB associated PA Sequence analysis first, followed by gene targeted del/dup if only one or no PV is found

Answer 161

Exon dels account for ~20% of PCCA dz causing alleles PCC catalyzes the conversion of propionyl CoA to D methymalonyl-CoA which eventually enters the Krebs cycle as succinyl-CoA Most PCCA PVs are private; CNV variants are responsible for 18% of reported variants Most PVs in PCCA cause protein instability Most PVs in PCCB are predicted to alter the active site and reduce the enzymatic activity

Answer 162

enzyme assay for activity of propionyl-CoA carboxylase in lymphocytes or cultured skin fibroblasts followed by molecular dx

Answer 163

Clinical poor feeding, vomiting, irritability, lethargy, progressive encephalopathy, seizures, coma, respiratory failure Lab high anion gap metabolic acidosis, ketonuria, hyperammonemia, hypoglycemia, increase in 3-OH propionic acid and methylcitric acid, hyperglycinemia, anemia, leukopenia, thrombocytopenia

Answer 164

May remain asymptomatic and suffer a metabolic crisis under catabolic stress or experience a more insidious onset Clinical encephalopathy, coma and/or seizures precipitated by catabolic stress, vomiting, protein intolerance, FTT, hypotonia, developmental regression, movement disorders, isolated cardiomyopathy Lab with or without metabolic acidosis or hyperammonemia increased 3-OH propionic acid and methylcitric acid, hyperglycinemia MRI abnormalities including basal ganglia lesions

Answer 165

Acidosis, hyperammonemia, pancreatitis, metabolic stroke, cardiomyopathy, bone marrow suppression, seizures, and encephalopathy Infectious complications (sepsis, bacterial meningitis) often accompany metabolic crisis and are major contributors to mortality

Answer 166

DD, developmental regression, ID, seizures, hypotonia, spasticity, and movement disorders predisposed to basal ganglia lesions- may precede an acute "stroke-like" episode as altered mental status, dystonia, choreoathetosis, or hemiplegia acute psychosis in older individuals typically the presenting feature can also see delayed myelination, white matter changes, basal ganglia abnormalities, cerebellar hemorrhage, and cerebral atrophy on MRI

Answer 167

Cardiomyopathy- both dilated and hypertrophic, avg age of onset 7yo; early manifestations can include tachypnea, hepatomegaly, hypotension, tachycardia, or bradycardia prolonged QT interval commonly detected leading to syncope, arrhythmia, and cardiac arrest pancreatitis may be recurrent and could lead to insulin-dependent diabetes; poor feeding and lack of appetite common; liver issues: hepatomegaly, hypoalbuminemia, abnormal liver function tests anemia. leukopenia, and thrombocytopenia are common

Answer 168

high frequency of recurrent infections seen in 60-80% of affected individuals; bone marrow suppression, immune dysfunction, frequent hospitalizations, and potential nutritional deficiencies caused by diet could contribute eye findings include: dyschromatopsia, optic atrophy, scotomas, abnormal electroretinogram; optic neuropathy in 11-25% of pts SNHL has been reported Severe osteopenia has been described

Answer 169

null variants and out of frame small indels result in LOF alleles that are associated with more severe PA homozygous missense variants in which partial enzyme activity is retained have been associated with a less severe phenotype

Answer 170

homozygous PCCB variant in Amish and Mennonite pops, p.Asn536Asp, is associated with high residual PCC activity. Low risk of developing metabolic crisis, but can lead to late onset cardiomyopathy Highest birth incidence in Greenlandic Inuits (1:1000)

Answer 171

methylmalonic acidemia biotinidase and holocarboxylase synthetase deficiencies Maternal B12 deficiency Mitochondrial disorder

Answer 172

assessment of growth parameters, ability to feed, need for G-tube placement, neurologic status lab assessment of nutritional status, CBC to monitor for cytopenias clinical eval for cardiomyopathy and arrhythmia with EKG, 24 hr Holter monitor, echo EEG and brain MRI in symptomatic individuals Developmental eval Dilated eye exam Hearing eval Immunology consult Maintain a high index of suspicion for endocrine, immune, and renal problems and address accordingly

Answer 173

promotion of anabolism and removal of toxic intermediates; medical emergency and requires transfer to a center with biochemical genetics and ability to support urgent hemodialysis Tx precipitating stress factors; reverse catabolism by giving IV glucose and lipids; manage protein intake to reduce propionic precursors, avoidance of protein transiently may be required; nitrogen scavenger meds, oral n-carbamoylglutamate; hemodialysis, carnitine supplementation

Answer 174

At home detection and monitoring of urine ketones Diet modification under the direction of the metabolic team any injury, hospitalization, or sx procedure should involve consultation with the metabolic team seizures are a frequent complication requiring ASM; use of valproic acid in organic acidemias is avoided dermatologic manifestations (persistent dermatitis or eczema) warrant nutritional reassessment

Answer 175

modification of diet to control the intake of propiogenic substrates (isoleucine, valine, methionine, and threonine) Levocarnitine Antimicrobial therapy via oral metronidazole has been shown to reduce propionic acid production by intestinal gut flora Biotin supplementation Orthotopic liver transplant may be indicated for those who still experience frequent metabolic decompensations, uncontrollable hyperammonemia, and poor growth (NOT CURATIVE- does not completely protect against metabolic stroke, hyperammonemia, or metabolic decomp)

Answer 176

prolonged fasting, catabolic stressors, and excessive protein intake Lactated Ringer's solution not recommended Avoid meds that can prolong QT interval Neuroleptic antiemetics (promethazine) can mask symptoms of progressive encephalopathy

Answer 177

primarily based on the quantification of propionylcarnitine (C3) on dried blood spots ratios of C3/C2, C3/C0, C3/C16, C3/glycine, or C3/methionine are recommended for "positive" NBS acylcarnitine analysis by mass spec aa analysis of blood spot will show normal methionine and elevated C3/methionine ratio

Answer 178

eval for prevention of hyperammonemia and metabolic ketoacidosis Daily intramuscular vitamin B12 administration (Hydroxocobalamin) initiation of low protein diet carnitine supplement Testing for methylmalonic acid, 2 methylcitrate, and total homocysteine

Answer 179

elevated plasma methylmalonic acid elevated levels of urine MMA, presence of 3-OHpropionate, 2-methylcitrate, and tiglyglycine on urine organic acids elevated concentrations of glycine, possibly alanine and normal methionine elevated propionylcarnitine (C3) on plasma acylcarnitine profile elevated plasma ammonia, metabolic ketoacidosis, pancytopenia, lactic acidosis, hypoglycemia normal serum B12 and plasma homocysteine

Answer 180

severe ketoacidosis and lactic acidosis hyperammonemia anemia, neutropenia, and/or thrombocytopenia on CBC isolated renal tubular acidosis or chronic renal failure in untreated infants and children

Answer 181

complete (mut0) or partial (mut-) deficiency of methylmalonyl-CoA mutase, encoded by MMUT Diminished synthesis of methylmalonyl-CoA mutase enzyme cofactor 5' deoxyadenosylcobalamin, associated with cblA, cblB, or cblD-MMA complementation groups caused by biallelic PVs in MMAA, MMAB, or MMADHC, respectively deficient activity of methylmalonyl-coenzyme A epimerase encoded by MCEE

Answer 182

include use of a multigene panel (MCEE, MMAA, MMAB, MMADHC, MMUT) most commonly variants in MMUT

Answer 183

In vivo responsiveness to vitamin B12 should be determined for all individuals given hydroxocobalamin followed by assessment of production of MMA and related metabolites by serial urine organic acid analyses and/or measurement of plasma concentrations of MMA, propionylcarnitine, and homocysteine reduction in plasma or urine mean methylmalonic acid concentration indicative of responsiveness

Answer 184

mut0 enzymatic subtype, cblB can result in death despite aggressive intervention, can also present with an acute neonatal crisis presents during infancy; can be normal at birth but develop lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds rapidly progress to coma due to hyperammonemic encephalopathy severe high anion gap metabolic acidosis, ketosis and ketonuria, hyperammonemia and hyperglycemia dialysis may be needed thrombocytopenia and neutropenia can be seen

Answer 185

can occur in the first few months or years of life exhibit feeding problems (anorexia, vomiting), FTT, hypotonia, DD until dx is established, infants are at risk for catastrophic decomp child may die despite intensive intervention of prompt tx is not initiated can have devastating injury to the basal ganglia can also present with isolated renal tubular acidosis or chronic renal failure

Answer 186

complete absence of symptoms to severe metabolic acidosis with increased MMA and 2-methylcitrate and ketones in the urine at initial presentation metabolic ketoacidosis, hypoglycemia, seizures, DD, and spasticity not responsive to B12 supplementation

Answer 187

mut0 and cblB subtypes have a higher rate of mortality, neurologic, and other multisystem complications than those with mut- and cblA subtypes ID may or may not be present even in those with severe dz all individuals are at risk of developing renal insufficiency that can progress to end stage renal dz requiring kidney transplant (creatinine is a late marker of renal dysfunction) some develop "metabolic stroke" which can produce an incapacitating movement disorder acute pancreatitis is a well recognized complication growth failure is frequent and multifactorial, result of severe chronic illness functional immune impairment results in an increased susceptibility to severe infections can exhibit pancytopenia with bone marrow hypoplasia and/or dysplasia that most frequently reverts to normal with tx late-onset optic atrophy associated with acute/subacute vision loss liver u/s can show hepatomegaly; have been reports of hepatoblastoma and hepatocellular carcinoma

Answer 188

MMAB c.556C>T (p.Arg186Trp): most common PV in 29-33% of alleles from European and North American cohorts (homozygous individuals present in the neonatal period and not responsive to hydroxocobalamin tx those with at least one c.700C>T (p.Gln234Ter) PV have more variable, generally later age of presentation/dx, some demonstrate a biochemical response to hydroxocobalamin therapy located in the last exon resulting in partially functional protein MMUT people with 2 truncating PVs usually have the mut0 subtype mut- enzymatic subtype PV usually plays a dominant role when in compound heterozygous state with a mut0 enzymatic subtype PV

Answer 189

consultation with metabolic physician and specialist metabolic dietician assessment of vitamin B12 responsiveness screening lab tests (serum B12, serum chem panel including renal function and liver enzymes, CBC w/differential, iron status, and folate, arterial/venous blood gas, plasma ammonium and lactic acid concentration, urinalysis and urine ketone measurement, quantitative aas, urine organic acids, serum methylmalonic acid and methylcitrate levels, measurment of free and total carnitine, pancreatic anzymes (amylase and lipase), serum albumin, total protein, and prealbumin cardiac eval (BP, EKG, echo) measurement of growth parameters baseline bone age and density (DXA) consultation with neurologist ophthalmology eval audiology eval consultation with social work/psychologist

Answer 190

vitamin B12 supplementation (if responsive) restriction of natural protein (propiogenic aa precursors, while maintaining a high calorie diet) address feeding difficulties, recurrent vomiting, and growth failure lifelong carnitine supplementation reduction in propionate production from gut flora (metronidazole)

Answer 191

administration of high energy IV fluids lipid emulsion to provide sufficient calories decrease/omit protein for 24-48hrs carnitine supplementation N-carbamylglutamate (Carbaglu)/nitrogen scavengers for hyperammonemia; hemodialysis may be necessary neurologic consultation/Brain MRI consider giving granulocyte-colony stimulating factor for BM failure

Answer 192

fasting, stress, increased dietary protein, supplementation with valine and isoleucine (increase toxic metabolite load), nephrotoxic meds (ibuprofen), agents that prolong QTc in the EKG

Answer 193

results from failure to convert methylmalonyl-CoA into succinyl-CoA in the mitochondrial matrix *variants have been reported in MCEE and MMUT that are intronic, may not be detected by routine panels/WES* LOF

Answer 194

based on quantification of isovalerylcarnitine (C5-carnitine) in dried blood spots by tandem mass spec additional testing of urinary organic acids is required to establish the dx

Answer 195

C5-carnitine metabolites, isovalerylglycine, and 3-hydroxyisovaleric acid on analysis or urinary organic acids by gas chromatography-mass spec variants in IVD by molecular genetic testing

Answer 196

single gene sequencing analysis of IVD, then perform gene-targeted del/dup

Answer 197

early onset acute metabolic decomp (within the first two weeks or later in life; vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet), epilepsy, DD, ID and/or impaired cognition, movement disorder, poor weight gain, growth deficiency can present with metabolic decomp before NBS is available more favorable prognosis than other organic acidemias

Answer 198

PV p.Ala311Val commonly identified on NBS and is associated with attenuated IVA either as homozygous or compound homozygous present with mild elevations of C5-Carnitine with normal cognition, no dietary tx or meds, should be protected from overtreatment. If they have prolonged catabolism, tx with IV glucose, rehydrate with normal saline, consider temporary use of carnitine

Answer 199

other organic acidemias, urea cycle disorders, NAGS

Answer 200

consult with metabolic physician and specialist metabolic dietician nutrition/feeding assessment consultation with neurologist developmental assessment consultation with PT, OT, speech

Answer 201

goal is to reduce leucine and enhancing physiologic detox of isovaleryl-coenzyme A reduce total natural protein (leucine) intake conjugation of isovaleryl-coenzyme A using carnitine or combined carnitine and glycine carnitine supplementation glycine supplementation Daily: low leucine diet in infants, protein-controlled diet in adolescents and adults PT

Answer 202

for increased catabolism: temporary stop of protein intake, IV glucose to restore anabolism, normal saline for rehydration consider use of buffers for metabolic acidosis nitrogen scavengers for hyperammonemia

Answer 203

excess dietary protein/protein malnutrition inducing catabolic state prolonged fasting catabolism during illness

Answer 204

results in reduced enzyme activity in the mitochondrial isovaleryl-conenzyme A dehydrogenase and, subsequently, in accumulation of isovaleryl- conenzyme A and its metabolites LOF

Answer 205

based on fluorescent or colorimetric tests for biotinidase activity on dried blood spots confirmational testing requires f/u measurement of biotinidase activity in serum/plasma need to start tx before confirmational testing is done if NBS is +

Answer 206

metabolic ketolactic acidosis organic aciduria (although urinary organic acids can be normal in those who are symptomatic) hyperammonemia (mildly elevated)

Answer 207

detection of deficiency biotinidase enzyme activity in serum/plasma (ACMG established these standards- profound biotinidase deficiency: >10% activity; partial biotinidase deficiency: 10-30% activity) identification of biallelic PVs in BTD

Answer 208

sequence analysis first then del dup analysis for those of Amish ancestry, can start with c.1330G>C (p.Asp444His) and c.1368A>C (p.Gln456His) LOF

Answer 209

*Those who are dx before symptoms and are tx have normal development* symptoms appear between 1wk-10yrs Seizures, hypotonia, ataxia, DD, SNHL in 76%; optic atrophy, scotoma, skin rash, alopecia, recurrent viral or fungal infection, hyperventilation, laryngeal stridor, central apnea

Answer 210

may develop symptoms only when stressed one child had hypotonia, skin rash, and hair loss during a stressful event but symptoms resolved after biotin tx

Answer 211

symptomatic children can experience reversal of all their symptoms with biotin tx biochemical abnormalities and seizures rapidly resolve after biotin tx then improvement of the cutaneous abnormalities hair growth returns optic atrophy and hearing loss may be resistant to therapy some treated children have rapidly achieved developmental milestones normal life span is expected as long as they continue lifelong biotin supplementation

Answer 212

Profound: most PVs cause complete loss or near complete loss of biotinidase enzyme activity, more likely to be deletions, insertions, or nonsense PVs; increased risk for earlier onset of symptoms Partial: those who have one p.Arg444His and one profound allele still have enzymatic function (20-25%); if homozygous, expected to have 45-50% enzyme activity and do NOT require therapy

Answer 213

Generally higher in pops with a high rate of consanguinity (Turkey, Saudi Arabia) Increased in the Hispanic pop

Answer 214

consultation with metabolic physician and specialist metabolic dietician measurement of growth parameters neurologic eval audiologic eval

Answer 215

consultation with metabolic physician and specialist metabolic dietician measurement of growth parameters nutrition/feeding team eval neurologic eval ophthalmologic eval full skin and mucosal exam clinical assessment for breathing issues developmental assessment audiologic eval assess for hx of recurrent viral or fungal infections

Answer 216

Biotin therapy is lifelong should be tx with oral biotin in the free form as opposed to the bound form protein restricted diet not necessary if in metabolic decomp, IV hydration and bicarbonate for acidosis

Answer 217

raw eggs should be avoided bc they contain avidin, an egg white protein that binds biotin, thus decreasing its availability consideration of biotin supplementation for the mother

Answer 218

measuring glutarylcarnitine (C5DC) in dried blood spots (96% sensitivity) requires f/u testing with EITHER urine organic analysis OR quantitative glutaric and 3-OHglutaric acid (preferable)

Answer 219

identification of biallelic PVs in GCDH via single gene testing; sequence analysis generally performed first, then del/dup detection of significantly reduced activity of enzyme glutaryl-CoA dehydrogenase in cultured fibroblasts or leukocytes (shortcomings- difficulty distinguishing from affected individuals, which is particularly true for the dominant negative variant; large blood volumes are required)

Answer 220

if untx, 80-90% of children will experience an acute encephalopathic crisis in the first 2yrs of life disability and mortality are high after acute crises progressive macrocephaly seizures

Answer 221

onset after 6yo chronic headaches, macrocephaly, epilepsy, tremor, dementia frontotemporal hypoplasia, abnormal signal of the white matter chronic kidney dz may occur dystonia due to basal ganglia injury

Answer 222

Most GCDH variants are missense variants two subtypes: high excreters and low excreters high: no or very low glutaryl-CoA dehydrogenase activity (0-3%) sensitivity on NBS is 100% low: up to 30% residual glutaryl-CoA dehydrogenase activity (at least one hypomorphic allele), sensitivity on NBS is 84%

Answer 223

Canavan dz, Leigh syndrome, Isolated methylmalonic acidemia, propionic acidemia

Answer 224

consultation with metabolic physician and specialist metabolic dietician swallow study for gastro/feeding concerns developmental assessment consultation with neurologist consultation with psychologist and/or social worker consultation with PT, OT, and speech therapist

Answer 225

the main goal is to reduce lysine oxidation and enhance physiologic detoxification of glutaryl-CoA low lysine diet carnitine supplementation emergency tx during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts maintenance of adequate trp levels (depletion may cause severe neurologic deficits) referral to neurologist for ongoing dystonic movement disorders

Answer 226

administer high energy fluids, decrease/omit natural protein for 24hrs, increase carnitine supplementation for catabolism can present with myalgia, muscle tenderness, and/or urinary discoloration with increased CK neurologic consultation (may need ASM), MRI of the brain judicious use of IV sodium bicarbonate for metabolic acidosis

Answer 227

excessive dietary protein or protein malnutrition inducing catabolic state prolonged fasting catabolic illness inadequate caloric provision during other stressors, especially when fasting is involved (sx) given increased risk of subdural hemorrhage, avoid or have extreme caution with contact sports and physical activities that involve high risk for minor head injuries

Answer 228

caused by insufficiency or absence of functional glutaryl-CoA dehydrogenase (GCDH); results in accumulation of upstream byproducts accumulation of glutaric acid and 2-OH-glutaric acid causes neurotoxicity results from LOH of GCDH

Answer 229

c.91+5G>T (Ojibway-Cree First Nation founder variant) and others are low excreter phenotype and more difficult to detect conclusively on biochemical testing p.Gly185_ser190del (c.553_570del18) is a suspected dominant negative allele

Biochemical Genetics 1 Flashcards

Aminoacidopathies, urea cycle disorders, and organic acidemias (255 cards)