Download A novel mutation in the AVPR2 gene in a Palestinian family

Abdulsalam Abu Libdeh, MD
Pediatric Endocrinologist
Makassed Islamic Hospital
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3 months old male infant, referred from AlWatani hospital c/o fever, irritability, FTT and
vomiting.
Past history:
product of FT,NVD, birth wt: 3.6kg, at Rafidia
hospital.
At 22d of age admitted to Al-Watani hospital
as he developed fever, irritability, vomiting
and FTT.
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Investigations at al-Watani:
Na :177
K: 4.5
Urea: 44 Crea: 0.9
LFT: NL
CBC: NL
Urinalysis : free
Family history:
Parents were healthy and not consanguineous. A male
sibling was diagnosed clinically previously to have
nephrogenic diabetes insipidus.
He was started on hydrochlorothiazide 2mg/kg/day,
but due to inadequate response, the patient was
referred to Makassed hospital.
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Physical Examination:
Wt: 4.42kg <3rd%
Lt: 58cm
25th%
Hc: 37.5cm <3rd%
Temp: 37c
HR: 130/min
Positive findings on P/E
Cachectic , irritable
BP: 72/45
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Investigations:
Na+: 150
K+: 3.7
s.osmolality: 304mOsm/kg
BUN: 13
Crea: 0.5
LFT: NL
Glu: 97
CBC: NL
Blood gas: PH 7.52, HCO3 29, BE +6
Urine: osmolality: 145mOsm/kg
Na: 27
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Investigations:
Urine output: 9cc/kg/hr
Urine culture: positive for Klebsiella
Blood culture: negative
Renal U/S : normal
GFR: 43ml/min/1.73m2
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Diagnosis
Diabetes Insipidus
Central
Nephrogenic
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Minirin test:
S.osmolality
Serum Na
Urine osm
Before
304
149
65
After
318
157
96
Diagnosis: Nephrogenic Diabetes Insipidus
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Kaluril (Amiloride & hydrochlorothiazide)
4mg/kg/day
Indomethacin 2mg/kg/day
Feeding 180cc/kg/day (oral & gavage)
Upon discharge:
Na: 139
s.osm: 323mOsm/kg
urine osm: 85mOsm/kg
U.O.P: 2.4cc/kg/hr
Wt: 5.1kg
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Primers for amplification and sequencing of the
AVPR2 gene were:
Exon 1:
For: attgaacttgctcctcaggc
Rev.: gcttccctgaatcgtcaaac
Exon 2-start: For: ctaggagccaggaagtggg
Rev.: gaagatgaagagctggggc
Exon 2-end: For: tcctcctacatgatcctggc
Rev.: tggaggatctaggttgggttc
Exon 3:
For: gtggctagggctgacgg
Rev.: ccagtggctcccaggac
Patient
Sequencing the DNA of the affected patient showed mis-sense mutation
with replacement of G by A in codon 82 (TGC---TAC). This mutation
predicted a substitution of Cysteine to Tyrosine (C82Y) at the amino
acid residue of the AVPR2 gene
Mother
Mother was heterozygous for this mutation (carrier)
Father
Sister
Sister was heterozygous for this mutation (carrier)
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Definition:
NDI is a clinical disorder, characterized by a
urinary concentrating defect resulting from
resistance of the collecting duct to the
antidiuretic action of vasopressin (AVP).
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Classification:
Hereditary
X-linked
V2R
Autosomal recessive
AQP2
Autosomal dominant
AQP2
Acquired
Drugs (lithium, amphotericin B)
Ureteral obstruction
Acute or chronic renal failure
Renal cystic disease
Interstitial nephritis
Nephrocalcinosis
Toxic nephropathy due to hypokalemia
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X-linked recessive NDI is caused by mutations
in the gene encoding the V2 vasopressin
receptor (V2R) and is the most frequent genetic
cause of the inherited NDI.
To date, 178 different mutations have been
reported for V2R NDI, and the mutations
spread throughout all portions of the protein.
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There are two different receptors for ADH:
V1 (AVPR1) & V2 (AVPR2) receptors.
Activation of the V1 receptors:a. Induces vasoconstriction
b. Enhancement of prostaglandin release, while
Activation of V2 receptors:a. Mediate the antidiuretic responses.
b. Peripheral vasodilation
c. The release of factor VIIIc and von Willbrand’s
factor from endothelial cells.
Pathogenesis
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Clinical manifestations:
Massive polyuria
Volume depletion
Hypernatremia
Hyperthermia
Irritability
Constipation
FTT
Developmental delay & mental retardation
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Clinical manifestations:
Diminished appetite & poor food intake due to
consumption of large volume of water
Growth abnormalities.
Behavioral problems, including hyperactivity
& short term memory problems.
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Diagnosis:
water deprivation test
If the serum osmolality is 290mOsm/kg or
higher with a urine osmolality value
<290mOsm/kg, water deprivation test is not
necessary.
To distinguish between central DI & NDI:
administration of vasopressin 10-20mcg,
followed by serial urine and serum osmolality
measurements hourly for 4hrs.
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Maintenance of adequate fluid intake & access
to free water. Infants require gastrostomy or
NG tube feeding to ensure adequate fluid
administration throughout day & night.
Minimizing urine output by limiting solute
load with a low osmolar, low-sodium diet.
For infants, human milk or a low solute
formula, such as Similac PM 60/40 is preferred.
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Administering medications directed at
decreasing urine output.
Thiazide diuretics (2-3mg/kg/d) effectively
induce Na loss & stimulate proximal tubule
reabsorption of water.
Potassium-sparing diuretics, amiloride
(0.3mg/kg/d) by its additive effect with
thiazide are often indicated.
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NSAIDs – indomethacin (2mg/kg/d) has an
additive effect in reducing water excretion in
some patients, dependent upon inhibition of
renal prostaglandin synthesis.
Exogenous ADH: most patients with NDI have
partial rather than complete resistance to ADH.
It is therefore possible that attaining
supraphysiologic hormone levels will increase
the renal effect of ADH to a clinically important
degree.
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Experimental approaches: most patients with
congenital x-linked NDI have defective V2
vasopressin receptors that are unable to properly
fold intracellularly and, as a consequence, correctly
transfer to the cell surface.
In vitro, the administration of selective, cell
permeable nonpeptide V2 and V1a receptor
antagonists were able to rescue mutant V2
receptors by promoting their proper folding and
maturation. This resulted in the expression of
functional cell surface V2 receptors, suggesting
that such a therapeutic approach may be fruitful.
Abu Libdeh Abdulsalam, Dweikat Imad & Abu-Libdeh Bassam
Department of Pediatrics, Makassed Hospital, Jerusalem
Thank you for your attention