Monogenic(diabetes:( - NZSSD

1 Monogenic(diabetes:( A(guideline(for(NZ(h ealthcare(prac88oners(Phenotypes(for(com mon( monogenic (subtypes(Why(diagnose(MODY ,(MIDD(or(ND?( Isolated*mild* *hyperglycaemia* Small*increment*on*OGTT* Not*associated*with*micro*or*macrovascul ar* *even*in*the*absence*of*glucose*lowering * * Absence*of*family*history*is*common*as*d etected*only*incidentally*or*upon*screen ing* Progressive*beta*cell*failure*commonly*p resents*with*hyperglycemia*in*early*adul thood* *elevated*postAprandial*glucose,*with*la ter*elevated* *glucose*and*marked*excursion*on*OGTT*(> *mmol/l)* *to*sulphonylureas* *Gliclazide* Glycosuria*with*blood*glucose*<*10*mmol/ L* Elevated*HDL* Similar* *to*HNF1A,*but*with* *neonatal*hypoglycemia*or*macrosomia*eve n*without*maternal* diabetes * Maternally*inherited* diabetes *and*deafne ss*(MIDD)*and*maturity*onset* diabetes *of *the*young*(MODY)*subtypes*are*thought*t o*account*for*1A2%*of* diabetes *cases,*an d*are*frequently*mistaken*for*type*1*or* 2* diabetes *( *2000*cases*in*New*Zealand).)))))))))))) )))))))

2 ** Neonatal* diabetes *(ND)*diagnosed*within* 6*months*of*life*is*not*usually*type*1*d iabetes*and*all*need* * **Other&forms&of&rare& monogenic & diabetes ,&clearly&recognisable&due&to&their&asso ciated&syndromes&(eg:&Wolfram,&Alstrom, Up*to*1%*of*unselected*cases*of* diabetes * Up*to*60%*of*cases*of* diabetes *associate d*with*sensorineural*deafness*and*matern al*family*history** Excess*proteinuria,*macular* *dystrophy* It*changes*management* No*glucose*therapy*for*GCK* *outside*of*pregnancy* Low*dose*sulphonylurea*for*HNF1A*and*HNF 4A* Coenzyme*Q10*and*thiamine*for*MIDD* No*maternal*renal*donors*in*MIDD*who*are *obligate*carriers*of* >G* Sulphonylurea*therapy*rather*than*insuli n*for*Neonatal* diabetes *(KCNJ11,*ABCC8)* It*improves*quality*of*life*by*guiding*b est*therapy** It*alters*prognosis* GCK* *not*associated*with*micro*or*macrovascu lar* * It*alters*screening*in*at*risk*family*me mbers** *glucose*of* *in*GCK*families* Early*lowering*of*renal*threshold*for*gl ucose*in*HNF1A** Early*hearing*screening*for*obligate*mat ernal*carriers*of* >G* It*alters*management*in*pregnancy** Only*50%*of*mothers*with*GCK* *will*require*insulin*during*pregnancy*i f*their*fetal*growth*is*increased,** Babies* *HNF4A* *are*at*increased*risk*of*macrosomia*and *neonatal*hypoglycemia,*independent*of*m aternal*glycaemia*or* *status* It*enables* *counseling*of*family*members*at*risk*wi th* * * *and*management* *for*those*already*diagnosed*with*diabet es*in*extended*family*members* It*can*generate* *for*molecular*and*clinical*research,*im proving*our*understanding*and*management *of* monogenic * diabetes * Presents*from*birth*to*6*months*(1.))

3 *100,000*live*births)* Occasional*severe*associated*neurologica l*symptoms* Free(gene8c(tes8ng,*may*enable*oral*ther apy* monogenic ( diabetes (refers(to(single( gene(disorders(resul8ng(in( diabetes ((GCK (muta8ons((MODY2)((20K50%(MODY(cases((HN F1A(muta8ons((MODY3)(20K50%(MODY(cases(H NF1B(muta8ons((MODY5)(5%(MODY(cases(Neon atal( diabetes ((KCNJ11,(SUR1,(INS,(6q24)( ((HNF4A(muta8ons((MODY1)(5%(MODY(cases( Associated*with*renal*cysts,* *renal*dysplasia,* *kidney*disease,** Abnormal*liver*enzymes* *atrophy*with*exocrine* *Maternally(inherited( diabetes (and(deafn ess((MIDD)(((November 2012 *New*Zealand*Society*for*the*Study*of*Di abetes*2012* Monogenic(diabetes:( A(guidel ine(for(NZ(healthcare(prac88oners(Diagno s8c(algorithm(for(assessment(of(suspecte d( Monogenic(diabetes:( diabetes (diagnosed (<(35(yrs(Atypical(Type(1( diabetes ( FH* *of* monogenic * diabetes * No*history*of*DKA* GAD* * *if*within*5*years*of*diagnosis*of* diabetes * Prandial* *>200*pmol/L*if*beyond*5*years*of* diabetes **Atypical(Type(2( diabetes ( FH* *of* monogenic * diabetes * An*absence*of:* Obesity* HTN/Dyslipidaemia* PCOS*(Females)* Acanthosis*nigricans** *glucose* * HbA1c*40A*60mmol/L* Small*increment*(<* )*on*OGTT* If*neither*parent*known*to*have* diabetes /IFG,*confirm* *glucose*>* *in*at*least*one*parent* No*microvascular* Te s t ( fo r (GCK Familial*,*progressive*young*onset*diabe tes* >2*family*members*affected* *to*Sulphonylureas* Elevated*HDL> *(HNF1A)* *hsCRP*< *(HNF1A*only)* In* *to*above.)))))))))))))))))))))))))))))) )))))))))))))))))))))))))))))))))))))))) )))))))))))))))

4 * History*of*transient*neonatal*hypoglycae mia* History*of*macrosomia* Deafness* Maternal*deafness* Maternal* diabetes * Pigmentary*maculopathy* Myopathy* Stroke* Elevated*lactate* Renal*cysts* Abnormal*liver* *tests* Genitourinary* * Exocrine*pancreas* *Te s t ( fo r (HNF1A Te s t ( fo r (HNF4A Addi8onal(features?(Te s t ( fo r (MIDD((( >G) Te s t ( fo r (HNF1B If negative Yes No Te s t ( fo r ( (KCNJ11,((SUR1,(INS(Other(neonatal(genes Diagnosis**<*6*months*Neonatal( diabetes (November 2012 2*EDTA*required*for*MODY* * *at*Auckland*Hospital .* 2*EDTA*(purple*top)*blood*samples*(minimum*1mL*for*neonates)*are*required*for*KCNJ11,*SUR1,*INS,*6q24*and*other*neonatal* diabetes *gene*analysis.**Please*send*2*EDTA*directly*to*Exeter*via*your*local*laboratory*to*avoid*delays*in*DNA* ,*and*prompt* *during*neonatal*period,*using*accompanying*forms*found*under*neonatal* diabetes *on* * For*MIDD*( >G)*tests,*specify* DNA*for* >G*analysis *on*your*local*laboratory*form,*and*your *local*laboratory*will*send*the*sample*t o*Canterbury*Health*Laboratories*directl y.)))))))))))))))))))))))

5 *Buccal*cells*or*urine*samples*are*prefe rable*to*blood*as*the* *of*mutant*mitochondrial*DNA*(heteroplas my*level)*is*greater*in*these*.ssues*(hi ghest*in*muscle).*A Buccal*cells*may*be*collected*using*eith er*mouth*wash*or*a*dry*bacterial*swab.** Ensure*the*mouth*has*been*rinsed*first*i f*within*2*hours*of* *to*ensure*no*food*debris*is*present.**A sk*the* *to*to*swish*10mls*of*sterile*water*in*t heir*mouth*for*approximately*30*seconds* and*collect*this*in*a*clean*container.** Or*vigorously*swab*the*inside*of*the*che ek*approximately*15*.mes*each*side.**Pla ce*the*swab*in*a*clean*container*contain ing*sterile*water,*seal*and*send*(may*ne ed*to*snap*off*the*long* *stem).*A Urinary*epithelial*cells*collect*20A30ml s*of*early*morning*urine.*DNA*yield*may* depend*on*how*quickly*the*sample*is*proc essed.*Addi8onal(cost(for(gene(dele8ons( analysis(using*array*is*$550,*which*is*c urrently*recommended*if* *HNF1B*as*55%*of*cases*are*due*to*gene* **For*GCK,*HNF1A*and*HNF4A,*gene* *account*for*2%*of*cases.))))))

6 *Cascade(tes8ng(of*family*members*for*kn own* * *in*proband*incurs*a*charge*of*$ **Please*specify*proband*and* *(if*known)*on*Form*B.**Cascade* *is*not*indicated*for*MIDD.*Te s t(Price((NZ$)(Turnaround(8me((mths)(GCK* *3*HNF1A* *3*HNF4A* *3*HNF1B* *3*MIDD* *1*Neonatal* diabetes *genes*Free*through* Exeter*1* *of*a* *or*gene* *allows*the*definite*diagnosis*of*monoge nic* diabetes *to*be*made.**However,*failu re*to*detect*these*does*not*exclude*a*di agnosis.**Reasons*for*not* *a* *abnormality*in* *with*a*high*clinical*suspicion*of*monog enic* diabetes *could*be*(1)*present*labor atory*technology*is*not*sufficiently* *or*specific*for* *all*pathogenic* *or* *(2)*not*all* *genes*have*been* *(3)*the*index*case*may*not*have*monogen ic* diabetes *as*the*currently*recognised* features*are*not*sufficiently*specific*f or*this**Assessing(the(significance(of(r are/novel(gene(variants(detected(in(the( index(case:**Several*types*of*evidence*a re*used*to*determine*the*likely*pathogen icity*of*such*gene*variants*(1)*searchin g*published*literature,*epidemiological* studies*and*established*databases*(2)*in *vivo* *studies*(3)*in*silico*(molecular*sorwar e)*studies.)))))))))))))))))))

7 ** *care*is*required*to*evaluate*novel*vari ants*in*nonACaucasian*ethnic*groups.*Ell ard,&Diabetologia 553;&2008&Interpreta8on(of(gene8c(test(r esults((November 2012 *New*Zealand*Society*for*the*Study*of*Di abetes*2012* Monogenic(diabetes:( A(guidel ine(for(NZ(healthcare(prac88oners(CKpep8 de:(*Helpful*in* *between*T1D*or* monogenic * diabetes *as*un detectable*serum* *usually*seen*arer*5*years*of*T1D*diseas e* *(DCCT),*while*persistence*of* * *(when*glucose*is*>*8mmol/L)*beyond*5*ye ars*arer*T1D*>200pmol/L*makes*T1D*unlike ly.**Recently,*persistence*of* *in*T1D*beyond*5*years*has*been*describe d*(Wang,& diabetes &Care 470,&2012)*with*the*majority*being*below *100pmol/L*(1A5%*of*Type*1D).**Islet(aut oan8bodies:((Helpful*in* * monogenic * diabetes *from*T1D.(GAD*or*IAA 2* *remain*detectable*for*many*years,*with* 70%*of*T1D*having*either* *11*years*arer*diagnosis*(Borg,Acta&Paed iatr 51,&2000).**The*prevalence*of*these* *in*those*with*HNF1A,*GCK*or*HNF4A*has*b een*found*to*be*the*same*as*in*control*s ubjects*at*1%*(McDonald,&Diabe@c&Medicin e 1033,&2011)*hsCRP(biomarker(for(HNF1A:*t he*CRP*gene*has*HNF1A*binding*sites*in*i ts*promoter*and*low*hsACRP*has*been*seen *in*HNF1A* *compared*with*other*forms*of* monogenic * diabetes *such*as*HNF4A,*GCK,*T1D*and*T2D .))))))))))))))))))))))

8 **The*highest*discriminatory*value*of*hs CRP*is*between*HNF1A*and*T2D*with*cut*of f*hsCRP< *showing*modest*79%* *and*70%*specificity,*hence*should* *be*used*in* *with*clinical* **A*lower*cut*off*level*< *mg/L*achieved*a* *of*71%*and*specificity*of*70%*for* *between*HNF1A*and*HNF4A,*GCK,*or*HNF1B.*(McDonald,& diabetes &Care 1862,&2011).*The*hsACRP*is*not*useful*if*elevated*>10*as*in*the*presence*of* *HDL:**In*the*absence*of*insulin*resista nce*related*lowering*of*HDL* *of*T2D,*the*HDL*level*is*moderately*dis criminatory*between*HNF1A*and*T2D*:*plas ma*HDL*>* *was*75%* *and*64%*specific*at* **HNF1A*from*T2D*(McDonald,&Clin&Chim&Ac ta 32,&2012).*HDL*levels*are*similar*betwee n*HNF1A,*T1D*and*healthy*controls.*Lower *HDL*levels*are*seen*in*GCK*compared*to* T1D,*and*HNF1A*(animal*studies*suggest*H DL*levels*may*depend*on*GCK* )*Fendler,&Clin&Endocrinol 7,&2011.*GCK:**May*stop*all*glucose*lowe ring*therapy*(Murphy,&Nat&Clin&Pract&End ocrinol 13,&2008).**Once*stable*glucose*is*confi rmed*without*glucose*lowering*therapy*(t o*confirm*there*is*no*coincidental* *type*of* diabetes ),*blood*glucose*monito ring*is*no*longer*necessary.

9 **Screening*for*microvascular*risk*may*b e* **Screening*and*therapy*for*cardiovascul ar*risk*factors,*such*as*blood*pressure, *lipids,*and*HbA1c*should*be*based*on* *individual*risk*profiles.** *or*confirmatory* * *of*family*members*is*generally*not*requ ired*as* *glucose*(> )*is*a*good*marker*of*GCK*status*in*an*a ffected*pedigree.*All(women(with(GCK(sho uld(be(advised(to(seek(referral(to(diabe tes(in(pregnancy(clinic(upon(pregnancy,( as(they(may(require(insulin(therapy(in(p regnancy(depending(on(whether(their(fetu s(also(carries(the(muta8on.((Insulin*the rapy*of*maternal*hyperglycemia*is*reserv ed*for*those*who*have*accelerated*fetal* growth*during*the*third*trimester*(surro gate* *of* *fetal*GCK* ).**Large*insulin*doses*(at*least* )*are*usually*required.*Antenatal* *of*the*fetus*for*GCK* *is*not*advised*unless*CVS*or*amniocente sis*is*being*performed*for*another*reaso n.**HNF1A*and*HNF4A:**Guidance*for*trans ferring* *from*insulin*to*sulphonylureas*is*avail able*on* **If* * *of*HNF1A*is* ,*then*screening*for*glycosuria*is*beler *than* *glucose*given*the*lowered*renal*thresho ld*in*HNF1A.)))))))))))))))))))))))))))) )))))))

10 ** *therapy*in*HNF1A*from*age*40*given*incr eased*risk*of*CVD*mortality*despite*elev ated*HDL,*as*low*ApoM*(Steele,&Diabe@c 161,&2010)*.*HNF1B:*Enables* * *of*first*degree* *and*prompt*surveillance*for*clinical*di seases.**Almost*all*have*renal*disease*( * *kidney*disease,* *renal*dysplasia,*solitary* *kidney,*horseshoe*kidney,*renal*cysts)* oren*found*in*children*within*the*first* year*of*life.**De*novo*cases*are*common* (without*family*history).*Other*associat ed*features*are* diabetes ,* *atrophy*(oren*subAclinical*exocrine*def iciency),*urogenital* ,*gout*and*abnormal*liver*enzymes.**Earl y*insulin*therapy*is*needed.**MIDD*( >G):**Avoid*mevormin.**Thiamine*(50mg*da ily)*and*coenzyme*Q10*(150mg*daily)* *may*be*helpful*(Suzuki,&Diabetologia 8,&1998).** *or*cascade* * *of*family*members*is*not*recommended*as *almost*all*maternal* *will*have*obligate*carrier*status*and*l evel*of*heteroplasmy*( *load)*in*peripheral*.ssues*is*not*usefu l*in* *clinical*course.**(Murphy,&Diabet&Med&2 5 13,&2008)**KCNJ11*and*SUR1:*Guidance*for *transferring*neonatal* diabetes * *from*insulin*to*sulphonylureas*is*avail able*on* *Management(changes((Diagnos8c(clues(for (index(case(finding((November 2012 predic8ve (tes8ng,*while*in*those*already*known*to *have* diabetes *this*is*known*as* diagnos8c (tes8ng.))))))))))))