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))))))))))))))))))))

2 * *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).** 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.)

3 &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)

4 * 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.)

5 *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 .))))))))))))))))))) )))))))))))))))))))))))))))))))))))))))) ))))))))))

6 ( 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.))))))))))))))))

7 * 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.)))))))))))))))))) )))))

8 * 2*EDTA*(purple*top)*blood*samples*(minim um*1mL*for*neonates)*are*required*for*KC NJ11,*SUR1,*INS,*6q24*and*other*neonatal * diabetes *gene*analysis.**Please*send*2* EDTA*directly*to*Exeter*via*your*local*l aboratory*to*avoid*delays*in*DNA* ,*and*prompt* *during*neonatal*period,*using*accompany ing*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.*Buccal*cells*or*urine*samples*are*pre ferable*to*blood*as*the* *of*mutant*mitochondrial*DNA*(heteroplas my*level)*is*greater*in*these*.

9 Ssues*(highest*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).

10 *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*$550,*which*is*c urrently*recommended*if* *HNF1B*as*55%*of*cases*are*due*to*gene* **For*GCK,*HNF1A*and*HNF4A,*gene* *account*for*2%*of*cases.*Cascade(tes8ng (of*family*members*for*known* * *in*proband*incurs*a*charge*of*$ **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.))))))))))))))