A novel mutation in the AVPR2 gene in a Palestinian family with nephrogenic diabetes insipidus

1
A novel mutation in the AVPR2 gene in a
Palestinian family with nephrogenic diabetes
insipidus

• Abdulsalam Abu Libdeh, MD
• Pediatric Endocrinologist
• Makassed Islamic Hospital

2
Case presentation

• 3 months old male infant, referred from Al-Watani
  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.

3
Case presentation

• 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.

4
Case presentation

• Physical Examination
• Wt 4.42kg lt3rd
• Lt 58cm 25th
• Hc 37.5cm lt3rd
• Temp 37c HR 130/min BP
  72/45
• Positive findings on P/E
• Cachectic , irritable

5
Case presentation

• 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

6
Family pedigree

• ?
• ?

7
Case presentation

• Investigations
  Urine output 9cc/kg/hr
• Urine culture positive for Klebsiella
• Blood culture negative
• Renal U/S normal
• GFR 43ml/min/1.73m2

8

• Diagnosis
• Diabetes Insipidus

Central
Nephrogenic
9
Management

• Minirin test
• Diagnosis Nephrogenic Diabetes Insipidus

S.osmolality Serum Na Urine osm
Before 304 149 65
After 318 157 96
10
Management

• 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

11
Molecular diagnosis
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Sequencing of AVPR2

• 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

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Sequence result
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
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Sequence result
Mother
Mother was heterozygous for this mutation
(carrier)
15
Sequence result
Father
16
Sequence result
Sister
Sister was heterozygous for this mutation
(carrier)
17
AVPR2
18
3-D Model of the AVPR2
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Nephrogenic Diabetes Insipidus

• 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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Nephrogenic Diabetes Insipidus

• 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 Nephrogenic Diabetes Insipidus

• 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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X-linked NDI

• 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
  Willbrands
• factor from endothelial cells.

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X-linked NDI
Pathogenesis
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X-linked NDI

• Clinical manifestations
  Massive polyuria
• Volume depletion
• Hypernatremia
• Hyperthermia
• Irritability
• Constipation
• FTT
  Developmental delay mental
  retardation

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X-linked NDI

• 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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Nephrogenic Diabetes Insipidus

• Diagnosis
  water deprivation test
  
  If the serum osmolality is 290mOsm/kg
  or higher with a urine osmolality value
  lt290mOsm/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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Treatment of NDI

• 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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Treatment of NDI

• 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.

29
Treatment of NDI

• 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.

30
Treatment of NDI

• 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.

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A novel mutation in the AVPR2 gene in a
Palestinian family with nephrogenic diabetes
insipidus

• Abu Libdeh Abdulsalam, Dweikat Imad Abu-Libdeh
  Bassam
• Department of Pediatrics, Makassed Hospital,
  Jerusalem

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Thank you for your attention