diabetes mellitus an inborn error of metabolism ? dr grace poon department of paediatrics and...

Diabetes MellitusDiabetes Mellitus

An Inborn Error of Metabolism ?An Inborn Error of Metabolism ?

Dr Grace PoonDr Grace Poon

Department of Paediatrics and Adolescent MedicineDepartment of Paediatrics and Adolescent Medicine

Queen Mary HospitalQueen Mary Hospital

HKSPEM Clinical Meeting

8 May 2008

PKHPKH Male / 14 yearsMale / 14 years

• Para 1 FT LSCS for fetal distress in Canossa Hospital

• Mother with GDM since 7 mths of gestation – on diet control

• IUGR – induction of labour

• Born SGA with birth weight of 2.4 kg

• PGM and MGF both have NIDDM

• Hospitalized for RSV bronchiolitis at 2.5 months

• Developed DKA whilst in hospital – pH 7.05, BE -23, blood glucose 26.2 mmol/L, gross glucosuria and ketonuria

• Complicated by acute pulmonary oedema and mild cerebral oedema

• Diagnosed to have neonatal diabetes mellitus

• Started on insulin therapy (Aug 94)

• USG pancreas normal (Sep 94)

• Could stop insulin after 5 months (Jan 95 at CA 8 months)

• HbA1c 7.6% (Oct 94) 5.7% (Jan 95)

OGTT (May 95 – CA 1 year)OGTT (May 95 – CA 1 year)

0 30min 60min 90min 120min 150min

Insulin (mIU/L) 2.3 9.9 5.8 3.3 <1 <1

C-peptide

(fasting 0.5-3 ng/ml)

1.4 2.2 1.7 1.9 2.1 1.7

Glucose (mmol/L) 4.6 9.4 9 8.6 6.1 4.6

* Samples haemolysed: insulin and c-peptide could be spuriously low

• Islet cell Ab negative (Sep 00)• Serial OGTT between 1996 to 2001 showed normal

glucose response• HbA1c 5-6.1% (Mar 96 – Nov 02)• Onset of puberty since July 2005

Mar 1996

Jun 1996

Feb 1999

Feb 2000

Jan 2001

Sep 2001

Nov 2002

Mar 2005

HbA1c 5% 5.6% 6% 6% 6.1% 5.9% 5.8% 6.5%

OGTT (Oct 05 – CA 11y 5m)OGTT (Oct 05 – CA 11y 5m)

0 30min 120min

Insulin (mIU/L)

2.8 7.5 21

Glucose (mmol/L)

5.3 10.6 10.1

Impression: Impaired glucose tolerance HbA1c 6.7%

Defaulted FU until June 06Defaulted FU until June 06OGTT (Jun 06 – CA 12y 1m)OGTT (Jun 06 – CA 12y 1m)

0 30min 120min

Insulin (mIU/L)

5.8 21 21

Glucose (mmol/L)

7.6 13.9 12.1

Impression: Diabetic response HbA1c 7.2%

Islet cell Ab negative

Glucagon stimulation test (Aug 06)Glucagon stimulation test (Aug 06)

Glucose

(mmol/L)

Insulin (mIU/L)

C-peptide (0.27-1.27

nmol/L)

T-5 8.5 4.2 0.41

T0 8.4 2.2 0.43

T5 9.4 30 1.15

T10 9.8 4.1 0.73

T15 10.9 4.6 0.5

Haemolysed samples

• Started on daily dose of Daonil (glibenclamide) 2.5mg since Aug 2006 (CA 12y 3m)

• HbA1c

• Daonil increased to 5mg daily since April 2008

Jun 2006

Aug 2006

Jan 2007

Jun 2007

Aug 2007

Feb 2008

HbA1c 7.2% 7.8% 6.5% 6.2% 6.2% 7.4%

Started on Daonil

Neonatal diabetes and Neonatal diabetes and

abnormal development of the pancreasabnormal development of the pancreas

Neonatal diabetes mellitus (NDM)Neonatal diabetes mellitus (NDM)• First described by Kitselle in 1852

• Classically defined as diabetes mellitus occurring in the first 6 weeks of life in term infants

• Some suggests a cut off for early onset DM at 6 months

• Single gene disorders rather than classical autoimmune type 1 diabetes

• Incidence: 1 in 300,000-400,000 live births

• Transient (TNDM) vs Permanent (PNDM)– based on the grounds of resolution or persistence

beyond the first year of life

Transient neonatal Transient neonatal

diabetes mellitus (TNDM)diabetes mellitus (TNDM)

TNDMTNDM

• TNDM contributes 50-60% of cases of neonatal DM

• Develop diabetes in the first few weeks of life but go into remission in a few months

• The pancreatic dysfunction may be maintained throughout life, with possible relapse to a permanent diabetes state usually initiated at times of metabolic stress such as puberty or pregnancy or as adults

• Regular follow-up of TNDM is recommended and parents should be informed of the risk of recurrence

• Remission of TNDM is temporary and more than 60% of cases relapse at a median age of 11 years

• Fasting blood sugar and insulin, HbA1c and insulin sensitivity and insulin response of IVGTT are normal during the remission phase

Permanent neonatal Permanent neonatal diabetes mellitus (PNDM)diabetes mellitus (PNDM)

PNDMPNDM

• Insulin secretory failure occurs in the late fetal or

early postnatal period

• Does not go into remission

Comparison of several features in TNDM and Comparison of several features in TNDM and PNDM cases in the French cohort (n=50)PNDM cases in the French cohort (n=50)

TNDM (n=29) PNDM (n=21) p value

Gestational age (weeks) 38.2 ± 2.2 39.2 ± 1.6 p = 0.15

Birth weight (g) 1987 ± 510 2497 ± 690 p < 0.006

Birth length (cm) 44.3 ± 3.4 47.5 ± 2.4 p < 0.006

Head circumference (cm) 31.5 ± 1.8 33 ± 1.9 p < 0.02

IUGR (n=20/27) 74% (n=7/19) 36% p < 0.03

Median age at diagnosis (days) (range)

6 (1-81) 27 (1-127) p < 0.01

Initial insulin dose (unit/kg/day) 0.6 ± 0.25 1.4 ± 1.2 p < 0.006

Metz C et al. J Pediatr 2002;141:483-489

TNDM vs PNDMTNDM vs PNDM

• Comparing with infants with PNDM, patients with TNDM:

– More likely to have IUGR

– Less likely to develop ketoacidosis

– Younger at diagnosis of diabetes

– Have lower initial insulin requirements

• Considerable overlap occurs between the 2 groups and TNDM cannot be distinguished from PNDM on the basis of clinical features

Aetiology of transient neonatal Aetiology of transient neonatal diabetes mellitus (TNDM)diabetes mellitus (TNDM)

Transient neonatal DMTransient neonatal DM

Chromosome 6 anomalies • Paternal duplications• Paternal isodisomy• Methylation defect

Potassium channel activating mutations• ABCC8 (SUR1) and rarely KCNJ11 (Kir6.2) mutations

Unidentified genetic defects

Chromosome 6 anomaliesChromosome 6 anomalies(OMIM 601410)(OMIM 601410)

Chromosome 6 anomalies:Chromosome 6 anomalies:a disease linked to imprintinga disease linked to imprinting

• Uniparental isodisomy (UDP6)

– 2 haplo-identical copies of chromosome 6 inherited

from the father with no contribution from the mother

• Unbalanced duplication of paternal chromosome 6q24

• Loss of the normal methylation from maternal 6q24

Two imprinted genes in 6q24Two imprinted genes in 6q24

• ZAC (Zinc finger protein associated with Apoptosis and cell Cycle arrest)

• HYMAI (hydatidiform, mole-associated and imprinted transcript)

ZACZAC• A zinc finger protein which potently induces apoptosis and

cell cycle arrest and prevents tumour formation

• A key regulator of peroxisome proliferator-activated receptor gamma (PPAR)

• Activation of PPAR is sufficient to inhibit -cell proliferation, and PPAR overexpression significantly compromises glucose-stimulated insulin secretion

• Overexpression of ZAC, either due to extra copies of paternal origin or loss of the silencing effect of methylation on the maternal allele is the likely cause of 6qTNDM

HYMAIHYMAI

• Uncertain if HYMAI plays a role in TNDM

• It has no open reading frame and its function is not clear

Chromosome 6q anomaliesChromosome 6q anomalies• Usually present in the first week of life with profound

diabetes requiring insulin therapy

• Significant IUGR (mean BW 1980 gm at term)

• Go into remission at a median age of 12 weeks

• Likely to relapse at times of metabolic stress such as during puberty or intercurrent illness

• Although the relapse is characterized by loss of classical insulin response to hyperglycaemia, there is evidence that insulin is still available, as there is excellent insulin response on glucagon stimulation, suggesting that the G-coupled protein receptor response remains intact through cAMP (might be an area of therapeutic intervention in future)

Chromosome 6q anomaliesChromosome 6q anomalies

• Some children have macroglossia and anterior abdominal wall defects, as described in Beckwith-Wiedemann syndrome

• Not only do these children lose the maternal methylation at 6q, they also have hypomethylation at other imprinted loci, such as the Beckwith-Wiedemann locus, resulting in significant phenotypic variation

(Mackay et al. Hum Genet 2006;120:262-269)

Chromosome 6 anomalies and the Chromosome 6 anomalies and the potassium channel activating mutations potassium channel activating mutations

cause the vast majority of cases of TNDMcause the vast majority of cases of TNDM

KK++(ATP) channels in glucose metabolism(ATP) channels in glucose metabolism

The islet KThe islet KATP ATP channelchannel

• A critical regulator of -cell insulin secretion

• In the normal response to increased glucose exposure and its metabolism within -cell, ATP levels increase with a concomitant decrease in magnesium-adenosine diphosphate (Mg-ADP) levels, allowing closure of the KATP channel and membrane depolarization, which allows calcium influx into the cell and leads to insulin secretion

The islet KThe islet KATPATP channel channel

• A hetero-octamer made up of 2 types of subunits: 4 regulatory sulphonylurea receptors (SURs) embracing 4 pore-forming inwardly rectifying potassium channels (Kir)

• A 1:1 SUR1:Kir6.2 stoichiometry is both necessary and sufficient for assembly of active KATP channels

• SUR, a member of ABC transporter family, originates from 2 separate genes and therefore occurs in several spliced isoforms

• SUR1 is found in the pancreatic - cell and neurons

• SUR2A occurs in heart cells whilst SUR2B in smooth muscle

The islet KThe islet KATPATP channel channel

• Kir6.2 subunits form the channel pore in the majority of tissues, such as pancreatic -cell, brain, heart and skeletal muscle

• Whilst Kir6.1 can be found in smooth vascular muscle and astrocytes

• These different channel forms have different pore properties and adenine nucleotide sensitivities

• The KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) and ABCC8 (ATP-binding cassette, subfamily C, member 8) genes, encoding the Kir6.2 and SUR1 respectively are located at 11p15

The channelopathiesThe channelopathies

Potassium channel activating mutationsPotassium channel activating mutations

• Mutations in KCNJ11 and ABCC8 genes, encoding the

Kir6.2 and SUR1 subunits of the pancreatic KATP

channel involved in regulation of insulin secretion,

account for 1/3 to 1/2 of the PNDM cases but also for

TNDM cases

• Molecular analysis of chromosome 6 anomalies and the

KCNJ11 and ABCC8 genes provides a tool for

distinguishing transient from permanent neonatal

diabetes mellitus in the neonatal period

KCNJ11 mutationsKCNJ11 mutations


• Mutations in KCNJ11 that encode the Kir6.2 subunit of the KATP channel are the most common cause of PNDM and account for 30% of all cases

• The KATP channel is variably unresponsive to ATP, making the membrane hyperpolarized and preventing influx of calcium and efflux of insulin

KCNJ11 mutationsKCNJ11 mutations• Median age of presentation ~ 3-4 weeks of age as

opposed to babies with 6q anomalies who tend to present in the first week of life

• Born SGA but not as small as those with 6q anomalies (mean BW 2497g vs 1980g)

• All display low insulin levels despite dramatic hyperglycaemia

• 30% with ketoacidosis

• 20% have associated neurological disease with developmental delay

KCNJ11 mutationsKCNJ11 mutations• Epilepsy or muscle weakness is sometimes present,

indicating that the same potassium channels play a role in the functioning of CNS

• Children at the most severe end of this spectrum can be profoundly affected - ‘DEND’ (developmental delay, epilepsy and neonatal diabetes)

• An intermediate form (i-DEND) associated with milder developmental delay and no epilepsy

• The mutation causing isolated diabetes produce less change in ATP sensitivity than those associated with diabetes plus neurological disease (Q52R, V59G)


• Sulphonylureas close KATP channels by an ATP-independent mechanism

• Some patients with diabetes due to Kir6.2 mutations have been successfully transferred to oral sulphonylurea therapy at doses ranging from 0.5-1.0 mg/kg/day of glyburide

• Pearson et al. demonstrated that 44 of 49 patients (90%) aged 3 months to 36 years could be successfully transferred to oral therapy with a highly significant and sustained improvement in HbA1c (8.1% to 6.4%)

• Patients with neurological features are less likely to be successful in managing their DM using sulphonylureas

NEJM 2006;355:467-477

ABCC8 mutationsABCC8 mutations

ABCC8 mutationsABCC8 mutations

• The basal Mg-nucleotide-dependent stimulatory action of sulphonylurea receptor-1 (SUR1) encoded by ABCC8 is increased, which effectively prevents closure of the KATP channel

• Recently Babenko et al. demonstrated that activating mutations in the ABCC8 gene encoding the SUR1 subunit of the channel can also cause permanent neonatal DM that is responsive to sulphonylurea therapy

NEJM 2006;355:456-466

KK++(ATP) channels and neonatal diabetes(ATP) channels and neonatal diabetes

Aetiology of permanent neonatal Aetiology of permanent neonatal diabetes mellitus (PNDM) diabetes mellitus (PNDM)

Permanent neonatal DM (1)Permanent neonatal DM (1)• Heterozygous activating mutation in KCNJ11 gene and

in ABCC8 gene (Kir6.2 and SUR1 subunits of the pancreatic KATP channel)

• Insulin (INS) gene mutation

• Severe pancreatic hypoplasia associated with insulin promoter factor-1 (IPF-1) mutation and with cerebellar hypoplasia due to pancreatic transcription factor 1A (PTF1A) mutation

• Homozygous glucokinase gene mutation: insensitivity to glucose

Permanent neonatal DM (2)Permanent neonatal DM (2)

• IPEX syndrome and FOXP3 mutation: diffuse

autoimmunity

• Associated with epiphyseal dysplasia: Wolcott-Rallison

syndrome and EIF2AK3 gene mutation

• Mitochondrial disease

• Possibly associated with enterovirus infection

• Associated with hypothyroidism, glaucoma and GLIS3

mutation

Insulin gene mutationsInsulin gene mutations

Insulin (INS) gene mutationsInsulin (INS) gene mutations• Stoy et al. reported 10 missense mutations in INS

gene in 21 patients (20 with neonatal DM and 1 with type 2 diabetes) from 16 families in which NDM seems to segregate as a dominant trait and ABCC8 and KCNJ11 mutations were not found

• Not associated with -cell autoantibodies

• INS mutations accounts for 15-20% of cases of PNDM – similar to ABCC8 mutations (19%) but less than KCNJ11 mutations (30%)

Stoy J et al. PNAS 2007;104:10540-15044

Insulin (INS) gene mutationsInsulin (INS) gene mutations

• These patients are older at diagnosis, presenting at a median age of 9 weeks, with 15/16 being diagnosed in the first 6 months, 3 diagnosed between 6 months and 1 year, and the father of a proband at 30 years with type 2 DM

• Usually presenting with DKA or marked hyperglycaemia and was treated with insulin from diagnosis

• These patients with permanent diabetes without extrapancreatic features except for a low birth weight

Stoy J et al. PNAS 2007;104:10540-15044

Pancreatic agenesis/hypoplasia and the Pancreatic agenesis/hypoplasia and the insulin promoter factor-1 (IPF-1) geneinsulin promoter factor-1 (IPF-1) gene

IPF-1 mutation and PNDMIPF-1 mutation and PNDM

• First described in 1997 by Stoffers et al. in a child with PNDM and pancreatic exocrine insufficiency due to pancreatic agenesis (Nat Genet 1997;15:106-110)

• The proband was homozygous for a mutation (Pro63fsdelC) in IPF-1, the gene involved in the master control of exocrine and endocrine pancreatic development, being responsible for the coordinated development of the pancreas in-utero and also for the continued functional integrity of pancreatic islet cells

IPF-1 mutation and PNDMIPF-1 mutation and PNDM• Within the extended family were 8 individuals in 6

generations with early-onset diabetes akin to type 2 diabetes

• These were identified as heterozygotes for the same mutation with the mutant truncated isoform of IPF-1 acting as a dominant negative inhibitor of wild type IPF-1 activity; the resultant illness was reassigned as Maturity-Onset Diabetes of the Young (MODY) 4

• Additional studies have also identified that less severe IPF-1 mutations can cause autosomal dominant late-onset forms of type 2 diabetes

IPF-1 mutation and PNDMIPF-1 mutation and PNDM

• Only one further case report of pancreatic agenesis has been ascribed to an IPF-1 mutation and this was a compound heterozygous mutation of the gene

• Since there is complete absence of pancreatic tissue and exocrine function is also compromised, these patients will require the use of pancreatic enzyme supplementation

Pancreatic agenesis/hypoplasia Pancreatic agenesis/hypoplasia and the pancreatic transcription and the pancreatic transcription

factor 1A (PTF1A) genefactor 1A (PTF1A) gene

PNDM with cerebellar hypoplasiaPNDM with cerebellar hypoplasia• 3 members of a consanguineous Pakistani family with

neonatal diabetes and cerebellar hypoplasia were described in 1999

• Suggestive of an autosomal recessive inheritance pattern

• The infants all died within a few months of birth from a combination of metabolic dysfunction, respiratory compromise and sepsis

• A further child of North European descent was later identified with an identical phenotype and complete pancreatic agenesis

PNDM with cerebellar hypoplasiaPNDM with cerebellar hypoplasia

• This syndrome was found to be linked to mutations in the transcription factor PTF1A, a major gene involved in pancreatic development and also expressed in the cerebellum

• These patients have pancreatic hypoplasia associated with microcephaly linked to cerebellar hypoplasia

• About 19 cases of pancreatic agenesis/hypoplasia have been published, but most cases remain unexplained at the molecular level

Glucokinase gene mutationsGlucokinase gene mutations

Glucokinase (GCK) mutationsGlucokinase (GCK) mutations

• MODY 2 is caused by mutations in the glucokinase gene and usually leads to mild hyperglycaemia in affected individuals

• Glucokinase is a key regulator of glucose metabolism in islet cells controlling the levels of insulin secretion

• Homozygous GCK mutations have been described but are uncommon causes of PNDM

• This diagnosis should be considered in families with a history of glucose intolerance, MODY in first degree relatives and especially if consanguinity is suspected

IPEX IPEX (OMIM 304790)(OMIM 304790)

IPEX (Immune dysregulation, Polyendocrinopathy, IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome)Enteropathy, X-linked syndrome)

• The only one of the currently identified neonatal diabetes syndromes in which autoimmunity plays a central role

• Mutations in 2 genes have been identified: FOXP3 and CD25 (interleukin-2 receptor alpha)

• Both genes are important for the normal function of regulatory T cells that play a central role in regulating adaptive immune responses to maintain tolerance to host tissues

• In IPEX, this self-tolerance is lost and the result is a devastating autoimmune response


• Type 1 diabetes auto-antibodies (GAD, IAA, ICA) are frequently described, as are those directed against the thyroid gland and various other organs

• Enteropathy (100%), failure to thrive (>90%) and early-onset (often neonatal) diabetets (>90%) occur in almost all cases

• Other features frequently described include exfoliative dermatitis, haemolytic anaemia, thrombocytopenia, Addison’s disease and autoimmune hypothyroidism


• There are several treatment options for IPEX:

– Supportive therapy

– Immunosuppressive agents such as tacrolimus, steroid and cyclosporine have shown varying degrees of efficacy, but toxicity to other organs such as the kidney has been problematic

– BMT

• Prognosis remains guarded for children with this condition

Wolcott-Rallison syndrome Wolcott-Rallison syndrome (OMIM 226980)(OMIM 226980)

Wolcott-Rallison syndromeWolcott-Rallison syndrome

• An autosomal recessive disorder characterized by infancy-onset diabetes (often within the neonatal period) associated with a spondylo-epiphyseal dysplasia

• A constellation of other features includes hepatomegaly, mental retardation, renal failure and early death

• Mutation of the gene encoding eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) on chromosome 2p12 has been shown to cause this syndrome

Wolcott-Rallison syndromeWolcott-Rallison syndrome

• EIF2AK3 is highly expressed in islet cells, liver, kidneys and developing bone

• It has a role in protein translation and regulates the synthesis of unfolded proteins in the endoplasmic reticulum which could account for the multiple system involvement reported in this condition

Mitochondrial diabetesMitochondrial diabetes


• Neonatal diabetes may also exist in the context of a mitochondrial disorder

• Usually associated with other organ dysfunction, which may be recognized after the diagnosis of neonatal DM

• Commonly associated with sensorineural deafness

• Characterized by progressive non-autoimmune -cell failure


• Maternal transmission of mutated mitochondrial DNA can result in maternally inherited diabetes

• Several mutations have been implicated but the strongest evidence relates to a point substitution at nucleotide position 3243 (A to G) in the mitochondrial tRNA [leucine (UUR)] gene

Other very rare forms of NDMOther very rare forms of NDM

Heterozygous Hepatocyte Nuclear Factor Heterozygous Hepatocyte Nuclear Factor (HNF) -1(HNF) -1 mutation mutation

• Heterozygous mutations of the transcription factor HNF-1 (HNF1 homeobox B) gene have been associated with a form of MODY5, which is characterized by dominantly inherited diabetes mellitus with renal cysts

• This has been described in one child with PNDM and some small renal cysts whilst the other sibling only had transient hyperglycaemia but with more profound renal dysplasia

GLI-similar protein 3GLI-similar protein 3 (GLIS3)(GLIS3) mutationsmutations

• In 2006, Senee et al. described a frameshift mutation or deletions in the transcription factor GLIS3 in 3 consanguineous families with a history of neonatal diabetes, congenital hypothyroidism and facial dysmorphology (large, flat, square-shaped face with a thin and bird-shaped curved nose)

• Additional features in some but not all patients included congenital glaucoma, liver fibrosis and cystic kidneys

Possible association with enterovirus infectionPossible association with enterovirus infection

• A single case report has suggested that maternal enterovirus (echovirus 6) infection in pregnancy (end of first trimester) can lead to autoimmune, neonatal-onset diabetes with the presence of anti-insulin and glutamic acid decarboxylase antibodies at or very soon after birth

• Ruling out IPEX, the pancreas in this female child was very hypoplastic and the authors suggested a role for maternally transmitted enterovirus either by direct influence on pancreatic organogenesis or through aggressive -cell-targeted autoimmune attack

Diabetologia 2000;43:1235-1238

Main types of neonatal diabetes, their genetic basis, co-morbidities, treatment, outcome and relative frequencies as potential diagnoses

Treatment options in Treatment options in neonatal diabetes mellitusneonatal diabetes mellitus

• Insulin therapy and high caloric intake are the basis of treatment

• All neonates presenting acutely with diabetes should be started on insulin therapy

• In the case of 6q anomalies, diabetes will be transient but insulin is required until remission to prevent dehydration and allow normal growth

• In permanent neonatal diabetes due to conditions other than KCNJ11 and possibly ABCC8 mutations, insulin is also required long-term

• Some patients with mutations in KCNJ11 and ABCC8 may be transferred from insulin therapy to sulphonylureas

Genetic counsellingGenetic counselling

The risk of recurrence is different depending on whether The risk of recurrence is different depending on whether it is the transient or permanent form of neonatal diabetes it is the transient or permanent form of neonatal diabetes and the different molecular mechanisms identifiedand the different molecular mechanisms identified

Chromosome 6 anomaliesChromosome 6 anomalies• Cases of UPD6 are sporadic with low recurrence risk to

siblings and offspring

• In familial cases of unbalanced duplication of 6q24, affected male will have 50% risk of passing it to an offspring; the risk of passing a duplication of 6q24 from the mother to her offspring is low

Imprinting anomaly: logic says that the mother should pass it on but so far no familial case is known and the risk of transmission is unknown. The cause of imprinting relaxation is not identified and the identified children with this anomaly are too young to procreate

• The sibling and offspring risks for sporadic cases of methylation defect are not known

PNDM and Mendelian inheritance PNDM and Mendelian inheritance should be counselled accordingly should be counselled accordingly

• Recurrence risk is 25% in the autosomal recessive disorders ( EIF2AK, GLIS3, IPF-1 and PTF1A genes)

• IPEX is an x-linked disorder

• Mutations in genes encoding the potassium channel subunits are transmitted in the heterozygous state in a dominant way

ConclusionsConclusions

ConclusionsConclusions

• Effective treatment of neonatal diabetes requires thorough understanding of the underlying disease processes

• Successful studies illuminating these processes have not only improved our knowledge of pancreatic development and physiology, but also have revolutionized the treatment options for some patients

• The progress made in our scientific and clinical understanding of these extremely rare diseases is a perfect example of how studying seemingly rare illnesses can improve our overall knowledge of much more common conditions

Thank youThank you

diabetes mellitus an inborn error of metabolism ? dr grace poon department of paediatrics and...

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