Biochemical Genetics 2 Flashcards

Question

How is galactokinase deficiency tested for

Answer 1

after positive NBS, GALT enzyme activity measured -- if normal and clinical suspicion is high (GALT level is high but GAL1P levels are normal), galactokinase enzyme assay should be initiated can also do full gene sequencing followed by del/dup, no targeted mutation testing

Answer 2

Generalized: enzyme activity is profoundly decreased in all tissues tested Peripheral: enzyme activity is deficient in RBC and circulating WBCs but normal or near normal in all other tissues Intermediate: enzyme activity is deficient in RBC and circulating WBCs and less than 50% of normal levels in other cells tested

Answer 3

elevated RBC hemolysate gal-1P concentration urinary galactose concentrations high elevated urinary galactitol concentration generalized aminoaciduria normal GALT, GALK, and GALM concentrations

Answer 4

in states in which the NBS program includes measurements of both total galactose and GALT enzyme activity: total galactose is elevated and GALT enzyme activity is normal in states where total galactose is only measured if GALT activity is low, results for NBS will be normal

Answer 5

ONE OR MORE of the following: reduced GALE enzyme activity in RBC as determined by traditional spectrophotometric assay reduced GALE enzyme activity in RBC using liquid chromatography/mass spec GALE enzyme activity can be measured in fibroblasts or lymphoblasts to help distinguish between the generalized, peripheral, and intermediate forms but is not currently offered on a clinical basis

Answer 6

biallelic PVs in GALE sequence analysis of GALE is performed first followed by gene targeted del/dup analysis

Answer 7

hypotonia, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, cataracts, renal dysfunction SNHL, physical and cognitive DD and/or learning difficulties

Answer 8

usually asymptomatic even on a regular milk diet appear to remain asymptomatic even if maintained on a normal milk diet

Answer 9

usually asymptomatic even on a regular milk diet and are only identified through NBS tx by dietary galactose/lactose, at least in infancy, and thus far those who have been followed appear to remain clinically well

Answer 10

neurologic eval, developmental assessment, orthopedics, PT/OT, nutrition and feeding eval, liver function tests, urinalysis, ophthalmologic eval, audiologic eval

Answer 11

GALT deficiency (classic galactosemia, clinical variant galactosemia, duarte variant galactosemia) GALK deficiency

Answer 12

switch from breast milk or milk-based formula to one with trace levels of galactose or lactose; dietary restriction involves continued restriction of dairy products standard tx for contractures/clubfoot feeding therapy for poor weight gain/FTT sx removal of cataracts if they do not resolve with dietary restriction hearing aids for hearing loss those with peripheral GALE deficiency, do not need tx

Answer 13

although biochemical testing to detect carriers is also a possibility, the ranges for control and carrier GALE enzyme activity overlap, thus making molecular genetic testing the preferred method for carrier detection theoretically, prenatal testing can be accomplished via amniocytes/CVS but due to lack of GALE reference range for the relevant sample type, it is not usually done on a clinical basis

Answer 14

GALE catalyzes an essential step in the galactose metabolism converting UDP-galactose to UDP-glucose cataracts associated with epimerase deficiency galactosemia are believed to be caused by galactitol accumulation in the ocular lens LOF

Answer 15

benign condition, usually detected incidentally on NBS fructose in the urine no tx necessary

Answer 16

hypoglycemia lactic acidemia hypophosphatemia hyperuricemia hypermagnesemia hyperalanemia

Answer 17

established in a proband with the following after exposure to fructose, sucrose, sorbitol, and/or sucralose biallelic PVs in ALDOB on molecular genetic testing (sequence analysis first then del/dup) deficient hepatic fructose 1-phosphate aldolase (aldolase B) on liver bx Fructose tolerance testing ("fructose challenge") can be hazardous for dx and should not be used

Answer 18

fructose-1-phosphate aldolase B enzyme assays and fructose assay enzyme panels on frozen liver tissue may be important options while molecular genetic testing is the first line dx test for HFI, assay of aldolase B activity on liver bx is more invasive but more sensitive than molecular genetic testing

Answer 19

nausea, bloating/ascites, vomiting, sweating, abdominal pain, enlarged liver, growth delays, lethargy, seizures, progressive coma, recurrent/profound hypoglycemia, metabolic acidosis, liver dysfunction (hepatomegaly despite fructose restriction, hepatic adenoma and fibrosis), and/or renal insufficiency (proximal tubular dysfunction); coagulopathy acute hypoglycemia which can lead to death; ONE OF THE FEW INBORN ERRORS OF METABOLISM THAT HYPOGLYCEMIA OCCURS IN THE IMMEDIATE STATE AFTER EATING

Answer 20

when dietary fructose, sucrose, sorbitol, and/or sucralose restriction is implemented early in life and adherence is maintained, prognosis for individuals with HFI is excellent

Answer 21

yes, predisposed to gout/crystal arthropathy increases in plasma uric acid concentration in response to fructose ingestion compared to controls

Answer 22

Neonatal hemochromatosis infectious hepatitis, sepsis FAODs Disorders of gluconeogenesis (Fructose 1,6 Bisphosphate deficiency) Organic acidemias Type 1 congenital disorders of glycosylation (HFI causes a secondary disorder of glycosylation)

Answer 23

baseline status by biochemical geneticist dietary management by dietician ophthalmologic involvement assess liver enzymes to assess hepatic involvement assess renal function by measuring related analytes and electrolytes

Answer 24

IV glucose fresh frozen plasma or exchange transfusion for hepatic insufficiency tx of metabolic acidosis immediate and complete elimination of fructose and supplement with glucose, maltose, and cornstarch

Answer 25

dietary restriction of fructose, sucrose, and sorbitol remove sources of fructose to control hepatomegaly and renal involvement ensuring adequate vitamin supplementation in the setting of reduced fruit and vegetable intake is imperative

Answer 26

fructose tolerance testing to dx HFI vaccine for rotavirus vaccine in the US which is routinely administered prior to the discovery of HFI in an infant and contains a high amount of sucrose per dose

Answer 27

aldolase B participates in fructose metabolism, mostly in the liver, renal cortex, and intestinal mucosa normally aldolase B rapidly coverts IV fructose to glucose, resulting in hyperglycemia; fructose may also be converted to lactate, provoking metabolic acidosis LOF of enzyme aldolase B

Answer 28

Turkey, Spain, Central Europe, France, US, Italy

Answer 29

strong clinical suspicion for: hypoglycemia, high anion-gap metabolic acidosis (lactic acidemia with possible elevate lactate:pyruvate ratio, hyperalanemia), ketosis, pseudo-hypertriglycemia, hyperuricemia, increased free FAs in some cases HIGH GLYCEROL 3-PHOSPHATE IS AN IMPORTANT BIOMARKER ON URINE ORGANIC ACID ANALYSIS

Answer 30

identification of biallelic PVs on molecular genetic testing (perform sequence analysis first then gene-targeted del/dup analysis); dels of exons as well as whole gene dels have been reported deficient fructose-1,6-bisphosphatase 1 activity in liver or mononuclear WBCs (while enzymatic activity in leukocytes and liver is very specific, testing is not widely available)

Answer 31

episodic due to lactic acidosis and ketotic hypoglycemia which are often triggered by fasting or febrile infections or increased fructose levels most frequent in early life and subsequently decrease in frequency nearly half present in the first 4d of life with an acute crisis, results from hypoglycemia due to deficient glycogen stores episodes of hyperventilation, apneic spells, seizures, coma, hepatomegaly, hypotonia, transient liver dysfunction, irritability, lethargy, dyspnea in between crises, children are asymptomatic and majority experience normal growth and psychomotor development continued catabolism leads to multiorgan failure (liver, brain, later heart), morbidity/mortality are high, sepsis, blindness, Reye syndrome like presentation have been reported

Answer 32

Hereditary fructose intolerance glycogen storage dz type 1 FAODs mitochondrial respiratory chain disorders and krebs cycle disorders

Answer 33

consultation with metabolic physician and specialist metabolic dietician abdominal u/s, baseline liver function tests, baseline serum lipid panel, baseline serum uric acid to assess for hepatomegaly developmental assessment

Answer 34

restriction of fructose, sucrose, glycerol, and sorbitol increased frequency of carb feedings intake of glucose polymers ketonuria is an early indicator of impending crisis prevent hypoglycemia by slowly absorbed carbs such as uncooked cornstarch at bedtime to prevent nocturnal hypoglycemia

Answer 35

IV glucose for hypoglycemia administer sodium bicarbonate and restrict fructose, glycerol, sucrose, and sorbitol for metabolic acidosis hepatomegaly and elevated transaminases resolve spontaneously

Answer 36

avoid food with fructose, sucrose, glycerol, and/or sorbitol fructose tolerance testing (fructose challenge) can be hazardous and should not be performed

Answer 37

pre pregnancy: prevent hypoglycemia and monitor for early detection pregnancy: close monitoring for hypoglycemia, maintenance of glycemic control by taking uncooked cornstarch at night as needed; increase in dietary intake and glucose monitoring as needed during labor: continuous glycose infusion to remain euglycemia biochemical testing is not a reliable method for prenatal dx as FBP1 enzyme activity has been reported to be low in the human placenta

Answer 38

deficiency impairs glucose production from all gluconeogenic precursors, including dietary fructose LOF of fructose-1,6-bisphosphatase 1 function

Answer 39

hypoglycemia mildly elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) high blood lactate high uric acid hyperlipidemia (triglycerides and cholesterol)

Answer 40

biallelic PVs in G6PC1 (GSD Ia) or SLC37A4 (GSD Ib) on molecular testing deficient hepatic enzyme activity (glucose-g-phosphatase catalytic activity [GSD Ia]) from liver bx; glucose-6-phosphate exchanger activity (GSD Ib) is no longer clinically available

Answer 41

concurrent gene testing of sequence and gene-targeted del/dup analysis of G6PC1 and SLC37A4 Targeted analysis for PVs can be performed FIRST in individuals of AJ or Amish ancestry

Answer 42

sample needs to be frozen liver bx most individuals with GSD Ia will have enzyme activity <10% of normal; in rare individuals with milder clinical manifestations, enzyme activity can be higher MOLECULAR GENETIC TESTING IS INCREASINGLY THE PREFERRED CONFIRMATORY TEST COMPARED TO INVASIVE LIVER BX

Answer 43

poor growth (leading to short stature), hepatomegaly and nephromegaly (due to accumulation of glycogen and fat). lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia, hypoglycemic seizures, doll-like facies, full cheeks, thin extremities, protuberant abdomen, possible splenomegaly during infection IN TYPE 1B, eruptive xanthomas, diarrhea, acquired von Willebrand dz (bleeding tendency, epistaxis, easy bruising)

Answer 44

poor growth and stature in adulthood; frequent fractures and osteopenia are common; delayed puberty (can be normal w tx), some progress to ESKD and need a kidney transplant, gout can develop after puberty due to hyperuricemia, systemic HTN in second decade of life due to kidney dz progression development of hepatic adenomas with more females having them, can turn into hepatocellular carcinoma; pancreatitis due to severe hypertriglyceridemia, variable degrees of gliosis and encephalomalacia in brain, anemia (GSD1A due to hepatic adenoma, GSD1b due to enterocolitis and inflammatory bowel dz), GSD1B assocaited with chronic neutropenia and impaired neutrophil and monocyte function (recurrent infections), polycystic ovaries in some females, thyroid autoimmunity and hypothyroidism caused by abnormal T cell function

Answer 45

In G6PC1 (associated w GSD1A) better improvement of bone mineral density is seen with optimized diet and vitamin D supplementation severe anemia often associated with hepatic adenomas, with kidney failure, persistent, menorrhagia, poor nutrition, and often multifactorial in SLC37A4 (GSD 1b) severe neutropenia and related enterocolitis and intestinal mucosal inflammation may occur leading to severe anemia risk for thyroid autoimmunity and hypothyroidism is increased

Answer 46

AJ (carrier frequency for most common PV (p.Arg83Cys) is 1.4% c.648G>T identified in 88% of affected individuals with Japanese ancestry and c.379_380dupTA in 50% with Hispanic Americans

Answer 47

Fructose-1,6-bisphosphatase deficiency Gaucher dz Niemann-Pick dz type B (chronic visceral ASMD)

Answer 48

conc. of glucose, lactic acid, uric acid, lipids; liver imaging and liver functioning all to asses hepatomegaly measurements of growth and eval of nutritional status measure bone density and serum hydroxyvitamin D for skeletal at 10yo echo, lipid panel with triglycerides for cardio at 10yo kidney function tests neurodevelopmental assessment and assessment for evidence of seizures eval for anemia, platelet aggregation studies, von Willebrand factor and antigen activity CBC to evaluate for neutropenia Assess gastro system for signs of enterocolitis and/or bowel ulcers

Answer 49

includes care from metabolic specialist, metabolic dietician, hepatologist, GI specialist, social worker, GC, and psychologist medical nutrition therapy: uncooked cornstarch (often started between 6mo-1yo, amylase required to digest cornstarch and may not be produce enough until 2yo); meals and snacks q3-4hrs that are rich in complex carbs; nasogastric or gastrostomy tube for continuous feeding; diet with ~60% complex carbs, 10-15% protein, and 25-30% fat that is limited in trans fat and saturated fat; supplementation with calcium and vitamin D, complete multivitamin with minerals (especially iron and zinc) hepatic adenomas tx with surgery, ethanol injections, and radiofrequency ablation. liver transplant considered when those fail or if rr is suspicious of malignant transformation take HMG-CoA reductase inhibitors and fibrate (Lipitor, gemfibrozil) for hyperlipidemia ACE inhibitors to tx renal dz allopurinol to prevent gout, should be discontinued when a women is planning a pregnancy antifibrinolytics and DDAVP for bleeding diathesis human granulocyte colony-stimulating factor (G-CSF) may be helpful preventing infections in those with GSD T1B thyroid hormone supplementation for tx of hypothyroidism Gene therapy are currently being developed

Answer 50

sucrose, galactose, fructose, and products with those ingredients in them, sorbitol combined oral contraception should be avoided due to negative effects on hepatic adenomas progestin-only contraceptives can be considered, but potential to risk low bone mineral density and osteoporosis metformin and lactate containing infusions (Ringer's lactate) amoxicillin/clavulanic acid associated with increased risk of diarrhea glucagon should not be used to tx hypoglycemia bc it is ineffective and may increase the risk of lactic acidosis

Answer 51

avoid low blood glucose and stress importance of monitoring glucose baseline u/s of liver and kidneys prior to pregnancy consider MFM consultation exposure to ACE inhibitors int he second and third trs can cause fetal damage and death high dose allopurinol have been shown to interfere with embryo development in animals lipid lowering drugs may lead to adverse fetal effects and should be avoided

Answer 52

G6PC1 encodes G6Pase, a multicomponent enzyme system localized in the ER, helps catalyze terminal rxn of glucogenolysis and gluconeogenesis in hepatocytes and renal cells SLC37A4 encodes a transporter protein that helps transport G6P into the lumen of the ER expressed ubiquitously in tissues such as liver, kidney, large intestine, small intestine, skeletal muscle, and to a lesser extent the brain and heart, unlike G6Pase LOF

Answer 53

Sensitive analysis of acid alpha-glucosidase (GAA) enzyme activity can be performed on dried blood spots using mass spec confirmation is recommended by molecular testing Countries with NBS for Pompe: Taiwan, Austria, Japan, US (NY, Missouri, Kentucky, Illinois)

Answer 54

deficient GAA enzyme activity elevated creatine kinase in all individuals with infantile onset and some with late onset elevation of urinary glucose (tetrasaccharide)

Answer 55

proband with deficiency of acid alpha glucosidase enzyme biallelic PVs in GAA sequence analysis followed by del dup; pseudodeficiency allele (p.Gly576Ser) which is common in Asian pops, interferes with interpretation of enzyme testing in NBS programs targeted analysis can be performed for the following: AA with IOPD (50-60% have the PV p.Arg854Ter); Chinese with IOPD (40-80% have the PV p.Asp645Glu); Adults with LOPD (50-85% have the PV x.-32-13T>G in the compound heterozygous state Dx of Infantile onset can be established rapidly after + NBS result when physical exam, echo, and elevated CPK support the dx; recommended that dx be confirmed with molecular testing or measurement of GAA in another tissue such as isolated lymphocytes or mixed leukocytes

Answer 56

the lower the activity, the earlier the age of onset of dz complete deficiency of GAA enzyme activity (<1% of normal controls) is associated with infantile onset partial deficiency of GAA (2-40% of normal controls) is associated with late onset

Answer 57

generally recognized at 4mo hypotonia/muscle weakness, cardiomegaly, hepatomegaly, left ventricular hypertrophy, cardiomyopathy, respiratory distress, murmur, macroglossia, feeding difficulties, FTT, absent deep tendon reflexes, normal cognition, SNHL w/out tx, death occurs in the first 2yrs of life from cardiopulmonary insufficiency; death from ventilatory failure typically occurs in childhood

Answer 58

male sex, severity of skeletal muscle weakness, and duration of dz are all risk factors for severe respiratory insufficiency may present from the first decade to as late as the seventh decade can mimic limb-girdle muscular dystrophy progressive proximal muscle weakness, respiratory insufficiency, exercise intolerance, orthopnea, sleep apnea, scoliosis, hepatomegaly, macroglossia, difficulty chewing and swallowing, GI issues, chronic pain, increased respiratory infections, decreased deep tendon reflexes, Gower sign, joint contractures

Answer 59

biallelic PVs that produce no enzyme activity result in infantile onset dz, are likely to have two null variants age of onset and progression are most likely directly proportional to the residual GAA enzyme activity PVs missense and splicing variants may result in either complete or partial absence of GAA enzyme activity

Answer 60

infantile: SMA 1, Danon dz late onset: limb-girdle muscular dystrophy, duchenne-becker muscular dystrophy, GSD V

Answer 61

IOPD Nearly all affected infants have cardiomegaly on chest x-ray majority of affected infants have left ventricular hypertrophy and many have biventricular hypertrophy (EKG) most have varying degrees of respiratory insufficiency yet objective assessment of pulmonary functions in infants is difficult at best evaluate for possible feeding difficulties, assessment of growth is appropriate, all should be eval for GERD baseline hearing eval including tympanometry LOPD baseline radiographic evaluation is indicated but only rarely reveals cardiomegaly recommended Holter monitoring at initial eval affected individuals should be evaluated with formal pulmonary function tests (which show pulmonary insufficiency) assessment of nutritional status is recommended

Answer 62

ERT (Myozyme and Lumizyme) should be initiated as soon as the dx of IOPD or symptomatic Pompe dz is established. Gene therapy is being looked into 24hr Holter monitoring is useful in characterizing the type and severity of rhythm disturbance PT, may need aggressive management for those with contractures of the pelvic girdle in infants and children speech therapy specialized diets and max nutrition with some requiring gastric feedings for IOPD; Those with LOPD often managed on a soft diet respiratory support including CPAP and BiPAP may be required; macroglossia and severe respiratory insufficiency in the infantile form may necessitate tracheostomy

Answer 63

infections need to be aggressively managed, immunizations need to be kept current; anesthesia only when necessary bc reduced cardiovascular return and underlying respiratory insufficiency pose significant risks use of digoxin, ionotropes, diuretics, and afterload-reducing agents may worsen left ventricular outflow obstruction, although they may be indicated in the later stages of the dz hypotension and volume depletion should be avoided

Answer 64

unreliable for carrier determination bc of significant overlap in residual enzyme activity levels between obligate carriers and the general populations

Answer 65

sib pair concordance in IOPD is high in children with null PVs. Age and severity of manifestations in LOPD may vary between affected FMs

Answer 66

high resting serum creatine kinase activity cycle and walking tests are physiological exertion tests to detect the pathognomonic heart rate response of the second wind phenomenon seen in those with GSDV Forearm non-ischemic exercise test detects low values of post-exercise plasma lactate to ammonia ration and has high sensitivity and specificity

Answer 67

sequencing of PYGM (most PVs are detected in sequencing) then del dup myophosphorylase is the muscle isoenzyme of glycogen phosphorylase; qualitative histochemistry or quantitative biochemical analysis in a muscle bx or muscle homogenate is dx (residual activity is virtually undetectable); cannot be done on fetal tissue since this is expressed only in differentiated muscle cells

Answer 68

metabolic myopathy in the first decade of life; ~10% have mild manifestations and remain virtually asymptomatic during daily activities of life, in some instances progressive weakness in the sixth or seventh decade of life exercise intolerance, myalgia, fatigue, are all typically relieved by rest (any skeletal muscle can be affected), difficulty with mastication, dysphagia, oral motor function; rhabdomyolysis and myoglobinuria, hx of dark urine

Answer 69

GSD V relief of myalgia and rapid fatigue after a few minutes of rest due to increased supply of blood-borne glucose and free fatty acids as exercise progresses (aerobic exercise is favored for these individuals)

Answer 70

Physical exam with emphasis on muscle strength/weakness Basal serum CK activity Consultation with genetics

Answer 71

simple healthy lifestyle interventions in diet and regular low impact exercise is the most effective means of preventing and managing exercise intolerance in GSD V Tx that shows some benefit is oral sucrose, carbohydrate-rich diet, ramipril, and low dose creatine

Answer 72

exercises including static muscle contractions, dynamic high-intensity exercises, high involvement of muscle contractions (jumping), very intense dynamic aerobic exercise general anesthetics due to risk of acute muscle damage that may cause muscle ischemia and rhabdomyolysis

Answer 73

lack or deficiency of muscle glycogen phosphorylase, which catalyzes the breakdown of glycogen into glucose-1-phosphate in this tissue LOF; skeletal muscle shows lack or deficiency of glycogen phosphorylase

Answer 74

single most important lab observation is hypoglycorrhachia (reduced CSF glucose concentration)

Answer 75

normal blood glucose concentration with high CSF glucose concentration identification of a heterozygous PV (rarely biallelic PVs) in SLC2A1 by molecular genetic testing single gene analysis followed by del dup if molecular genetic testing does not detect a PV, consider performing erythrocyte glucose uptake assay (abnormally low assay implies abnormality in SLC2A1)

Answer 76

GLUT1 deficiency functional measure of glucose transport across the cell membrane; have abnormal levels that range from 35-75% of controls which confirms the dx viewed as the diagnostic gold standard for this dz

Answer 77

~90% of individuals appear normal at birth, commonly experience infantile-onset epileptic encephalopathy refractory to anticonvulsants and associated with delayed neurologic development; acquired microcephaly, ataxia, dystonia, and spasticity, seizures between 6mo and 1yr often the first indication of brain dysfunction, multifocal spike discharges on EEG, varying degrees of speech and language impairment, varying degrees of cognitive impairment/ID, gait disturbances, diffuse hypometabolism of the cerebral cortex and regional hypometabolism of the cerebellum and thalamus

Answer 78

intermittent ataxia, choreoathetosis, dystonia, alternating hemiplegia, varying degrees of cognitive impairment/ID, varying degrees of speech and language impairment, gait disturbances, diffuse hypometabolism of the cerebral cortex and regional hypometabolism of the cerebellum and thalamus

Answer 79

glucose is the principal fuel source for brain metabolism; the glucose transporter, Glut1, the protein product of SLC2A1, is the fundamental vehicle that facilitates glucose entry into the brain erythrocyte glucose uptake assay is a functional surrogate measure of residual Glut1 transporter function. Absence of Glut1 transporter expression is embryonic lethal

Answer 80

missense variants in mild and moderate cases splice site and nonsense variants and indels and exon deletions occurred almost exclusively with moderate and severe dz complete gene dels cluster in those with severe dz LOF

Answer 81

inherited in an AD manner is complete asymptomatic parent harboring the variant implies a mosaic state

Answer 82

EEG, brain imaging including FDG-PET in selected individuals, neuropsychological assessment

Answer 83

ketogenic diet which provides an alternative fuel for brain metabolism, highly effective in controlling the seizures and improving gait disturbance antiepileptic drugs are generally ineffective alpha-lipoic acid has been shown to facilitate glucose transport in Glut4-dependent cultured skeletal muscle cells L-carnitine supplementation to avoid carnitine deficiency avoidance of carb containing foods, IV fluids, and meds that will interrupt the state of ketosis therapies under investigation: triheptanoin and gene therapy

Answer 84

barbiturates aggravate the Glut1 transport defect in erythrocytes of individuals with Glut1 methylxanthines (caffeine) are known to inhibit transport of glucose by Glut1 clinical consequences of valproic acid cannot be predicted so should be avoided

Answer 85

~10% of individuals have an affected parent, the other 90% represent sporadic cases and have the disorder as the result of de novo PVs in SCL2A1

Answer 86

plays a role in lipid metabolism and intermediary metabolic pathways helps in transporting the LCFAs from the cytoplasm to the mitochondrial matrix more than 95% of the body's carnitine is found in skeletal muscle; liver, heart, and kidneys have the rest

Answer 87

due to a carnitine transport defect of the OCTN2 carnitine transporter system encoded by the SLC22A5 gene (AR) pts may lose up to 95% of the filtered carnitine in the urine. The parents of a child with PCD may lose 2x-3x the levels of normal urinary excretion

Answer 88

if age of onset is bwn 3mo-2yrs hepatic encephalopathy characterized by poor feeding, lethargy, and irritability; hepatomegaly, nonketotic or hypoketotic glycemia, lactic acidosis, hyperammonemia, and elevated hepatic enzymes if age of onset is btwn 2-4yo hypotonia, skeletal muscle weakness, exercise intolerance, episodes of rhabdomyolysis, myoglobinuria, elevated creatine kinase sudden cardiac death remains a risk in adults

Answer 89

low plasma free carnitine levels sequence analysis of SLC22A5 gene followed by aCGH if sequence analysis is not conclusive; if that does not identify PVs, functional assay of the cultured skin fibroblasts is the preferred test

Answer 90

by tandem mass spec, low plasma free carnitine levels are detected in newborns. due to placental transfer of carnitine from the mother to the fetus, low fetal plasma creatinine levels shortly after birth can reflect maternal plasma carnitine levels if NBS is positive, both the baby and mother are re-tested 2wks later to determine who has the PCD

Answer 91

Echo, electrocardiogram, serum creatine kinase, serum transaminases, blood sugar levels lifelong tx with high dose oral L-carnitine acute episodes of hypoglycemia is tx promptly with 10% dextrose and tx of accompanying metabolic abnormalities including immediate carnitine supplementation

Answer 92

hypoketotic hypoglycemia elevated liver enzymes (AST/ALT) hyperammonemia elevated total serum carnitine elevated ratio of free carnitine to acylcarnitine species (C0/C16+C18) elevated C12 dodecanedioic acid on urine organic acids ELEVATION OF TOTAL CARNITINE AND HYPOKETOTIC HYPOGLYCEMIA SHOULD INCREASE SUSPICION FOR CONDITION

Answer 93

sequence analysis of CPT1A is performed first followed by del dup analysis (rarely variants here) targeted analysis may be considered first for the PVs p.Pro479Leu in populations with a very high frequency of the allele (Alaska, Inuit pop, Siberians) OR carnitine palmitoyltransferase 1A deficiency on cultured skin fibroblasts (residual enzyme activity btwn 1-5%)

Answer 94

onset of symptoms is typically rapid fetal CPT1A deficiency has been associated with acute fatty liver of pregnancy typically in the third trimester fasting-induced encephalopathy in early childhood, potentially a fatal presentation can also initially present later in life appear developmentally and cognitively normal unless previous metabolic decomp has resulted in neurologic damage long term liver damage as a result of recurring hepatosteatosis renal tubular acidosis

Answer 95

CPT I is a mito membrane protein that converts long chain fatty acid acyl-CoA molecules to their corresponding acylcarnitine molecules, provides an alternative source of fuel when glycogen reserves are significantly reduced and fuels ketogenesis for metabolism in peripheral tissues that cannot oxidize fatty acids in the reduced activitiy of CPT1 caused by biallelic PVs, FAs cannot enter the mito for energy production; CPT1A is expressed in the liver, kidney, leukocytes, and skin fibroblasts

Answer 96

MCAD deficiency CPT II deficiency VLCAD deficiency

Answer 97

in affected individuals with profound and/or prolonged exposure to hypoglycemia: a complete neurologic eval to detect secondary neurologic damage those who present with acute hypoglycemia, sufficient amounts of IV fluid containing 10% dextrose should be provided as quickly as possible high carb diet (70% of calories) that is low in fat (<20% of calories, 1/3 should be medium chain triglycerides) is recommended, supplementation of essential FAs may be necessary frequent feeding, cornstarch overnight to prevent hypoglycemia

Answer 98

prolonged fasting especially during febrile or gastro illness potentially hepatotoxic agents such as valproate and salicylate should be avoided

Answer 99

primarily based on quantification of acylcarnitine levels (C14:1, C14:2, C14, C12:1) and their ratios C14:1 level > 1umol/L on NBS very strongly suggests dx; those with a level >0.8umol/L suggests the dx although this can also occur in carriers and some healthy individuals with no PV ACADVL PVs a significant number of individuals with an abnormal NBS have one PV are are likely carriers who have been detected bc of the low specificity of the initial NBS acylcarnitine screening assay

Answer 100

Admission to the hospital, fluid resuscitation, infusion of IV glucose, nutritional eval, institution of enteral nutrition with supplementation of medium chain fat, cardiac eval

Answer 101

single gene testing with sequence analysis first and del dup second (only one reported variant) in ACAVDL analysis of FA beta oxidation in cultured fibroblasts: typically accumulate excess tetradecanoyl (C14) carnitine, whereas individuals with less severe phenotypes may shift accumulation toward dodecanoyl (C12) carnitine analysis of VLCAD enzyme activity: measurement in leukocytes, cultured fibroblasts, liver, heart, skeletal muscle, or amniocytes by the electron transfer flavoprotein or ferricenium reduction assay can be used to confirm the dx

Answer 102

most individuals identified by NBS are asymptomatic 1. severe early onset cardiac and multiorgan failure form presents in the first months of life with HCM or DCM, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. Cardiomyopathy and arrythmias are often lethal 2. hepatic or hypoketotic hypoglycemic form presents during early childhood with hypoketotic hypoglycemia without cardiomyopathy, poor feeding in newborn period 3. late onset myopathic form most common phenotype, presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps, and/or pain and/or exercise intolerance

Answer 103

severe dz associated with no residual enzyme activity, often resulting from null variants. ~81 are truncating variants specific homozygous missense PV p.Cys237Arg is associated with cardiac dz common p.Val283Ala variant is typically associated with the non-cardiac phenotypes

Answer 104

MCAD deficiency like the hepatic hypoglycemic form Intermittent rhabdomyolysis like McArdle Dz

Answer 105

fasting precautions should begin immediately, breast milk without supplemental medium chain triglycerides can continue as long as fasting precautions are taken consultation with metabolic physician/specialist metabolic dietician baseline lab studies: serum creatine kinase concentrations, liver transaminases, blood glucose concentrations electrocardiogram: assess for arrythmias echo: assess for cardiomyopathy and cardiac dysfunction nutrition/ feeding team eval

Answer 106

consultation with metabolic physician and specialist metabolic dietician baseline lab studies: serum creatine kinase and liver transaminases physical exam of abdomen to assess for hepatomegaly developmental assessment

Answer 107

use of IV glucose, monitor for cardiac rhythm disturbance, monitor rhabdomyolysis, avoid triggers (fasting, long chain fats, irritation of the myocardium cardiac dysfunction may be reversible with early, intensive supportive care and diet modification Triheptanoin (C7): an odd medium chain FA that can correct the secondary depletion of TCA cycle intermediates occurring in these disorders restriction of LCFAs, frequent feeding and prevention of catabolism from overnight fasting, avoidance of severe exercise in older persons, supplement with L carnitine for secondary carnitine deficiency speech/PT/rehab therapy for speech/gross motor delays

Answer 108

administer high-energy fluids w electrolytes to decrease catabolism from a stressor standard tx for cardiomyopathy/cardiac failure ample hydration and alkalization of urine for rhabdomyolysis

Answer 109

fasting, myocardial irritation, dehydration, high-fat diet (long-chain fats) including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, volatile anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate

Answer 110

placental and fetal beta oxidation may temporize or improve maternal FA beta oxidation but labor and postpartum period are catabolic states and place the mother at higher risk for rhabdomyolysis and subsequent myoglobinuria monitor labs: plasma carnitine panel, creatine kinase level, plasma acylcarnitine profile, RBC or plasma essential fatty acids, vitamins A, D, and E, CBC, ferritin level, comprehensive metabolic panel cardiomyopathy: echo and assessment by cardio/MFM

Answer 111

VLCAD is a homodimer associated with the inner mito matrix; controls a critical point in the supply of electrons to the respiratory chain, and also provides a pathway permissive to the production of ketones LOF

Answer 112

based on the results of a quantitative acylcarnitine profile on dried blood spot cards elevations of C8-acylcarnitine with lesser elevations of C6- and C10-acylcarnitine values above the cutoff reported by the screening lab are considered positive f/u testing include plasma acylcarnitine analysis, urine organic acid analysis, and urine acylglycine analysis PPV is currently considered to be very high for tandem mass spec, although false negatives have been reported in newborns with low free carnitine levels A NEWBORN WHOSE BLOOD SAMPLE HAS BEEN SUBMITTED FOR NBS MAY BECOME SYMPTOMATIC BEFORE THE SCREENING RESULTS ARE AVAILABLE. SEVERE LETHAL PRESENTATIONS IN THE FIRST WK OF LIFE HAVE BEEN REPORTED

Answer 113

plasma acylcarnitine analysis (characterized by the prominent accumulation of C8- with lesser elevations of C6-, C10-, and C10:1- acylcarnitines; decreased levels of free carnitine and acetylcarnitine may be seen with carnitine deficiency) urine organic acid analysis: medium-chain dicarboxylic acids are elevated with characteristic pattern- hexanoylglycine > octanoylglycine> decanoylglycine- while ketones are inappropriately low; during acute episodes, suberylglycine and dicarboxylic acids may be elevated urine acylglycine analysis will detect urinary n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine. More sensitive and specific for the identification of asymptomatic individuals and those with mild or intermittent biochemical phenotypes that may be missed by organic acid analysis alone

Answer 114

sequence analysis of ACADM followed by del/dup analysis targeted analysis for common northern European PVs may be performed first in those with northern European backgrounds OR those with Japanese backgrounds of which certain variants account for ~60% of alleles examined in the Japanese pop

Answer 115

analysis of FA beta oxidation in cultured fibroblasts involves acylcarnitine analysis accumulation of C6- C10 acylcarnitines as described for plasma analysis confirms the dx noninvasive testing using palmitate in individuals with suspected FAODs

Answer 116

collect postmortem blood and bile spots on filter paper cards of the type used for NBS for subsequent acylcarnitine analysis

Answer 117

A KNOWN CAUSE OF SIDS appear normal at birth and historically have presented between the age 3-24mo hypoketotic hypoglycemia may begin with or accompanied by seizures; metabolic stress can lead to vomiting and lethargy, quickly progressing to coma and death hepatomegaly, increased anion gap, hyperuricemia, elevated liver transaminases, and hyperammonemia sudden and expected death was historically common as the first manifestation of MCAD deficiency; early death before the return of NBS results still occurs cerebral edema, fatty infiltration of the liver, kidneys, and heart loss of developmental milestones, acquired aphasia, ADHD, chronic muscle weakness, fatigue, muscle pain, and reduced exercise tolerance, risk for obesity, prolongation of the QTc interval, chronic kidney dz

Answer 118

disorder of mitochondrial fatty acid B oxidation medium and short chain fatty acids passively diffuse across the mito membrane independent of carnitine transport and are activated to CoA esters in the mitochondrial matrix impairs the energy supply to peripheral tissues through ketogenesis and increases glucose dependency and utilization; results in hypoketotic hypoglycemia, metabolic acidosis, liver dz, and lethargy, which progresses to coma and death when glycogen stores are depleted LOF

Answer 119

most individuals are compound heterozygous for the c.985A>G PV and another deletion or PV or homozygous for the above variant individuals homozygous for the common variant above had the highest C8 NBS values and were most likely to have neonatal symptoms individuals who are compound heterozygotes for the above variant and c.600-18G>A have a mild phenotype and may not be detected by NBS due to residual MCAD enzyme activity

Answer 120

SCAD deficiency VLCAD deficiency LCHAD deficiency and TFP deficiency systemic primary carnitine deficiency CPT1A deficiency

Answer 121

plasma acylcarnitine analysis, plasma free and total carnitine levels, urine acylglycine analysis, urine organic acid analysis, consultation w genetics

Answer 122

blood glucose concentration, liver function tests, blood gas analysis, ammonia, lactic acid, CBC w differential, electrolytes, and blood cultures (in case of fever)

Answer 123

most impt: reversal of catabolism and prevention of hypoglycemia by providing simple carbs by mouth or IV fluids if the individual is unable to receive sufficient oral intake to maintain anabolism; IV administration of glucose should be initiated immediately followed by 10% dextrose with appropriate electrolytes infants require feeding q2-3hrs; overnight feeds, a bedtime snack, or uncooked cornstarch to ensure sufficient glucose supply; normal healthy diet containing no more than 30% of total energy from fat may be followed; overfeeding should be avoided bc of the risk for obesity low dose L-carnitine supplementation when free carnitine levels are below the normal range

Answer 124

hypoglycemia should be avoided to prevent catabolism high-fat/low-carb diets alcohol consumption (particularly binge drinking) elicits metabolic decomp aspirin exacerbates MCAD deficiency

Answer 125

presence of increased butyrylcarnitine (C4) concentrations in the plasma and/or increased ethylmalonic acid (EMA) concentrations in urine UNDER NON-STRESSED CONDITIONS biallelic PVs in ACADS

Answer 126

primarily based on acylcarnitine analysis by tandem mass spec to detect elevated blood C4 (butyrylcarnitine)

Answer 127

acylcarnitine profile testing is used to confirm C4 elevations urine acylglycines detect elevated ethylmalonic acid as confirmatory testing for NBS or dx testing urine organic acids detect EMA and dicarboxylic acid 2 common variants can lead to a biochemical phenotype but are not clinically relevant

Answer 128

perform sequence analysis first then del dup (no dels or complex arrangements have been reported) c.511C>T and c.625G>A result in biochemical abnormality when in trans with a PV but is not associated with clinical manifestations of SCADD

Answer 129

severe dysmorphic facial features, feeding difficulties/FTT, metabolic acidosis, ketotic hypoglycemia, lethargy, DD, seizures, hypotonia, dystonia, and myopathy also reported in individuals with no symptoms

Answer 130

no need for tx since it is viewed more as a biochemical phenotype and less of a dz avoid fasting longer than 12 hrs and an age appropriate heart-healthy diet

Answer 131

PGT/prenatal testing is unnecessary and not recommended due to generally benign phenotype

Answer 132

most individuals do not present with the classic picture of metabolic acidosis and hypoketotic hypoglycemia characteristic of FAODs most PVs are missense that lead to protein misfolding which has been postulated to cause pathologic cellular effects of SCAD

Answer 133

primarily based on quantification of the analyte 3-hydroxypalmitoyl carnitine (C16-OH) and 3-hydroxyoleoylcarnitine (C18:1-OH) on dried blood spots (above the cutoff is considered + and need f/u plasma acylcarnitine and urine organic acid profiles medical interventions need to begin immediately

Answer 134

elevation of 3-hydroxy derivatives of C16, C18, and C18:1 is highly suggestive elevations of 3-hydroxy-dicarboxylic acids and lactic acid

Answer 135

LCHAD deficiency: elevation of long-chain 3-hydroxyacylcarnitine species in plasma and/or increased excretion of 3-hydroxy-dicarboxylic acids in urine in combo with biallelic PVs in HADHA; distinguishing requires identification of isolated long chain 3 hydroxyacyl-CoA dehydrogenase deficiency on enzymatic assay in lymphocytes or skin fibroblasts TFP deficiency: same as above in addition to biallelic PVs in HADHA and/or HADHB and requires identification of deficient in all three TFP enzymatic activities in lymphocytes or skin fibroblasts an in vitro probe analysis on skin fibroblasts can be assayed for acylcarnitine after 96hrs of incubation: there is substantial accumulation of C16-OH for those with the conditon

Answer 136

perform sequence analysis of HADHA first, perform gene targeted del/dup analysis; if HADHA testing is negative, perform sequence analysis of HADHB then del/dup analysis LOF

Answer 137

dilated cardiomyopathy (seen in those with severe neonatal presentation), hypoketotic hypoglycemia, liver dysfunction, liver failure, cardiomyopathy, hypotonia, muscle weakness, exercise intolerance, episodic muscle pain and myoglobinuria, peripheral neuropathy, retinopathy resulting in vision loss

Answer 138

the severe/cardiac presentation is more common in individuals with TFP deficiency than those w LCHAD encephalopathy, hypoketotic hypoglycemia, hepatomegaly, hepatosteatosis, lactic acidosis, liver failure, lethargy, poor feeding, seizures, apnea, coma, progressive dilated cardiomyopathy

Answer 139

the intermediate/hepatic presentation most common presentation in LCHAD deficiency and relatively uncommon in TFP deficiency vomiting, lethargy, poor feeding, hepatomegaly, muscle weakness, hypotonia, long QT intervals, DD, FTT

Answer 140

the mild/neuromyopathic presentation typical of mild TFP deficiency and rare in LCHAD muscle weakness, exercise intolerance, hypotonia, episodic rhabdomyolysis, diffuse muscle pain, profound weakness, myoglobinuria, and elevations of serum CK, peripheral neuropathy

Answer 141

peripheral neuropathy is a unique long term complication, age of onset ranges from infancy to adulthood, progressive and sensorimotor in nature retinopathy is more common in those with LCHAD than those with TFP; progressive and correlates with dz severity

Answer 142

HELLP syndrome and acute fatty liver of pregnancy are seen in about 15-25% of pregnancies in women carrying a fetus affected with LCHAD/TFP

Answer 143

homozygous c.1528G>C variants are associated with LCHAD. Most with LCHAD will have at least one allele with this variant. Few individuals who were compound hetero for this variant and another PV in HADHA were reported to have TFP deficiency; enzyme assay is needed to distinguish btwn these conditions individuals with HADHB missense PVs present with milder phenotypes than those with premature termination or frameshift variants. ~ 1/2 with HADHA PVs present with a severe/lethal phenotype, while ~70% of individuals with HADHB PVs have a milder phenotype

Answer 144

MCAD VLCAD CPT1A deficiency

Answer 145

consult with metabolic physician/specialist metabolic dietician analysis for metabolic decomp surveillance: Blood gas, ammonia, lactic acid, glucose, liver transaminases, electrolytes with bicarbonate, BUN, creatinine, CK, CBC w differential, plasma and total free carnitine, plasma acylcarnitine profile, urine organic acids, consider cardio consult and echo, consider neuro consult, consider ophthalmology consult, development assessment

Answer 146

avoidance of fasting, MCT supplementation (low fat diet (30%) of which 7-15% are from long chain fast and 15-25% are from MCT, triheptanoin to tx long chain FAODs L carnitine for secondary carnitine deficiency feeding therapy for FTT/poor weight gain developmental specialist as needed cardiac and neurologist interventions as needed for cardiac dysfunction and peripheral neuropathy, interventions per ophthalmologist

Answer 147

IV fluid w high dextrose to maintain blood glucose for hypoglycemia initiate bicarbonate therapy for severe metabolic acidosis hyperammonemia self resolves with reversal of catabolism start IV fluid with dextrose and electrolytes for rhabdo manage cardiac failure due to cardiomyopathy in collab with cardiologist

Answer 148

fasting, inadequate caloric provision during stressors, inadequate calories following vaccination (vaccination is safe), dehydration, high-fat diet, administer IV intralipids during an acute metabolic crisis (propofol, etomidate)

Answer 149

significant intrafamilial clinical variability may be observed between sibs who inherit the same biallelic HADHA or HADHB PVs; variability stems primarily from diet and severity of infection triggering metabolic decomp

Biochemical Genetics 2 Flashcards

Carbohydrate metabolism and Fatty acid oxidation disorders