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Maturity-Onset Diabetes of the
Young (MODY)
Dr. VŨ CHÍ DŨNG
National Hospital of Pediatrics
Case No. 1
DOB: June 25.1996
History
• 14.5 year old boy
• 2 months before admission: polydipsia, polyuria,
unknown weight loss
• 3 days before admission: vomiting, no fever,
abdominal pain, polyuria, lethargy then coma
On admission
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Weight: 30 kg
Height: 138 cm (< 3 percentile);
BMI 16 (3rd percentile)
SpO2: 100%, BP: 110/60 mmHg
BR: 35b/m; HR: 100b/m
Clear pulse
Coma: V/AVPU
Dehydration (+)
Others: unremarkable
Investigations
• BG: 97 mmol/l; HbA1C: 20.4%
• Insulin: 142 μU/ml; C-peptide: 0.296 ng/ml
• pH: 7.25; pCO2: 28.8 mmHg; HCO3-: 12 mmol/l;
BE -13 mmol/l
• Urea: 31.6 mmol/; Creatinine: 351 Mmol/l
• GOT: 17 UI/l; GPT: 44 UI/l
• Na: 113 mmol/l (corected 145.6); K: 3.5 mmol/l; Cl
86 mmol/l; Ca: 2.2 mmol/l
• Urinary glucose (500 mg/dl), ketonuria (5 mg/dl)
Diagnosis & Management
 DKA
 Management
– Infusion: NaCl 9% + KCl (40mmol/l)
– Insulin: 0.1 UI/kg/hour
– After 2 day of treatment: alert, no dehydration,
pH: 7.42; HCO3: 20 mmol/l; no ketonuria; high
blood glucose levels 24 – 35 mmol/l & still
kidney failure (creatinine 247-318 mol/l)
Investigations
 Abdominal ultrasound:
R kidney 80 x 42 mm, multi cyst 3 – 5 mm,
pyelectasis
L kidney 80 x 38 mm, nhu mô tăng âm nhẹ, trong
multi cyst 3 – 5 mm, pyelectasis
Investigations
• Abdominal CT scan:
Pancreatic body & tail were not seen
Pancreatic head had dimension of 13 x 17 mm
Right kidney 13.0 x 4.3 x 3.2 mm.
Left kidney 15.0 x 4.5 x 3.4 mm
In kidneys some cysts with dimension of 3 mm &
pyelectasis were seen
Case Summary
14.5 year old boy
Polydipsia, polyuria, DKA
No obese
Unclear family history of diabetes
BG: 97 mmol/l
kidney failure & kidney multi cysts, pancreatic
atrophy
Diagnosis: MODY type 5 ???
Heterozygous HNF-1β
missense mutation,
S148L (c.443C>T)
Case No. 2
DOB: 18 Nov 1996
History
• 1st child, full team, WOB 2200 gram
• Jaundice at 3 months of age
• Treated at department of hepatology during 10
days (diagnosis: hepatitis)
• Normal moto-mental development
At 7 years of age
• Right kidney atrophy was identified using
sintigraphy.
• Urea 10.6 mmol/l, creatinine 147 µmol/l, Na+ 142
mmol/l, K+ 3.4 mmol/l, Cl- 109 mmol/l, AST 408
U/l, ALT 729 U/l
• following up by nephrologist at NHP
At 14 years of age
• Polyuria, polydipsia, weight loss (2 kg/w)
• Plasma glucose: very high
• HbA1C 13.6%, urea 10.1 mmol/l, creatinin 250
µmol/l, AST 178 UI/l, ALT 123 UI/l
• Ultrasound: bilateral kidney atrophy: R 44 x 22
mm; L 73 x 36 mm
Mutation analysis
• Heterozygous for a novel HNF1B missense
mutation, p.Y169H.
• This mutation results in the substitution of the
amino acid histidine (charged polar) for tyrosine
(uncharged polar) at codon 169.
• No mutation in parents  de novo mutation
Monogenic Diabetes
• Single gene mutation that regulate beta-cell
function
• Dominantly or recessively inherited or may be a
de novo mutation & hence a spontaneous case
• Rare: 1-5% of total diabetes cases
• Primary defects of insulin secretion
• Treatment: Oral agents/insulin
• Forms: neonatal diabetes and MODY (MaturityOnset Diabetes of the Young)
Β-Cell
Diagnosis
Why diagnose monogenic diabetes?
• Predict clinical course of patient
• Explain other associated clinical features
• Most importantly guide the most appropriate
treatment
• Implications for other family members often
correcting the diagnosis and treatment
• Appropriate genetic counseling
Diagnosis
Clinical presentation of monogenic diabetes
• Neonatal diabetes & diabetes diagnosed within
the first 6 months of life
• Familial diabetes with an affected parent
• Mild (5.5–8.5 mmol/l) fasting hyperglycaemia
especially if young or familial
• Diabetes associated with extra pancreatic
features
MODY
• OMIM: describes MODY 1-11
Genes encode glucokinase, the transcription factors,
and insulin promoter
• Testing available for MODY 1-6
• Often discovered during routine blood testing
• Not overweight
• No risk factors for Type 2 Diabetes or metabolic
syndrome
• Autosomal dominant inheritance
• Family history of successive generations
Common characteristics
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Mild/moderate hyperglycemia (5.5 – 8.5 mmol/l)
First degree relative/similar degree of diabetes
Absence of diabetes autoantibodies
Absence of other autoimmunity
Presence of low insulin requirement (<0.5 u/kg/d)
past the usual “honeymoon” period
• Absence of obesity, hyperlipidemia, PCOS
• History of cystic kidney disease (MODY 5)
• Non-transient neonatal diabetes or DM1 before 6
months of age
MODY3 - Hepatocyte Nuclear Factor HNF1A
mutation
• Young-onset diabetes shows characteristics of not
being insulin dependent
• Family history of diabetes. This may be treated
with insulin and considered to be ‘T1DM’
• Oral glucose tolerance tests (OGTTs) in early
stages tend to show a very large glucose
increment, usually >5 mmol/L. Some subjects may
have a normal fasting value but still rise into the
diabetic range at 2 h
MODY3 - Hepatocyte Nuclear Factor
HNF1A mutation
• Glycosuria at relatively normal blood glucose
levels is often seen
• Marked sensitivity to sulfonylureas resulting in
hypoglycaemia
• Treatment - first treatment to be used in children
should be low-dose sulfonylureas
MODY1: HNF4A gene mutations
• Children & young adults with diabetes & a strong
family history of diabetes
• Less common than diabetes due to mutations of
HNF1A gene but has similar characteristics,
except no low renal threshold & age of diagnosis
may be later
MODY1: HNF4A gene mutations
• HNF4A mutations should be considered when
HNF1A sequencing is negative but clinical
features were strongly suggestive of HNF1A
• Treatment - Patients are often sensitive to
sulfonylureas
MODY2 - glucokinase mutations
• Strong family history of diabetes. Parents may
have ‘T2DM’ or may not be diabetic
• Fasting hyperglycemia is persistent & stable
over a period of months or years
• HbA1c is typically just below or just above upper
limit of normal range (5.5–5.7%)
MODY2 - glucokinase mutations
• OGTT: increment (2-h glucose – fasting glucose)
is small (typically <3.5 mmol/L)
• Treatment: do not need treating in paediatric
age range. There is very little, if any, response to
either oral hypoglycemic agents or insulin
MODY5: Renal cysts & diabetes
syndrome due to a HNF1B mutation
• Patients with mutations in HNF1B rarely present
with isolated diabetes.
• Renal developmental disorders, especially renal
cysts & renal dysplasia, are present in almost all
patients
• Other features which may be present in children
include uterine & genitalia developmental
anomalies, hyperuricemia, gout, and abnormal
liver function tests
MODY5: Renal cysts & diabetes
syndrome due to a HNF1B mutation
• Diagnosis of HNF1B should be considered in
any child with diabetes who also has nondiabetic renal disease
• Patients with HNF1B mutations usually require
insulin treatment.
• Pancreatic size is reduced reflecting a reduction
in both the endocrine and exocrine pancreas,
and subclinical exocrine deficiency is present in
most patients
MODY5 at NHP, Hanoi
 3/286 (1%) children with diabetes
• Case No. 3 (first case) confirmed diagnosis using
molecular analysis in 1/2011
• 1 case 14.5 years of age was confirmed in
4/2011: kidney failure from 7 years, diabetes from
13 years of age, right kidney atrophy & pancreas
MRI showed only tissue of head of pancreas,
novel mutation HNF1B: c.505T>C or
p.Tyr169His (p.Y169H)
• Other case: miss follow up
Other causes of familial diabetes
• Insulin promoter factor 1 (IPF1) (MODY4)
• NeuroD1 (MODY6)
• KLF11 (MODY7)
• carboxyl ester lipase (CEL) (MODY8)
• PAX4 (MODY9)
• Insulin (MODY 10)
• B lymphocyte kinase (BLK ) (MODY 11)
→ but these are unusual
MODY 1
MODY2
MODY3
MODY4
MODY5
MODY6
Locus
20q
7p
12q
13q
17cen-q21.3
2
Gene
HNF-4α
Glucokinase
HNF-1α
IPF-1
HNF-1β
NeuroD1
Distri-bution
Rare
8-63%
(2nd
common)
21-64%
(most
common)
Rare
Unknown
Rare
Age at
Diagnosis
Adolescent
Childhood
Adolescent
Early
adulthood
Adolescent
Adulthood
Associated
features
-
Reduced
birth wt
glucose
threshhold
for
glycosuria
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Renal cysts
Genital malformation
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Severity
Severe
Mild
Progressive
Mod-Severe
Mild?
Mild?
Unknown
Treatment
Sulfonylurea
Diet
Sulfonylurea
Sulfonylurea
Insulin
Insulin
Insulin
Complications
Frequent
Rare
Frequent
Rare
Rare
Unknown
 80 children with MODY
 38/80 (48.1%) had mutation
• 18/38: GCK mutations (MODY2)
• 11/38: HNF1A mutations (MODY3)
• 3/38: HNF4A mutations (MODY1)
• 6/38: HNF1B mutations (MODY5)
Thank you very much