Von geirke disease

GENETICALLY INHERITED DISEASE

1. Von GIERKE disease
•AlsoknownasGSDI–glycogenstoragediseasetype
•
•Aninheriteddisorderthatbuildsupglycogeninbodycells
•Organsandtissues-liver,kidneysandsmallintestinesandthus
impairstheirfunction
•Seenat3-4monthsofbabywhentheydon’ttakefeednormallyat
nights
•Frequency-1in1,00,000whereGSDIaisdominantascomparedto
GSDIb

2. Von GIERKE disease
Dr. Esther ShobaR
Assistant Profesor
KristuJayantiCollege

4. Etiology
•MutationsingeneG6PC(GSDIa)andSLC37A4(GSDIb)
•G6PCgenecodesforGlucose-6–phophatase(enzymepresenton
membraneofER)togetherwith
•SLC37A4codesfor-solutecarrierfamily37member4,whichfunction
asglucose6-phosphatetranslocaseprotein
•Thistwoworktogethertobreakglucose-6-phosphate
•Ifglucose-6-phosphateisnotbrokendowntheyconverttoglycogen
anfat,thisbecomestoxicanddamagesorgansandtissues(liverand
kidney)
•Atleast85mutationsarereportedinG6PCgene

6. SLC37A4 gene -solute carrier family 37 member 4
TheSLC37A4geneprovidesinstructionsformakingaproteincalled
glucose6-phosphatetranslocase
Thisproteintransportsthesugarmoleculeglucose6-phosphatefromthe
fluidinsidethecelltotheendoplasmicreticulum,whichisastructure
insidecellsthatisinvolvedinproteinprocessingandtransport
Atthemembraneoftheendoplasmicreticulum,glucose6-phosphate
translocaseworkstogetherwiththeglucose6-phosphataseprotein
(producedfromtheG6PCgene)tobreakdownglucose6-phosphate
Ifglucose6-phosphatecannotgettotheendoplasmicreticulum,it
cannotgetbrokendownandglucoseisnotproduced
Morethan80mutations

10. INHERITANCE PATTERN
•This condition is inherited in an autosomal recessive pattern, which
means both copies of the gene in each cell have mutations.
•The parents of an individual with an autosomal recessive condition
each carry one copy of the mutated gene, but they typically do not
show signs and symptoms of the condition.
•That is parents should be carriers

11. Symptoms
•Seen at 3-4 months of baby when they don’t take feed normally at nights
•Affected infants have low blood sugar that leads to seizures
•More of lactic acid, uric acid and excess amount to fats
•As they get older, children with GSDI have thin arms and legs and short
stature
•An enlarged liver may give the appearance of a protruding abdomen
•The kidneys may also be enlarged
•Delayed puberty because of abnormal development of the ovaries –
polycystic ovaries
•Adenomas (tumor) form in the liver, may be noncancerous (benign) or
cancerous (malignant)

12. Symptoms
•ResearchershavedescribedtwotypesofGSDI,whichdifferintheirsigns
andsymptomsandgeneticcause
•ThesetypesareknownasglycogenstoragediseasetypeIa(GSDIa)and
glycogenstoragediseasetypeIb(GSDIb)
•PeoplewithGSDIbhaveneutropenia(lessWBC),somoreinfections,
inflammationofintestinalwalls,inflammationofthegums(gingivitis),
chronicgum(periodontal)disease,abnormaltoothdevelopment,and
opensores(ulcers)inthemouth
•TheneutropeniaandoralproblemsarespecifictopeoplewithGSDIb
andaretypicallynotseeninpeoplewithGSDIa

13. LABORATORY DIAGNOSIS

14. LABORATORY DIAGNOSIS
•Molecular Genetics Tests
•Targeted variant analysis (14)
•Deletion/duplication analysis (22)
•Sequence analysis of select exons (2)
•Mutation scanning of the entire coding region (1)
•Sequence analysis of the entire coding region (39)

15. TREATMENT

16. Treatment -Gene therapy
Adenovirus-andadeno-associatedvirus(AAV)-mediatedgene
therapieshavebeenevaluatedforGSD-Iainthesemodelsystems.
adenoviraltherapyproducesonlyshorttermcorrectionsandonly
impactsliverexpressionofthegene
AAV-mediatedtherapydeliversthetransgenetoboththeliverand
kidney,achievinglongertermcorrectionoftheGSD-Iadisorder
GenetherapyforGSD-Ibintheanimalmodelisstillinitsinfancy,
althoughanadenoviralconstructhasimprovedthemetabolicprofile
andmyeloidfunction.
InitialstudiesusingAdenoassociatedvirus(AAV)serotype2–based
vectorsexpressingG6Pase-αtotreatinfantGSD-Iaindogsormice
showedsuboptimalimprovement
Adenoassociatedvirus(AAV)serotype8vectorsarealsoused

17. Treatment -Gene therapy
•Correctgeneinvectorsoffelineimmunodeficiencyvirus(FIV),a
nonprimatelentivirusandtransducedintheliverofthemurines
•thesevectorsarecapableofintegratingstablyintohepatocytecell
linesandadultmurineliversandleadtolong-termtransgene
expression
•SingleadministrationofFIVvectorscontainingthehumanG6Pase
genetoG6Pase-α
−/−
micedidnotchangethebiochemicaland
pathologicalphenotype
•However,adoubleneonataladministrationprotocolledto
normalizedbloodglucoselevels,significantlyextendedsurvival,
improvedbodyweight,anddecreasedaccumulationofliverglycogen
associatedwiththedisease