Monogenic

diabetes

in

children

and

young

adults

Challenges

for

researcher

clinician

and

patient

Monogenic

diabetes

results

from

one

or

more

mutations

in

a

single

gene

which

might

hence

be

rare

but

has

great

impact

leading

to

diabetes

at

a

very

young

age

It

has

resulted

in

great

challenges

for

researchers

elucidating

the

aetiology

of

diabetes

and

related

features

in

other

organ

systems

for

clinicians

specifying

a

diagnosis

that

leads

to

improved

genetic

counselling

predicting

of

clinical

course

and

changes

in

treatment

and

for

patients

to

altered

treatment

that

has

lead

to

coming

off

insulin

and

injections

with

no

alternative

-LRB-

Glucokinase

mutations

-RRB-

insulin

injections

being

replaced

by

tablets

-LRB-

e.g.

low

dose

in

HNFα

or

high

dose

in

potassium

channel

defects

and

-RRB-

or

with

tablets

in

addition

to

insulin

-LRB-

e.g.

metformin

in

insulin

resistant

syndromes

-RRB-

Genetic

testing

requires

guidance

to

test

for

what

gene

especially

given

limited

resources

Monogenic

diabetes

should

be

considered

in

any

diabetic

patient

who

has

features

inconsistent

with

their

current

diagnosis

-LRB-

unspecified

neonatal

diabetes

type

or

type

diabetes

-RRB-

and

clinical

features

of

a

specific

subtype

of

monogenic

diabetes

-LRB-

neonatal

diabetes

familial

diabetes

mild

hyperglycaemia

syndromes

-RRB-

Guidance

is

given

by

clinical

and

physiological

features

in

patient

and

family

and

the

likelihood

of

the

proposed

mutation

altering

clinical

care

In

this

article

I

aimed

to

provide

insight

in

the

genes

and

mutations

involved

in

insulin

synthesis

secretion

and

resistance

and

to

provide

guidance

for

genetic

testing

by

showing

the

clinical

and

physiological

features

and

tests

for

each

specified

diagnosis

as

well

as

the

opportunities

for

treatment

Introduction

Monogenic

diabetes

is

diabetes

that

results

from

one

or

more

mutations

in

a

single

gene

The

mutation

might

have

arisen

de

novo

and

hence

be

a

spontaneous

case

or

might

be

dominantly

or

recessively

inherited

Molecular

genetic

testing

specifies

a

diagnosis

in

-LSB-

-RSB-

The

mechanism

can

be

easily

understood

from

the

underlying

pathophysiology

In

children

almost

all

monogenic

diabetes

results

from

mutations

in

genes

that

regulate

β-cell

function

and

infrequently

from

mutations

resulting

in

very

severe

insulin

resistance

-LSB-

-RSB-

This

article

discusses

the

pathophysiology

and

clinical

manifestations

used

to

select

patients

eligible

to

genetic

testing

and

demonstrates

the

importance

in

the

treatment

of

monogenic

diabetes

Why

diagnose

monogenic

diabetes

Many

patients

with

genetically

proven

monogenic

diabetes

were

initially

incorrectly

diagnosed

They

received

a

diagnosis

of

neonatal

diabetes

or

diabetes

diagnosed

before

the

age

of

months

that

was

not

further

specified

-LSB-

-RSB-

or

diagnosed

as

type

or

type

diabetes

-LSB-

-RSB-

It

is

important

to

correctly

diagnose

monogenic

diabetes

because

not

only

does

it

help

to

elucidate

the

aetiology

of

the

patient

's

diabetes

and

explain

other

associated

clinical

features

it

can

also

predict

the

clinical

course

of

the

patient

and

guide

the

most

appropriate

treatment

For

instance

patients

might

not

need

any

treatment

or

might

be

able

to

switch

from

insulin

injections

to

tablets

such

as

sulfonylurea

-LSB-

-RSB-

Finally

a

diagnosis

has

implications

for

other

family

members

often

correcting

their

diagnosis

prognosis

and

treatment

as

well

as

allowing

appropriate

genetic

counselling

Normal

insulin

release

and

normal

insulin

sensitivity

The

β-cells

form

the

core

of

the

islets

of

Langerhans

and

are

responsible

for

the

synthesis

and

secretion

of

insulin

and

C-peptide

-LRB-

Fig.

upper

part

-RRB-

Insulin

's

main

function

stimulating

glucose

uptake

in

peripheral

tissue

is

regulated

by

insulin

binding

to

insulin

receptors

on

the

cell

membrane

of

peripheral

cells

such

as

muscle

cells

This

binding

initiates

an

intracellular

signalling

cascade

that

leads

to

an

increase

in

the

glucose

influx

-LRB-

Fig.

-RRB-

Fig.

β-cell

and

the

genes

involved

in

monogenic

diabetes

Mutations

in

different

genes

result

in

different

phenotypes

-LRB-

Tables

and

-RRB-

Also

different

mutations

in

the

same

gene

might

lead

to

different

phenotypes

as

shown

in

the

spectrum

of

phenotypes

in

for

instance

The

upper

part

shows

the

physiological

situation

from

insulin

synthesis

to

packaging

and

from

glucose

sensing

to

insulin

secretion

From

centre

to

right

Insulin

synthesis

and

packaging

Insulin

-LRB-

Ins

-RRB-

is

synthesized

in

the

nucleus

regulated

by

transcription

factors

and

after

translation

in

the

endoplasmatic

reticulum

-LRB-

ER

-RRB-

and

Golgi

apparatus

-LRB-

Golgi

-RRB-

stored

in

granules

From

left

to

right

down

Glucose

sensing

and

insulin

secretion

Glucose

enters

the

β-cell

by

passive

diffusion

facilitated

by

the

-LRB-

-RRB-

It

is

phosphorylated

by

the

enzyme

glucokinase

-LRB-

GCK

-RRB-

to

-LRB-

-RRB-

and

metabolised

to

ATP

via

glycolysis

or

even

further

via

the

Krebs

cycle

in

the

mitochondria

-LRB-

Mito

-RRB-

ATP

closes

the

KATP

channel

preventing

K

efflux

depolarising

the

cell

membrane

Depolarisation

opens

voltage

dependent

calcium

channels

-LRB-

VDCC

-RRB-

allowing

calcium

influx

The

rise

in

intracellular

calcium

-LRB-

-RRB-

helps

the

insulin

granules

to

fuse

with

the

cell

membrane

resulting

in

insulin

secretion.The

lower

part

shows

the

pathological

situation

due

to

mutations

in

the

genes

involved

in

monogenic

diabetes

The

proteins

encoded

by

the

genes

involved

are

given

in

bold

type

followed

by

the

clinical

presentation

if

mutated

-LRB-

in

brackets

and

italics

-RRB-

From

centre

to

right

Insulin

synthesis

is

mainly

influenced

by

nuclear

transcription

factors

that

may

also

be

involved

in

pancreatic

development

and

hence

mutations

may

result

in

pancreatic

atrophy

-LRB-

-RRB-

or

agenesis

-LRB-

-RRB-

rather

than

reduced

insulin

synthesis

per

se

as

in

TNDM

-LRB-

ZAC

-RRB-

or

MODY

-LRB-

-RRB-

Mutations

in

genes

that

are

involved

in

packaging

of

the

insulin

into

granules

in

the

ER

and

Golgi

apparatus

result

in

TNDM

-LRB-

HYMAI

-RRB-

β-cell

destruction

and

PNDM

-LRB-

in

Wolcott

Rallison

Syndrome

WCRS

-RRB-

diabetes

at

a

mean

age

of

six

as

part

of

the

Diabetes

Insipidus

Diabetes

Mellitus

Optic

Atrophy

and

Deafness

syndrome

-LRB-

DIDMOAD

-RRB-

alternatively

called

Wolfram

syndrome

-LRB-

WRS

-RRB-

-LRB-

-RRB-

or

in

diabetes

as

part

of

the

Thiamine

Responsive

Megaloblastic

Anaemia

Syndrome

-LRB-

TRMAS

-RRB-

alternatively

called

Roger

's

syndrome

Mutations

in

T-lymphocytes

may

also

lead

to

β-cell

destruction

and

PNDM

as

seen

with

mutations

in

as

part

of

the

Immunodysregulation

Polyendocrinopathy

Enteropathy

X-linked

-LRB-

IPEX

-RRB-

syndrome

From

left

to

right

down

Glucose

sensing

is

reduced

by

mutations

in

leading

to

TNDM

as

part

of

the

Fanconi-Bickel

Syndrome

GCK

resulting

in

and

mitochondrial

DNA-interfering

with

oxidative

phosphorylation

These

latter

three

mutations

reduce

ATP

and

increase

ADP

leading

to

a

decreased

ATP/Mg-adenosine

diphosphate

-LRB-

ADP

-RRB-

ratio

that

activates

the

KATP

channel

to

remain

open

Activating

mutations

in

the

KATP

channel

itself

-LRB-

-RRB-

reduce

sensitivity

to

ATP

and

hence

also

favour

the

open

state

of

the

channel

The

subsequent

efflux

of

potassium

prevents

depolarisation

of

the

cell-membrane

and

hence

prevents

insulin

secretionFig

cell

-LRB-

e.g.

muscle

cell

-RRB-

showing

the

impact

of

diverse

mutations

that

result

in

insulin

resistance

In

the

physiological

situation

insulin

binds

to

the

insulin

receptor

resulting

in

phosphorylation

-LRB-

P

-RRB-

of

a

tyrosine

-LRB-

Y

-RRB-

residue

of

the

insulin

receptor

-LRB-

-RRB-

This

phosphorylation

activates

phosphatidylinositol

-LRB-

-RRB-

resulting

in

glucose

transporter

-LRB-

-RRB-

being

translocated

to

the

cell

membrane

which

in

turn

leads

to

glucose

influx

In

the

pathological

situation

mutations

in

the

insulin

receptor

interfere

with

insulin

receptor

synthesis

posttranslational

processing

and

intracellular-transport

of

the

receptor

to

the

cell

membrane

or

lead

to

reduced

binding

of

insulin

reduced

activation

or

increased

degradation

of

the

receptor

The

result

is

no

phosphorylation

of

Y

and

hence

eventually

no

glucose

uptake

This

situation

occurs

in

Type

A

severe

insulin

resistance

Rabson-Mendenhall

and

Leprechaunism

In

the

presence

of

high

levels

of

triglycerides

-LRB-

TG

-RRB-

and

hence

free

fatty

acids

-LRB-

FFA

-RRB-

a

serine

-LRB-

S

-RRB-

residue

is

phosphorylated

preventing

phosphorylation

of

Y

and

hence

eventual

glucose

uptake

This

situation

occurs

in

congenital

generalised

lipoatrophy

and

familial

partial

lipodystrophy

In

all

these

pathological

situations

higher

levels

of

insulin

are

needed

for

glucose

uptake

and

hence

lead

to

reduced

insulin

sensitivity

and

insulin

resistance

Abnormal

insulin

release

and

abnormal

insulin

sensitivity

Most

monogenic

diabetes

in

children

results

from

mutations

in

genes

causing

β-cell

loss

or

β-cell

dysfunction

and

hence

affect

insulin

synthesis

packaging

glucose

sensing

or

insulin

secretion

-LRB-

Fig.

lower

part

-RRB-

-LSB-

-RSB-

Mutations

of

pancreatic

transcription

factors

may

result

in

reduced

pancreatic

growth

-LRB-

sub

-RRB-

total

pancreatic

agenesis

or

reduced

insulin

synthesis

per

se

and

may

present

as

neonatal

diabetes

-LRB-

ND

-RRB-

maturity

onset

diabetes

of

the

young

-LRB-

MODY

-RRB-

or

diabetes

as

part

of

a

syndrome

-LRB-

Fig.

lower

part

centre

-RRB-

Other

mutations

that

affect

insulin

synthesis

are

not

expressed

in

the

pancreatic

β

cell

but

in

the

regulatory

T

lymphocytes

where

overactivation

results

in

auto-immunity

against

β-cells

typically

causing

diabetes

in

the

first

months

of

life

Mutations

affecting

translation

cleavage

and

packaging

of

insulin

may

result

in

reduced

β-cell

number

or

reduced

number

of

granules

and

lower

concentrations

of

insulin

in

these

granules

-LRB-

Fig.

lower

part

right

-RRB-

Mutations

that

affect

insulin

secretion

involve

genes

that

regulate

glucose

sensing

and

affect

beta-cell

function

rather

than

its

development

or

destruction

They

include

functional

mutations

in

mitochondrial

DNA

-LRB-

Fig.

lower

part

left

-RRB-

All

these

mutations

reduce

sensitivity

to

glucose

and

its

metabolism

favouring

the

open

state

of

the

potassium

channels

prevent

depolarisation

and

hence

insulin

secretion

In

children

monogenic

diabetes

infrequently

occurs

from

mutations

resulting

in

very

severe

insulin

resistance

-LRB-

Fig.

-RRB-

-LSB-

-RSB-

They

are

mainly

caused

by

mutations

in

the

insulin

receptor

gene

that

affect

its

synthesis

and

posttranslational

processing

increase

receptor

degradation

reduce

binding

of

insulin

or

receptor

activation

-LSB-

-RSB-

These

give

rise

to

type

A

severe

insulin

resistance

Rabson-Mendenhall

syndrome

or

Leprechaunism

-LSB-

-RSB-

Alternatively

insulin

resistance

may

be

the

result

of

hypertriglyceridaemia

associated

with

congenital

generalised

lipoatrophy

or

familial

partial

lipodystrophia

-LSB-

-RSB-

When

to

consider

a

diagnosis

of

monogenic

diabetes

Given

the

limited

resources

available

it

is

vital

that

genetic

tests

are

used

in

situations

where

they

are

likely

to

be

positive

and

will

alter

clinical

care

This

will

involve

careful

clinical

selection

and

physiological

tests

like

C

peptide

and

autoantibody

measurement

as

well

as

examination

of

other

family

members

before

doing

molecular

genetic

tests

Monogenic

diabetes

should

be

considered

in

any

diabetic

patient

who

has

features

inconsistent

with

their

current

diagnosis

and

clinical

features

of

specific

subtypes

of

monogenic

diabetes

No

specified

diagnosis

or

features

inconsistent

with

current

diagnosis

A

diagnosis

of

diabetes

might

have

been

made

without

further

specifying

the

cause

as

in

neonatal

diabetes

or

diabetes

diagnosed

below

the

age

of

months

Also

the

majority

of

patients

with

genetically

proven

monogenic

diabetes

are

initially

incorrectly

diagnosed

as

Type

or

Type

diabetes

-LSB-

-RSB-

No

specified

diagnosis

of

neonatal

diabetes

or

of

diabetes

diagnosed

below

the

age

of

months

Neonatal

diabetes

was

defined

as

insulin

requiring

diabetes

diagnosed

within

the

first

months

of

life

It

is

an

area

that

has

rapidly

transitioned

from

a

clinical

to

a

molecular

genetic

classification

-LSB-

-RSB-

There

is

good

evidence

that

diabetes

diagnosed

in

the

first

months

of

life

is

not

type

diabetes

because

neither

autoantibodies

typical

for

diabetes

nor

an

excess

of

high

type

HLA

susceptibility

are

found

in

these

patients

-LSB-

-RSB-

Diabetes

diagnosed

before

the

age

of

months

irrespective

of

current

age

should

always

lead

to

further

molecular

genetic

testing

Also

because

many

years

after

diagnosis

patient

and

doctor

will

find

difficulty

in

recalling

the

exact

age

of

diagnosis

and

only

be

aware

that

it

was

at

very

young

age

Features

that

help

differentiate

between

the

different

subtypes

and

hence

guide

genetic

testing

are

further

described

in

the

section

below

and

in

Table

Table

of

diabetes

diagnosed

before

months

of

age

in

addition

to

undetectable

to

low

C-peptideProtein

-LRB-

Chromosome/gene

Syndrome

-RRB-

Clinical

pictureNumber

of

cases

describedMedian

birth

weight

ingrams

SDS

-LRB-

standard

deviation

score

-RRB-

Median

age

at

diagnosis

in

weeks

-LRB-

range

-RRB-

Family

history

reflected

by

inheritanceOther

clinical

featuresOther

testsTreatment

-LRB-

in

consanguineous

or

isolated

populations

-RRB-

Pancreatic

appearance

-LRB-

present/size

-RRB-

ZAC/HYMAI

-LRB-

imprinting

defect

-RRB-

TNDM

-LRB-

rare

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Macroglossia

-LRB-

-RRB-

NormalInsulin/pump

relapse

diet

insulin

-LRB-

-RRB-

-LRB-

rare

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Spontaneous

DKA

-LRB-

-RRB-

NormalHigh

dose

sulfonylurea

Dominant

-LRB-

-RRB-

Developmentaldelay

-RRB-

Epilepsy

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Recessive

Severeneurological

dysfunctionAtrophyInsulin/pump

Cerebellar

hypoplasia

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

RecessiveNo

pancreasInsulin/pump

Parents

may

have

early

onset

diabetes

as

heterozygotes

-LRB-

-RRB-

-LRB-

-RRB-

Dominant

-LRB-

-RRB-

Renal

development

disordersAtrophyInsulin/pump

Spotaneous

-LRB-

Wolcott-Rallison

Syndrome

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Recessive

Epiphyseal

dysplasia

-LRB-

-RRB-

Exocrine

dysfunctionInsulin/pump

Developmental

delay

-LRB-

-RRB-

Acute

liver

failure

-LRB-

-RRB-

Osteopenia

-LRB-

-RRB-

Hypothyroidism

-LRB-

-RRB-

-LRB-

IPEX

Syndrome

-RRB-

-LRB-

rare

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

X-linked

Hence

only

boys

affected

Chronic

diarrhoea

with

villous

atrophy

-LRB-

-RRB-

Insulin/pump

Pancreatic

and

thyroid

autoantibodies

-LRB-

-RRB-

Eczena

-LRB-

-RRB-

Anaemia

-LRB-

-RRB-

Thyroiditis

-LRB-

-RRB-

Often

die

in

first

year

-LRB-

Fanconi

Bickel

Syndrome

-RRB-

TNDMRecessive

Impaired

utilisation

of

glucose

and

galactoseInsulin/pump

Hepatorenal

glycogen

accumulation

Proximal

renal

tubular

dysfunction

glucosuria

Glucokinase

-LRB-

homozygote

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

RecessiveNormalInsulin/pump

Parents

have

fasting

hyperglycaemia

as

heterozygotes

Clinical

features

that

are

unusual

for

type

diabetes

Type

diabetes

shares

clinical

features

with

certain

types

of

monogenic

diabetes

such

as

young

age

of

diagnosis

normal

body

weight

and

insulinopaenia

-LSB-

-RSB-

so

that

a

monogenic

diagnosis

can

be

overlooked

Features

in

children

initially

thought

to

have

type

diabetes

but

that

should

suggest

a

possible

diagnosis

of

monogenic

diabetes

are

shown

below

of

these

are

absolute

and

should

be

considered

collectively

rather

than

in

isolation

-LSB-

-RSB-

The

approximate

percentage

of

patients

with

type

diabetes

is

given

in

brackets

Age

of

diagnosis

below

months

after

birth

-LRB-

-RRB-

-LSB-

-RSB-

Family

history

with

a

parent

affected

-LRB-

-RRB-

-LSB-

-RSB-

Endogenous

insulin

production

after

years

of

diabetes

-LRB-

the

honeymoon

phase

-RRB-

indicated

by

detectable

C-peptide

-LRB-

nmol/l

-RRB-

in

response

to

raised

glucose

-LRB-

mmol/l

-RRB-

-LRB-

-RRB-

Absence

of

islet

autoantibodies

especially

when

measured

at

diagnosis

-LRB-

-RRB-

-LSB-

-RSB-

The

great

variation

in

antibody

prevalence

in

series

probably

represents

differences

in

assays

and

means

it

is

hard

to

apply

published

series

directly

into

clinical

practice

Absent

antibodies

should

lead

to

other

investigation/consideration

rather

than

leading

directly

to

genetic

tests

Clinical

features

that

are

unusual

for

type

diabetes

Type

diabetes

in

children

and

young

adolescents

might

share

features

which

meet

former

classification

criteria

for

MODY

such

as

diagnosed

years

autosomal

dominant

inheritance

and

non-insulin

dependency

-LSB-

-RSB-

Patients

might

have

a

rather

low

body

mass

index

and

have

other

features

that

are

unusual

for

type

diabetes

These

should

raise

suspicion

for

the

current

diagnosis

to

be

correct

as

chances

for

these

features

occurring

in

type

diabetic

children

or

adolescents

are

low

as

shown

here

-LRB-

percentage

shown

in

brackets

-RRB-

No

evidence

of

insulin

resistance

with

fasting

C-peptide

within

the

normal

range

-LRB-

-RRB-

-LSB-

-RSB-

Ethnic

background

from

a

low

prevalence

type

diabetes

race

e.g.

European

Caucasian

-LRB-

-RRB-

-LSB-

-RSB-

Acanthosis

nigricans

not

detected

-LRB-

-RRB-

-LSB-

-RSB-

Not

markedly

obese

or

diabetic

family

members

who

are

normal

weight

-LRB-

-RRB-

-LSB-

-RSB-

Clinical

features

of

specific

subtypes

of

monogenic

diabetes

and

their

treatment

Typical

clinical

presentations

in

children

when

a

diagnosis

of

monogenic

diabetes

should

be

considered

can

mainly

be

classified

into

four

categories

that

are

further

discussed

below

Neonatal

diabetes

and

diabetes

diagnosed

within

the

first

months

of

life

-LRB-

Table

-RRB-

Familial

diabetes

with

an

affected

parent

-LRB-

autosomal

dominant

-RRB-

-LRB-

Table

upperpart

-RRB-

Mild

-LRB-

mmol/l

-RRB-

fasting

hyperglycaemia

especially

if

young

or

familial

-LRB-

Table

lower

part

-RRB-

Features

in

other

tissues

as

part

of

genetic

syndromes

associated

with

diabetes

-LRB-

Tables

and

-RRB-

Neonatal

diabetes

and

diabetes

diagnosed

before

the

age

of

months

irrespective

of

current

age

Diabetes

diagnosed

before

the

age

of

months

is

most

likely

to

have

a

genetic

cause

and

further

clinical

aspects

should

be

investigated

to

guide

genetic

testing

Clinically

two

subgroups

were

recognised

transient

neonatal

diabetes

mellitus

-LRB-

TNDM

-RRB-

that

resolved

at

a

median

of

weeks

and

then

did

not

require

any

treatment

although

as

many

as

of

cases

relapsed

during

the

paediatric

age

range

-LSB-

-RSB-

In

contrast

permanent

neonatal

diabetes

mellitus

-LRB-

PNDM

-RRB-

required

lifelong

insulin

injections

from

diagnosis

onwards

The

majority

of

patients

with

TNDM

have

an

imprinting

abnormality

of

the

transcription

factor

ZAC

gene

and

HYMAI

gene

encoding

an

untranslated

RNA

chromosome

-LRB-

Table

-RRB-

-LSB-

-RSB-

Apart

from

macroglossia

seen

in

there

are

no

non-pancreatic

features

-LSB-

-RSB-

The

second

commonest

cause

of

mutations

in

patients

with

diabetes

diagnosed

before

the

age

of

months

of

life

are

mutations

in

the

gene

encoding

the

subunit

of

the

KATP

channel

and

that

can

result

in

either

TNDM

-LRB-

-RRB-

or

PNDM

-LRB-

-RRB-

-LSB-

-RSB-

Despite

being

a

heterozygous

mutation

most

have

no

family

history

because

of

cases

are

spontaneous

mutations

Most

patients

have

isolated

diabetes

although

neurological

features

are

seen

in

of

patients

The

most

severe

is

the

Developmental

delay

early

onset

generalised

Epilepsy

and

Neonatal

Diabetes

-LRB-

DEND

-RRB-

syndrome

-LSB-

-RSB-

More

common

is

the

intermediate

DEND

syndrome

where

patients

have

less

severe

developmental

delay

and

do

not

have

early

onset

generalised

epilepsy

and

that

is

often

associated

with

the

mutation

-LSB-

-RSB-

Recently

activating

mutations

in

the

gene

encoding

the

subunit

of

the

KATP

channel

were

found

to

be

a

similar

cause

of

neonatal

diabetes

-LSB-

-RSB-

While

the

majority

of

cases

in

PNDM

are

the

result

of

mutations

in

the

gene

in

a

small

minority

of

patients

many

different

genetic

mutations

have

been

described

-LSB-

-RSB-

If

both

parents

are

glucose

intolerant

homozygous

or

compound

heterozygous

mutations

in

glucokinase

are

most

frequent

-LSB-

-RSB-

Features

that

help

differentiate

between

TNDM

PNDM

and

the

different

subtypes

guide

which

gene

to

test

for

and

are

described

in

Table

Concerning

treatment

imprinting

abnormalities

of

the

locus

show

initially

very

high

glucose

values

-LRB-

range

mmol/l

-RRB-

and

so

insulin

is

used

initially

although

the

dose

can

rapidly

be

reduced

Once

patients

have

relapsed

patients

should

remain

under

annual

follow

up

due

to

the

risk

of

diabetes

relapsing

Relapse

patients

are

not

insulin

dependent

and

can

be

treated

with

diet

initially

although

subsequently

often

need

insulin

-LSB-

-RSB-

The

long-term

response

to

oral

treatment

such

as

sulfonylurea

or

metformin

is

uncertain

Patients

with

mutations

have

all

the

clinical

features

of

insulin

dependency

as

present

with

ketoacidosis

and

they

usually

do

not

have

detectable

C

peptide

and

so

were

treated

with

insulin

-LSB-

-RSB-

It

has

recently

been

shown

that

these

patients

can

not

only

be

successfully

treated

with

oral

sulfonylureas

but

can

also

get

better

glycaemic

control

without

an

increase

in

hypoglycaemia

and

with

neurological

features

improving

as

well

-LSB-

-RSB-

The

doses

needed

are

high

when

calculated

on

a

per

kg

body

weight

basis

compared

to

adults

with

patients

typically

needing

mg

glibenclamide/kg/day

although

some

may

need

as

much

as

mg/kg/day

-LSB-

-RSB-

With

time

many

patients

have

been

able

to

reduce

their

doses

of

sulfonylurea

while

maintaining

excellent

glycaemic

control

-LSB-

-RSB-

Similar

results

have

recently

been

found

for

patients

with

activating

mutations

-LSB-

-RSB-

All

other

causes

need

to

be

treated

with

insulin

Some

paediatricians

find

these

patients

are

best

managed

on

subcutaneous

insulin

pumps

due

to

the

fluctuations

in

glucose

levels

In

patients

with

pancreatic

aplasia

exocrine

pancreatic

supplements

will

additionally

be

required

Familial

diabetes

with

an

affected

parent

Children

and

young

adults

with

a

strong

family

history

of

diabetes

Genetic

causes

of

a

family

history

of

diabetes

are

autosomal

dominant

and

non-insulin

dependent

A

diagnosis

of

Maturity

Onset

Diabetes

of

the

Young

-LRB-

MODY

-RRB-

should

be

considered

whenever

a

parent

has

diabetes

even

if

they

are

thought

to

have

type

or

type

diabetes

-LRB-

Table

-RRB-

MODY

comes

in

two

major

subgroups

-LRB-

-RRB-

the

result

of

transcription

factor

mutations

-LRB-

or

-RRB-

described

in

this

section

and

-LRB-

-RRB-

mutations

reducing

glucose

sensing

-LRB-

glucokinase

-RRB-

in

which

a

family

history

might

be

less

evident

because

it

only

presents

as

mild

hyperglycaemia

as

described

in

the

following

section

MODY

due

to

transcription

factor

mutations

often

present

in

adolescence/young

adulthood

show

progressive

hyperglycaemia

and

frequently

lead

to

complications

Of

the

transcription

factor

mutations

due

to

mutations

is

the

commonest

form

-LSB-

-RSB-

The

clinical

characteristics

of

patients

with

mutations

are

Young

onset

diabetes

that

shows

characteristics

of

not-being

insulin

dependent

e.g.

do

not

develop

keto-acidosis

in

the

absence

of

insulin

achieve

good

glycaemic

control

on

a

small

dose

of

insulin

Detectable

C-peptide

is

measured

when

on

insulin

with

glucose

mmol/l

after

years

of

diabetes

-LRB-

the

honeymoon

period

-RRB-

Family

history

of

diabetes

This

might

be

insulin

treated

and

considered

to

be

type

diabetes

This

would

typically

be

diagnosed

at

their

or

There

may

also

be

an

affected

grandparent

although

often

these

are

diagnosed

after

years.Glucosuria

at

relatively

normal

blood

glucose

levels

are

often

seen

as

these

patients

have

a

low

renal

threshold

-LSB-

-RSB-

Oral

glucose

tolerance

tests

in

early

stages

tend

to

show

a

very

large

glucose

increment

usually

mmol/l

-LSB-

-RSB-

Some

patients

might

have

a

normal

fasting

value

while

still

rise

into

the

diabetic

range

at

h.Marked

sensitivity

to

sulfonylurea

resulting

in

hypoglycaemia

despite

poor

glycaemic

control

before

starting

sulfonylurea

-LSB-

-RSB-

Table

diabetes

diagnosed

or

undiagnosed

due

to

mild

hyperglycaemiaGene/proteinClinical

pictureNumber

of

cases

describedMedian

age

at

diagnosis

in

weeks

-LRB-

range

-RRB-

Family

history

reflected

by

inheritanceOther

clinical

featuresOther

testsTreatmentGlucose

at

presentation

in

mmol/l

Median

-LRB-

range

-RRB-

OGTTFamilial

diabetes

-LRB-

-RRB-

DominantHyperglycaemia

is

rapidly

progressive

with

-LRB-

-RRB-

Large

increment

-LRB-

h

h

usually

mmol/l

-RRB-

Diet

low

dose

of

sulfonylureaLow

renal

threshold

glucosuriaSensitive

to

-LRB-

-RRB-

DominantHyperglycaemia

is

rapidly

progressive

with

-LRB-

-RRB-

Large

increment

-LRB-

h

h

usually

mmol/l

-RRB-

Low

dose

of

sulfonylureaNormal

renal

thresholdSensitive

to

sulfonylureaReduced

levels

of

apoAIII

apoCIII

and

triglyceridesOther

unusual

causes

-LRB-

-RRB-

-LRB-

-RRB-

CEL

-LRB-

-RRB-

Familial

diabetes

undiagnosed

due

to

mild

fasting

hyperglycaemiaGlucokinase

-LRB-

GCK

heterozygous

-RRB-

-LRB-

-RRB-

DominantHyperglycaemia

is

mild

-LRB-

fasting

mmol/l

-RRB-

-LRB-

-RRB-

Small

increment

-LRB-

h

h

usually

mmol/l

-RRB-

No

treatment

-LRB-

The

mild

hyperglycaemia

might

not

have

been

diagnosed

in

relatives/parents

-RRB-

Hyperglycaemia

is

only

slowly

progressive

with

age

usually

diagnosis

is

by

incidental

findingNormal

renal

threshold

Patients

with

gene

mutations

can

initially

be

treated

through

diet

although

they

will

have

marked

postprandial

hyperglycaemia

after

high

carbohydrate

food

as

the

β-cell

defect

results

in

insufficient

increase

in

insulin

secretion

with

hyperglycaemia

-LSB-

-RSB-

Most

patients

will

need

pharmacological

treatment

as

they

show

progressive

deterioration

in

glycaemic

control

throughout

life

and

are

at

risk

of

considerable

micro-vascular

and

macro-vascular

complications

-LSB-

-RSB-

The

first

treatment

to

be

used

in

children

who

are

not

controlled

on

insulin

should

be

low

dose

sulfonylureas

which

results

in

a

greater

lowering

of

glucose

than

metformin

-LSB-

-RSB-

These

patients

are

extremely

sensitive

to

sulfonylurea

and

as

long

as

they

do

not

have

problems

with

hypoglycaemia

can

be

maintained

on

these

for

many

decades

-LSB-

-RSB-

Glycaemic

control

in

sulfonylureas

is

often

better

than

that

achieved

on

insulin

especially

in

children

and

young

adults

-LSB-

-RSB-

The

dose

of

sulfonylureas

should

initially

be

low

-LRB-

of

the

normal

starting

dose

in

adults

-RRB-

to

avoid

hypoglycaemia

If

there

is

hypoglycaemia

despite

dose

titration

of

a

once

or

twice

daily

sulfonylurea

preparation

such

as

Gliclazide

a

slow

release

preparation

or

mealtime

doses

with

short-acting

agents

like

nateglinidine

may

be

considered

-LSB-

-RSB-

Mutations

in

the

hepatocyte

nuclear

factor

4α

-LRB-

-RRB-

gene

resulting

in

are

considerably

less

common

have

similar

characteristics

but

might

be

diagnosed

later

and

patients

have

no

low

renal

threshold

-LSB-

-RSB-

They

also

lead

to

reduced

levels

of

triglycerides

and

the

apolipoproteins

apoAIII

and

apoCIII

-LSB-

-RSB-

Diagnosis

should

be

considered

when

tests

negative

while

the

clinical

features

are

strongly

suggestive

for

-LSB-

-RSB-

Patients

with

α

mutations

are

usually

sensitive

to

sulfonylurea

-LSB-

-RSB-

The

handful

of

families

with

autosomal

dominant

non-insulin

dependent

diabetes

that

have

further

been

described

include

mutations

in

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

and

recently

the

carboxyl

ester

lipase

-LRB-

CEL

-RRB-

gene

-LRB-

-RRB-

-LSB-

-RSB-

but

these

are

so

unusual

they

do

not

need

to

be

tested

for

in

children

with

diabetes

except

in

a

research

setting

or

when

there

are

additional

phenotypes

such

as

pancreatic

exocrine

dysfunction

-LSB-

-RSB-

IPF

has

been

described

under

neonatal

diabetes

encodes

a

transcription

factor

that

binds

to

a

critical

Ebox

motif

on

the

insulin

promoter

and

plays

a

role

in

both

pancreatic

and

neuron

development

Mild

-LRB-

mmol/l

-RRB-

fasting

hyperglycaemia

especially

if

young

or

familial

Raised

fasting

blood

glucose

in

the

range

of

to

mmol/l

is

unusual

in

children

and

young

adults

This

always

raises

concern

that

they

may

be

about

to

develop

type

diabetes

or

have

type

diabetes

However

a

considerable

proportion

of

these

patients

with

persistent

mild

fasting

hyperglycaemia

will

have

a

heterozygous

mutation

in

the

glucokinase

gene

The

phenotype

associated

with

glucokinase

mutations

is

remarkably

similar

for

all

mutations

with

the

following

features

suggesting

a

diagnosis

The

fasting

hyperglycaemia

is

persistent

and

stable

over

a

period

of

months

or

years

-LSB-

-RSB-

is

typically

just

below

or

just

above

the

upper

limit

of

normal

-LRB-

to

-RRB-

In

an

oral

glucose

tolerance

test

the

increment

-LRB-

h

glucose-fasting

glucose

-RRB-

is

small

-LRB-

typically

mmol/l

-RRB-

although

because

of

the

variability

of

the

oral

glucose

tolerance

test

this

should

not

be

considered

an

absolute

criteria

-LSB-

-RSB-

Parents

may

have

type

diabetes

or

may

not

be

diabetic

On

testing

one

parent

will

have

a

mildly

raised

fasting

blood

glucose

in

the

range

of

mmol/l

as

this

is

an

autosomal

dominant

condition

-LSB-

-RSB-

Testing

of

fasting

glucose

in

apparently

unaffected

parents

is

important

when

considering

a

diagnosis

of

a

glucokinase

mutation

The

fasting

hyperglycaemia

does

not

deteriorate

significantly

and

the

glucose

is

regulated

at

the

higher

set

point

-LSB-

-RSB-

As

this

is

rarely

associated

with

any

microvascular

or

macrovascular

complications

even

when

no

treatment

is

given

throughout

life

and

as

there

is

very

little

if

any

response

to

either

oral

hypoglycaemic

agents

or

insulin

because

the

set

point

remains

the

same

these

patients

do

not

need

treating

in

the

paediatric

age

range

-LSB-

-RSB-

Genetic

syndromes

associated

with

diabetes

When

diabetes

in

a

child

is

associated

with

other

multi-system

disease

the

possibility

of

a

monogenic

syndrome

that

explains

all

features

should

be

considered

The

online

Mendelian

inheritance

in

Man

-LRB-

OMIM

-RRB-

website

-LRB-

access

through

the

NCBI

website

-RRB-

can

help

with

clinical

features

and

to

know

if

the

gene

has

been

defined

and

hence

molecular

genetic

testing

is

available

For

described

and

previously

undescribed

syndromes

see

the

ISPAD

rare

diabetes

collection

-LRB-

contact

through

link

on

the

ISPAD

website

or

through

-RRB-

The

most

common

genetic

syndromes

that

include

diabetes

are

described

below

and

in

Tables

-LRB-

insulin

synthesis/secretion

-RRB-

and

-LRB-

insulin

resistance

-RRB-

Table

features

in

addition

to

the

diabetes

insulin

synthesis/secretionGene/proteinClinical

pictureNumber

of

cases

describedMedian

age

at

diagnosis

in

weeks

-LRB-

range

-RRB-

Family

history

reflected

by

inheritanceOther

clinical

isolated

PNDM

or

MODY

Renal

developmental

disorders

especially

renal

cysts

and

dysplasiaInsulin

-LRB-

possibly

treat

exocrine

deficiency

-RRB-

cysts

and

diabetes

syndrome

-LRB-

RCAD

-RRB-

Uterine

and

genitalia

developmental

anomalies

Hyperuricaemia

gout

Abnormal

liver

function

insipidus

diabetes

mellitus

optic

atrophy

deafness

-LRB-

DIDMOAD

-RRB-

syndrome/Wolfram

syndrome

-LRB-

have

mutations

-RRB-

Especially

where

consanguineous

marriages

are

years

-LRB-

Most

years

-RRB-

Dominant

Diabetes

insipidus

Optic

atrophy

Bilateral

sensorineural

deafness

Dilated

renal

tracts

Truncal

ataxia

Protean

neurological

signs

has

the

complete

phenotype

increasing

with

increasing

-LRB-

Thiaminetransporter

protein

-RRB-

Thiamine

responsiveMegaloblastic

anaemia

-LRB-

TRMA

-RRB-

syndrome

Roger

's

syndromeRareRecessive

Thiamine

responsive

megaloblastic

anaemia

Sensorineural

deafnessThiamine

insulin

tRNA

-LRB-

leu

-LRB-

UUR

-RRB-

-RRB-

gene

-LRB-

A

to

G

tRNA

-RRB-

Maternally

inherited

diabetes

-LRB-

MID

-RRB-

Mitochondrial

myopathy

encephalopathy

lactic

acidosis

stroke-like

syndrome

-LRB-

MELAS

-RRB-

Sensorineural

deafness

Short

stature

Subclinical

exocrine

deficiency

HeteroplasmyInsulinTable

features

in

addition

to

the

diabetes

insulin

resistanceProteinClinical

pictureMedian

age

at

diagnosis

in

weeks

-LRB-

range

-RRB-

Family

history

reflected

by

inheritanceOther

clinical

featuresOther

features/testsTreatmentAcanthosis

nigricansInsulin

levelsAndrogen

excess

and

hypertrichosisInsulin

receptorType

AAdolescenceRecessive

-LRB-

usually

-RRB-

Insulin

resistance

in

absence

of

obesityYes

marked

PCO

-LRB-

Metformin/glitazones

-RRB-

insulin/pumpInsulin

receptorRabson-MendenhallCongenitalRecessive

-LRB-

usually

-RRB-

Abnormal

dentitionYes

marked

PCO

-LRB-

Metformin/glitazones

-RRB-

insulin/pump

Extreme

growth

retardationInsulin

receptorLeprechaunism

-LRB-

Donahue

syndrome

-RRB-

CongenitalRecessive

-LRB-

usually

-RRB-

Abnormal

faciesYes

marked

PCO

-LRB-

Metformin/glitazones

-RRB-

insulin/pump

SGA

and

growth

retardation

Large

genitalia

Rarely

survive

infancySeipin

lipodystrophyAdolescence

or

congenitalRecessive

Total

loss

of

subcutaneous

fatYes

may

be

marked

PCO

Recombinant

insulinLamin

AC&PPAR

γPartial

lipodystrophyDominant

Partial

loss

of

subcutaneous

fatMetformin

insulin

due

to

an

mutation

-LRB-

renal

cysts

and

diabetes

syndrome

The

transcription

factor

hepatocyte

nuclear

factor

β

is

expressed

in

primitive

pancreatic

duct

cells

involved

in

early

endocrine

cell

differentiation

incidentally

leading

to

PNDM

but

mainly

leading

to

with

pancreatic

atrophy

as

a

consistent

finding

when

assessed

by

abdominal

computed

tomography

-LSB-

-RSB-

Patients

with

mutations

rarely

present

with

isolated

diabetes

-LSB-

-RSB-

Renal

developmental

disorders

especially

renal

cysts

and

renal

dysplasia

are

present

in

almost

all

patients

with

mutations

or

gene

deletions

-LSB-

-RSB-

These

may

be

diagnosed

in

utero

and

precede

the

diagnosis

of

diabetes

A

diagnosis

of

should

be

considered

in

any

child

with

diabetes

who

also

has

non-diabetic

renal

disease

Other

features

are

presented

in

Table

Patients

with

mutations

unlike

patients

with

mutations

are

not

sensitive

to

sulfonylurea

and

hence

usually

require

insulin

treatment

-LSB-

-RSB-

Pancreatic

size

is

reduced

reflecting

a

reduction

in

both

the

endocrine

and

exocrine

pancreas

and

sub-clinical

exocrine

deficiency

is

present

in

most

patients

-LSB-

-RSB-

but

it

is

uncertain

if

this

should

be

treated

if

it

is

asymptomatic

Wolfram

or

DIDMOAD

syndrome

-LRB-

diabetes

insipidus

diabetes

mellitus

optic

atrophy

and

deafness

-RRB-

This

autosomal

recessive

syndrome

shows

mutations

in

the

gene

for

Wolfram

syndrome

-LRB-

-RRB-

in

at

least

of

patients

-LSB-

-RSB-

and

the

association

of

diabetes

with

progressive

optic

atrophy

below

years

of

age

is

diagnostic

-LSB-

-RSB-

Other

features

are

described

in

Table

with

the

complete

phenotype

seen

in

of

patients

with

increasing

prevalence

with

age

The

order

of

appearance

of

the

neurological

features

may

vary

even

within

families

Patients

with

Wolfram

syndrome

die

at

a

median

age

of

years

-LSB-

-RSB-

The

diabetes

is

non-autoimmune

and

insulin

deficient

and

presents

at

a

mean

age

of

years

-LSB-

-RSB-

Patients

require

insulin

treatment

from

the

time

of

diagnosis

but

autoantibodies

are

not

present

-LSB-

-RSB-

Roger

's

or

TRMA

syndrome

-LRB-

thiamine

responsive

megaloblastic

anaemia

-RRB-

The

diabetes

in

this

rare

recessive

genetic

syndrome

is

insulin

deficient

in

nature

and

both

the

diabetes

and

the

anaemia

are

responsive

to

thiamine

However

all

seem

to

develop

an

insulin

requirement

in

the

long

term

-LSB-

-RSB-

Further

details

are

described

in

Table

Mitochondrial

diabetes

Maternal

transmission

of

mutated

or

deleted

mitochondrial

DNA

-LRB-

mtDNA

-RRB-

can

result

in

maternally

inherited

diabetes

-LSB-

-RSB-

although

they

do

not

usually

occur

in

the

paediatric

age

range

Patients

suffer

from

sensorineural

deafness

and

short

stature

In

family

members

there

might

be

some

overlap

between

MIDD

and

MELAS

syndrome

-LSB-

-RSB-

The

heteroplasmy

in

proportions

of

mitochondrial

DNA

affected

lead

to

a

variety

of

phenotypes

The

diabetes

is

characterised

by

progressive

non-autoimmune

β-cell

failure

usually

manifests

outside

the

paediatric

age

range

and

may

progress

to

needing

insulin

treatment

rapidly

Other

features

are

described

in

Table

Insulin

resistance

syndromes

The

key

features

of

all

insulin

resistance

syndromes

are

acanthosis

nigricans

massively

raised

insulin

concentrations

and

androgen

excess

while

obesity

is

absent

-LRB-

Table

-RRB-

-LSB-

-RSB-

The

more

severe

the

insulin

resistance

and

the

earlier

the

onset

the

more

likely

is

diabetes

The

mechanism

of

the

main

insulin

resistance

syndromes

Type

A

Rabson-Mendenhall

Leprechaunism

and

Lipodystrophy

is

shown

in

Fig.

while

the

key

clinical

features

of

the

main

insulin

syndromes

are

presented

in

Table

-LSB-

-RSB-

Treatment

of

severe

insulin

resistance

is

very

difficult

and

most

patients

with

diabetes

have

poor

glycaemic

control

and

frequently

develop

long-term

complications

-LSB-

-RSB-

Treatment

approaches

include

the

use

of

the

insulin

sensitisers

metformin

and

glitazones

but

effectiveness

is

limited

when

the

insulin

resistance

is

very

severe

Insulin

is

the

main

stay

of

treatment

and

insulin

and

insulin

pumps

are

usually

required

-LSB-

-RSB-

In

partial

lipodystrophy

metformin

may

have

benefit

and

insulin

is

not

required

in

the

early

stages

-LSB-

-RSB-

In

total

lipodystrophy

the

response

of

diabetes

to

recombinant

lipodystrophy

-LSB-

-RSB-

can

be

dramatic

but

is

only

available

on

a

research

basis

Testing

for

a

molecular

monogenic

diagnosis

How

to

test

for

monogenic

diabetes

While

in

type

and

type

diabetes

there

is

no

single

diagnostic

test

this

is

not

the

case

in

monogenic

diabetes

where

in

of

cases

a

molecular

genetic

diagnosis

can

be

made

by

DNA

testing

These

are

offered

by

many

laboratories

but

should

preferably

be

performed

in

a

laboratory

that

is

experienced

and

specialised

in

such

diagnosis

irrespective

whether

this

requires

sending

samples

abroad

-LRB-

-RRB-

Some

recently

described

monogenic

genes

such

as

in

patients

in

whom

diabetes

was

diagnosed

before

the

age

of

months

can

be

screened

for

with

no

charge

-LRB-

-RRB-

Other

tests

are

more

expensive

-LRB-

up

to

Euro

or

USD

-RRB-

but

make

future

patient

care

cheaper

and

hence

testing

would

be

cost-effective

For

example

in

a

Swiss

centre

yearly

costs

for

type

diabetes

was

approximately

Euro

-LRB-

USD

-RRB-

per

type

patient

compared

to

Euro

-LRB-

USD

-RRB-

per

patient

-LSB-

-RSB-

Approval

from

the

patient

's

insurance

company

should

be

sought

prior

to

sending

DNA

when

applicable

Future

analyses

will

show

cost-effectiveness

for

the

different

subtypes

and

prove

earlier

diagnosis

to

be

more

beneficial

What

if

a

monogenic

diagnosis

can

not

be

made

Occasionally

molecular

genetic

test

results

are

negative

despite

unusual

clinical

features

or

typical

features

for

a

certain

monogenic

subtype

The

certainty

of

such

a

negative

result

increases

if

a

specialised

centre

performed

testing

Even

then

some

cases

remain

unsolved

These

can

be

referred

to

the

ISPAD

rare

cases

registry

-LRB-

see

website

or

contact

a.t.hattersley@exeter.ac.uk

-RRB-

to

allow

pattern

finding

and

closer

investigation

by

experts

if

a

novel

idea

evolves

hence

increasing

chances

for

new

and

future

insights

novel

diagnoses

and

improved

patient

care

Summary

Molecular

genetic

testing

can

define

a

diagnosis

in

of

all

diabetic

patients

with

monogenic

diabetes

Advances

in

this

field

have

led

to

the

identification

of

the

genes

associated

with

many

clinically

identified

subgroups

of

diabetes

and

explained

clinical

heterogeneity

in

conditions

defined

by

age

of

diagnosis

e.g.

neonatal

diabetes

and

MODY

Molecular

genetic

tests

are

now

available

to

help

define

the

diagnosis

and

importantly

alter

prognosis

and

optimise

treatment

of

children

young

adults

and

their

families

with

diabetes

As

these

tests

are

expensive

genetic

testing

should

be

limited

to

those

who

on

clinical

grounds

are

likely

to

be

positive

Considering

testing

for

monogenic

diabetes

is

hence

a

challenge

and

should

be

guided

by

unusual

features

of

the

current

diagnosis

specific

features

concordant

with

monogenic

subtypes

and

by

the

possibility

of

a

change

in

treatment

This

article

discussed

the

pathophysiology

and

clinical

manifestations

used

to

select

eligible

patients

and

guide

genetic

testing

and

demonstrates

its

importance

in

the

treatment

of

monogenic

diabetes

B I O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B I O O O O O O B I O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O

monogenic diabetes
neonatal diabetes
mody
gck