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FP_23_S3 > Methabolics > Flashcards

Methabolics Flashcards

1
Q

what are the 9 conditions tested for in NBS- which are genetic and which are metabolic?

A

genetic- sickle cell disease- CF- congenital hypothyroidism- phenylketonuriainborn errors of metablismMCADD medium chain acyl-coA dehydrogenaseIsovaleric acidemiaglutaric acidemia type 1maple syrup urine diseasehomocystinuriapredominantly treated by long term dietary management to prevent toxic build up of causative metabolite- due to deficiency in metabolism and toxic build-up

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2
Q

what is the phenotype in PKU?

A

results in severe MRgrowth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment.

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3
Q

what is the cause of PKU

A

AR genetic disease due to mutation in the DAH genephenyalanine dehydrogenase which converts phenylalanine to tyrosine resulting in a toxic build-up especially in the brain

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4
Q

how is PKU tested for?

A

NBS detects increased phenylalanine in the blood by tandem MS

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5
Q

How is PKU treated?

A

patients are put on a low phenylalanine diet which significatly reduces the risk of neurologic handicap but if diagnosed too late there may be no benefit as damage has already been done

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6
Q

what are the feature of congenital hypothyroidism

A

failure to thrive and don’r grow properlyphysical and mental handicapneonates may have a protuding tongue, jaundice, feeding difficulties and low hairline

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7
Q

The Hardy–Weinberg principle relies on a number of assumptions:

A

The Hardy–Weinberg principle relies on a number of assumptions: (1) random mating (i.e, population structure is absent and matings occur in proportion to genotype frequencies), (2) the absence of natural selection, (3) a very large population size (i.e., genetic drift is negligible), (4) no gene flow or migration, (5) no mutation, and (6) the locus is autosomal. When these assumptions are violated, departures from Hardy–Weinberg proportions can result.

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8
Q

what causes congenital hypothyroidism?

A

primary- agenesis or dysgenesis of the thyroid glandsecondary- deficient levels of TSHgenetically heterogeneous and associated win mutations in multiple gene - e.g. thyroid transcription factors

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9
Q

how is congenital hypothryoidism treated?

A

thyroxine supplementation

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10
Q

How CH screened for?

A

increased level of TSH- produced as abn thyrpid gland is not responding

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11
Q

what are the features of MCADD?

A

deficiency in fat metabolism and can result in death

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12
Q

what causes MCADD?

A

AR mutations in ADADM = build up medium chain fatty acids (C8) which the body can’t efficiently uses for gluconeogenesis resulting in low energy availability especially for the brain

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13
Q

How is MCADD screened for?

A

tandem mass spec for levels of medium chain FA C8 compared to C10

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14
Q

what is the treatment for MCADD?

A

dietry intervention- regularly eat to prevent need for gluconeogenesis

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15
Q

what are the features of sickle cell disease?

A

AR disease with het advantage so has high carrier freq in regions of world affected by malaria e.g. Africain hom form RBCs are sickle shaped and cannot flexibly bend to fit through small capillaries resulting in damage to blood vessels and organs, chronic pain ans infection

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16
Q

How is sickle cell disease screened for?

A

by seperating HB protein by isoelctric focusing or high performance liquid chromatography- abn Hb protein will have a different mass charge ration (IEF) or elution time (HPLC)genetic testing can also be carried out for to allow family testingother clinically significant heamoglobinopathies are also screened for

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17
Q

what causes CF?

A

mutation in the CFTR gene

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18
Q

How CF screened for ?

A

uses combination of genetic testing and IRT-IRT has a poor PPV on its onwn and is raised imediately after birth in all so need to wait till day 5 to test- genetic testing alone with a panel would identify a high number of carriers which should be avioded in prenatal testing1. test for IRT - if raised test, re assay then for 4 most common CF mutations- CF confirmed - no more testing- carrier- test with full CF panel and may need to IRT again if still not second mut detected- no mutation - IRT again

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19
Q

what are the features of CF?

A

mutlisystem disorder affecting- GI tract- fertility - BAVD- respiratory tract- recurrent infections, disseminated bronchiecstasis- failure to thrive- pancreatitis

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20
Q

How can CF be treated?

A

early intervention with high energy diet, medicine and physiotherapy does not cure but improves symptoms and outcomes

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21
Q

what are the features of maple syrup urine disease?

A

urine smells of maple syrupvomitinglethargyprogressive neurologic deteriorationdue to defect in keto acid dehydrogenase resulting in build up of leucine, iso-leucine and valine

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22
Q

how is maple syrup urine disease tested for?

A

tandem mass spec for leucine. iso-leucine and valine

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23
Q

what is the treatment for maple syrup urine disease?

A

low protein diet to prevent build up of amino acid and thiamineearly intervention prevents neurologic damage

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24
Q

what are the causes and features of homocystinuria?

A

AR didease due to mutation in cystathione b-synthase = catabolism of methionine and toxic accumulation of homocyteineresults in skeletal abn and LD

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25
Q

How is homocystinuria tested for?

A

tandem MS for undeviated MRM methionine

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26
Q

How is homocystinuria treated?

A

very low methionie diet and supplmetation - without treatment patients die before 30yrs

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27
Q

what are the causes and features of Glutaric acidemia type 1?

A

accumulation of glutyaric acid due to deficiency in glutaryl co-a dehydrogenasemacrocephaly and metabolic and neurologic crisis

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28
Q

How is Glutaric acidemia type 1 screened for?

A

Tandem mass spec for glutaryl carnitine

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29
Q

How is Glutaric acidemia type 1 treated?

A

low protein lysine restricted diet with carnitine supplementation

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30
Q

How is isovaleric acidemia tested for?

A

Tandem mass spec for isovalerylcarnitineconfirmed by analysis of urine organic acids

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31
Q

what are the causes and features isovaleric acidemia?

A

defective catabolism of leucine results in toxic accumulation of isovaleric acid and its glycine and carnitine derivativesvomiting, metabolic crisis, failure to thrive, coma and even NND

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32
Q

How is isovaleric acidemia treated?

A

long term dietary management

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33
Q

what are the features of inborn errors of metabolism?

A

Due to defects in metabolic pathwaysclassical symptoms are either due to an accumulation of a substrate which toxic to the body or a deficiency in a productgenerally AR or XLR

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34
Q

what are the presenting features if IEM?

A

Multisystem disorder can present with:failure to thrive and wight lossvomiting and lethargycytopeniaheart failureimmunodeficiencyhypotoniaNDD, seizure and strokeorganomeglay

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35
Q

How are IEM treated?

A

dietary restriction/management for disorders resulting from a toxic accumulation of products and supplementation for deficiency’s

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36
Q

what IEMs are tested for in the NBS programme?

A

medium chain acyl-coA dehydrogenase deficiencyhomocystinuriaglutaric acidemiaisovaleric acidemiamaple syrup urine diseasephnyketonuria

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37
Q

How are IEMs diagnosed?

A

traditionally tested for biochemically but this can be non specific e.g. czellweger syndrome can be cuased by multiple peroxisomal storage disordersbiochemical testing may also require invasive testing e.g. liver biopsy for glycogen storage disordersso genetic testing is also carried out as this can:- be used to identify carriers and inform prenatal testing or reproductive descisions- can help indicate mutation specific therpay e.g. PTC read through- provide prognostic information- provide specific diagnosis

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38
Q

what type of IEM is zellweger syndrome?

A

disorder of peroxisome biogenesis cause by multiple PEX gene and 3 different types

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39
Q

what is the phenotype, inheritance and testing for zellweger syndrome?

A

severe and can result in death < 1 yr- affects development, hearing, eyes and liverARbiochemical test is for very long chain fatty acids

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40
Q

Give an example of a urea cycle deficiency disorder?, the gene and testing

A

ornithine transcarbamylase deficiencydue to mutations in the OTC genecan test for decreased OTC enzyme deficiency

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41
Q

what is the role of the urea cycle and hence symptoms of ornithine transcarbamylase deficiency?

A

urea cycle is the primary mechanism for removing waste nitrogen from protein turn over and metabolising nitrogenous compoundsdeficiency result in hyperammonemia

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42
Q

Give an example of a disorder of cholesterol biosynthesis?

A

Semi-lemli-Opitz syndromedue to a deficiency in 7DHC7-dehydrocholesterol reductase

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43
Q

Give an example of a glycogen storage disorder

A

Pompe disease type IIhypotonia, cardiomegaly, FTT, respiratory distress and hearing loss

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44
Q

what causes Pompe disease?

A

deficiency in GAA enzymeacid gucosidase- essential for dregredation of glycogen to glucose in lysosomes and enzyme deficiency is biochemically diagnostic

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45
Q

what are lysosome storage disorders?

A

IEM due to the toxic build up of material in cells due to enzyme deficiencies so lysosomes cannot perform their normal functionsdue to mutations in emzymes that act in the lysosomes or transporters

46
Q

what is the role of the lysosome?

A

cellular membrane bound protein with an acidic content due to a H+ pump- usually function to digest materials and symptoms arise from the build up of partially degraded substances in the lysosomes

47
Q

what are the 3 main groups of lysosomal storage disorder and what material is accumulated?

A

mucopolysacharidoses- build up of glycosaminoglycansoligosaccharidoses- build up of oligosaccharidessphingolipodoses- build up of sphingolipids

48
Q

what are the genetic features of lysosomal storage disorders?

A

AR or XLRLOF mutationsincreased risk of neurodegenerative disorders in carries (alzheimers and parkinsons reported)

49
Q

is there NBS for lysosomal disorders?

A

Being considered as there is a better outcome if treatment started early- screening offered in Israel for Tay sachs- taiwan tests for Pompe and Fabrys

50
Q

what are sphingolipidoses?

A

disorder of lipid storagemutations in enzymes that break down sphingolipids - important for the CNS and form part of the myelin sheath

51
Q

Give an exmaple of 3 sphingolipidoses and the inheritance

A

Fabrys- X linkedGaucher - ARNiemann Pick - AR

52
Q

What are the mucopolysaccharidoses?

A

result in an accumulation of glycosaminoglycans which are very long chain fatty acidsdue to a deficiency in the enzymes required to break them down

53
Q

what are the common phenotypes of mucopolysaccharidoses?

A

affects skeletal muscle and cause neuronal dysfunction

54
Q

Give an example of 3 mucopolysaccharidosis (MPS) disorders

A

MPS II Hunter syndromeMPS III San Fillipo syndromeMPS IV Morquio syndrome

55
Q

What are the oligosaccharidoses?

A

glycogen storage disordersdue to a deficiency in enzymes required to degrade olligosaccharides into gycoproteins and glycolipids

56
Q

What are the clinical features of oligosaccharidoses?

A

affects skeletal muscle and cause neuronal dysfunction

57
Q

Give an example of 2 oligosaccharidoses

A

Pompe diseaseBattens disease (neuronal ceroid lipofuscinoses)

58
Q

what genes are affected in the hemoglobinopathies?

A

cause by pathogenic variants in the genes that encode the globin genes

59
Q

what are the genes for hemoglobin alpha and beta?

A

HB alpha is encoded by HBA1 and HBA2found on chr 16 in 2 4kb gene clustershave high sequence homology1 HBB gene on 11p

60
Q

what is the role of hemoglobin in the cell?

A

fe containing O2 transport metalloprotein in the red blood cells of vertebrates

61
Q

what is the pathogenic of the hemoglobinopathies?

A

pathogenic variants result in reduced synthesis of the hB or an abnormal Hb structure.this causes disease in the thalassemias but resulting in a chain imbalance between HBA and HBBexcess of a subunit rather than a lack of expression causes the clinical consequences in thalassemia

62
Q

how common are hemoglobinopathies? why

A

have a heterozygote advantage and protect against severe malaria in childhoodtherefore there are high levels in areas affected by Malaria e.g. Mediterranean (cyprus, turkey), middle East, Africa and Asia.there are also regionally specific disorders and therefore ethnic origin may point to a diagnosis

63
Q

what is a-thalassemia?

A

most common hemoglobinopathydue to mutation in one of the HBA genes (HBA1/2)defecit in a chain production results in an imbalance with B chain formation

64
Q

what are the genetic causes of a thalassemia?

A

deletion of 1 or both HBA genes accounts for 90%- most commonly sue to unequal corssing over betweeen the HBAS clusters on 2 chromosome 16’s due to the high sequence homologyremaining 10% are point mutations spread throughout the gene

65
Q

what is the phenotype genotype relationship in a thalassemia

A

the more copies of HBA that a missing the more severe the phenotype

66
Q

how many a thalassemia syndromes are there- what is the severity

A

type 1 have loss of 1 gene- symptomless carriertype 2- loss of 2 genes- asymptomatic but may have macrocytic anemia on examinationtype 3 - loss of 3 genes = affected with anemia, hemolysis and splenomegaly- may require blood transfusions- lack of HBA results in abn b-globin tetramers being formedtype 4- loss of all 4 genes- severe and onset in utero, results in still birth of early NND- early diagnosis may enable blood transfusion in utero but likely to still have abn- associated with rec misc- fetal form as HBA is expressed in the fetus

67
Q

what causes B- thalassemia?

A

due to a deficiency in B globin and there is a reduction in adult Hb in red blood cellsexpression begins at birth when fetal gamme globin declines so not associated with fetal onset as with HBA type 4

68
Q

what is b- thalassemia major

A

results in anemia and hepatosplenomegalyonset from 6 months and blood transfusions from 2 yrsmost severe formcan be treated with regular blood transfusion but risk of fe overload so also need to prescribe fe chelators to overcome this

69
Q

what is b- thalassemia intemedia

A

mild to mod anemiagenerally normal life but may need occasional blood transfusions

70
Q

what can modify the severity of b- thalassemia

A

due to imbalance in a and b chainsso severity can be reduced with co-inheritance with A-thal- variants that sustain gamma globin levels also decrease severity

71
Q

what is sickle cell disease and what is it caused by?

A

AR disorder due to mutations in HBSmost commonly homozygosity ofr c.20A>T Glu7Valresults in RBCs with an abnormal rigid ‘sickle’ shape- means they cant pass through small capillaries resulting in vascular occlusion = sickle crisis- bone and joint pain and necrosis- organ damage- anaemia- risk of infection- stroke

72
Q

How are hemoglobinopathies tested for?

A

full blood countHb pattern analysis using isolectric focusing, HLPC or capilliary electrophoresisDNA testing is used to confirm the mutation so carrier testing and prenatal diagnosis can be offered.

73
Q

what is the NHS sickle cell screening programme?

A

offers screening to all mothers as part of the antenatal care- if mother is a carrier the father is also offered testing- all pregnant women offered in high prevelance areas but in low prevelance areas only women identified as being at risk from a family origin questionnaire are tested- aim is to offer all women testing by 10 weeks gestation and to report result by 13 weeks to allow pregnancy decision making- involvement of genetic testing depends on the prev hem lab result and as a screening service is will not detect all possible deleterious outcomes.

74
Q

How can hemoglobinopathies be treated?

A

blood transfusion with concurrent fe chelationBM transplant for severe cases but risk of GVHDresearch currently looking into using lentiviral vectors (as they can carry large transgenes and infect quiescent cells) for gene therapy.- phase 1 trials are ongoing for SCD gene therapies

75
Q

what are the features of bleeding disorders?

A

due to an inability to from blood clots - result in excessive bleeding, oozing or re-initiation of bleeding, easy bruising.caused by a deficiency in platelets or clotting factors

76
Q

what is von willebrand disease and the causative gene?

A

VWF is a bleeding disorder caused by mutation in the VWF gene at 2p13

77
Q

what is the role of VWF

A

is essential for platelet depending homeostasis and carries factor VII (F8) protecting it from degredation to sites of vascular damage

78
Q

what are the 3 types of VWF and their inheritance?

A

Type 1 - partial quantitative deficiency in VWF- most mild disease and genetic testing is not generally indicated- AR or ADType 2 is a qualitative deficiecy with high penetrance and can be AR or ADType 3 is most severe and is a complete quantitative deficiency due to 2 null mutatnts- AR- genetic testing indicated and prenatal testing can be offered

79
Q

what complicates genetic analysis of the VWF gene?

A

it is a very large gene and there is a highly homologous PVWF psuedoegen

80
Q

what is the deficiency in heamophilia A, what is the inheritance and incidence?

A

Due to a deficiency in F8 Xq28XLRmore common than hemophilia B 1 in 5000

81
Q

how is hemophilia A diagnosed?

A

severity is defined by the plasma activity of the F8 coagulation factorgenetic testing first looks for a intron 22 or intron 1 inversion as this accounts for >50% of cases- intron 22 tested for by inverse PCR with primers designed to only produce a product when the inversion is presentnegative cases have further mutation screening by sequencing and MLPA

82
Q

what are the clinical features of hemophilia ?

A

decrease in clotting activity =joint and muscle bleeds, easy bruisingrecurrent bleeding in joints causes synovitisleading cause of death in hemorrhage in the CNSfemale carried are generally asymptomatic but may show mild features due to skewed X intactivation. Homozygous females are rare but present with the same features as males

83
Q

what is the deficiency in hemophilia B, inheritance and incidence?

A

deficiency in F9 xq27XLRless common than HA - 1 in 30,000

84
Q

what are inherited thrombophilias associated with?

A

increased risk of venous or arteriol thrombosisthrombosis is a predisposition to from blood clots inappropriately

85
Q

give 2 examples of inherited thrombophilias?

A

Factor V leiden thrombophiliaHereditaty antithrombin deficiency

86
Q

Give 3 examples of bleeding disorder?

A

Von Willebrand diseasehemophilia Ahemophilia B

87
Q

what are the clinical features of factor V leiden thrombophilia?

A

thrombosischaracterised by a poor anticoagulant response to activated protein Cusually no thrombotic event until adult and some may never develop one

88
Q

what causes factor V leiden thrombophilia

A

due to mutation in the Fv gene on 1q24FV is a glycorpotein made in the liver. In response to injury it is activated and acts with other factors to from a complex which converts inactive prothombin to active thrombin = blood clotsmutations result in 10x slower inactivation so there is excessive thrombin production and risk of abnormal clotting

89
Q

what is hereditary antithrombin deficiency

A

AD disorder resulting in increased risk of blood clotstypically DVT and pulmonary embolism

90
Q

How common is PKU?What gene is mutated?What metabolite accumulates?How is it tested for?

A

1/10,000, ARPAHPhenylalanineMS/MS for Tyrosine:Phenylalanine ratio and absolute concentrations on day 2-5 bloodspot. Genetic testing not routine.Consider DHPR mutations - they provide a similar phenotype, but are sensitive to BH4 supplementation (a restricted deit is not required in these patients)

91
Q

How common is CHT?What gene is mutated?What metabolite accumulates?How is it tested for?

A

1/4000, AR. 10% due to a genetic defectCan be primary (thyroid a-/dys-genesis) or secondary (TSH insensitivity)Cause by mutations in 8 different genes.Screen for present of TSH. Treat with Thyroxine to prevent serious disability

92
Q

How common is MCADD?What gene is mutated?What metabolite accumulates?How is it tested for?

A

1/10,000ACADM, common mutation in 88% (p.Lys304Glu) clinically diagnosed cases, but only homozygous in 50% of NBSP casesBuild-up of medium-chain fatty acids (C8) that accumulate in the lysosome.Measure using MS/MS to get ratio of C10:C8 and quantification of C8.Treat with diet, make sure they’re fed regularly

93
Q

How common is SCD?What gene is mutated?What metabolite accumulates?How is it tested for?

A

1/2000 UK babies, ARHBB mutation p.Glu6ValNo accumulation, two mutant b-chains produce HbS and change shape of cells.Tested by HPLC - will also detect multiple other Hb mutations, and can detect carriers

94
Q

How common is CF?What gene is mutated?What metabolite accumulates?How is it tested for?

A

1/2500, ARCFTRAbnormal Chloride channel functionIRT test using AutoDELFIA (flurescent Ab-based assay) if high, CF4 kit - if 1 mutation found - second spot, if none found - repeat IRT

95
Q

How common is MSUD?What gene is mutated?What metabolite accumulates?How is it tested for?

A

1/120,000, ARBCKAD complexLeucine, isoleucine, valine, alloisoleucine - elevated levels of all are suggestive, but not conclusive - second tier biochemical tests required.Classical form tested using MS/MS, but rarer milder forms may not be detected.Treat with low protein diet

96
Q

How common is Homocysteinuria?What gene is mutated?What metabolite accumulates?How is it tested for?

A

1/100,000, ARDefects in catabolism of homocysteine to methionineHomocysteine accumulatesDon’t test within first 24hr of life as methionine levels fluctuate. MS/MS test, quantify homocys and meth50% of patients in UK are responsive to Vitamin B6

97
Q

How common is Glutaric acidaemia type 1?What gene is mutated?What metabolite accumulates?How is it tested for?

A 
1/100,000, AR-Glutaric acid, lysine and tryptophanMS/MS to quantify C5DC in blood spotTreat with low protein diet
98
Q

How common is Isovaleric acidaemia?What gene is mutated?What metabolite accumulates?How is it tested for?

A

1/100,000, AR-Isovaleric acidMS/MS for C5 in blood spot - if increased, a full acylcarnitine scan is carried out to rule out GA2

99
Q

What three methods are responsible for inborn errors of metabolism?

A

Accumulation of toxic metaboliteActivation of alternative metabolic pathway > toxicLoss of product.

100
Q

Why is a genetic diagnosis important for IEMs?

A

Reproductive choiceDetermine carrier status and cascade screeningAn exact diagnosis is offered; genotype/phenotype correlations may existNo invasive procedures neededCan offer a quicker diagnosisPromotes use of specific, targeted therapies

101
Q

Name some IEMs

A 
Pompe diseaseMCADDWilson diseaseZelwegger syndromeMucopolysaccaridosisPKUOTC deficiencySLO
102
Q 
What is Pompe disease caused by?What sort of IEM is it?What are the associated clinical features?How is it diagnosed?How is it treated?
A

Mutations in GAA - lead to build up of GAAGlycogen storage disorderThree types: classical: Present in first 2 weeks of life with muscle weakness, hypotonia, cardiomegaly, HCM, feeding difficulties, deafness and failure to thrive.Death in first year of life.Non-classical Pompe is less severe. Less cardiac problems and present in first year of life.Late-onset Pompe shows progressive muscle weakness, but cardiac failure is rare.Diagnosed by reduced GAA activity in the bloodTreat with high protein diets and enzyme replacement therapy.Two common founder mutations.

103
Q

Whats a lysosome

A

membrane-bound organelles containing an array of enzymes capable of breaking down all types of biological polymers—proteins, nucleic acids, carbohydrates, and lipids. function as the digestive system of the cell, both degrading material taken up from outside the cell and digesting obsolete components of the cell itself

104
Q

how many lysosomal disorders are there

A

about 70

105
Q

What are the general symptoms of lysosomal storage disorders

A

normal at birth, go on to present with progressive neurological and motor deterioration.

106
Q

what are Lysosomal storage disorders

A

recessive class of metabolic disorders caused by mutations in proteins critical for lysosomal function. In all cases, insufficiency of a lysosomal function is involved. caused by LoF mutations (>50 known)

107
Q

What causes Gaucher Disease (GD)

A

1 ~1 in 60,000 in the general population(1 in 855 in Ashkenazi Jewish population)- GBA mutationsdetect by assaying glucosylceramidase enzyme activity in peripheral blood leucocytes or other nucleated cells

108
Q

what causes Niemann-Pick Disease Type C (NPC)

A

for mutations in NPC1 (90%) or NPC2 (4%) detect by Biochemical testing to demonstrate impaired cholesterol esterification

109
Q

what causes Fabry Disease

A

X-linked disorder with prevalence of 1 in 50,000 malesMutations in GLA :defects in alpha-galactosidase A (ά-Gal A),

110
Q

what causes Acid Sphingomyelinase (ASM) deficiency in Niemann Pick Disease types A & B

A

1 in 250,000 (1 in 40,000 in Ashkenazi Jewish population)SMPD1 mutations : deficiency of acid sphingomyelinase (ASM)detect by measurement of ASM enzyme activity in peripheral blood lymphocytes or cultured skin fibroblasts

111
Q

what causes Metachromatic leukodystrophies

A

mutations in ARSA, few by mutations in PSAPcasued by arylsulfatase A (ARSA) deficiency

112
Q

whats causes Tay-Sachs

A

HEXA mutations: defective alpha subunit of Hexosaminidase to be made affecting Hexosaminidase activity ~1/30-1/40 Ashkenazi Jewish population

FP_23_S3 (6 decks)

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