Limits...
Paradoxical hypertension and salt wasting in Type II Bartter syndrome.

Chan WK, To KF, Tong JH, Law CW - Clin Kidney J (2012)

Bottom Line: We report a low birth weight newborn baby who presented with repeated apnoea shortly after birth as well as hyponatraemia, hypochloraemia, hyperkalaemia and metabolic acidosis.Her biochemical features mimicked pseudohypoaldosteronism but with initial hypertension, which had not been described in BS.Her subsequent genetic study confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1 compatible with Type II BS.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, Queen Elizabeth Hospital, Hong Kong SAR, China.

ABSTRACT
Ante/neonatal Bartter syndrome (BS) is a rare hereditary disorder. It is characterized by renal salt wasting, hypokalaemic metabolic alkalosis, high renin and aldosterone but normal blood pressure. We report a low birth weight newborn baby who presented with repeated apnoea shortly after birth as well as hyponatraemia, hypochloraemia, hyperkalaemia and metabolic acidosis. Her biochemical features mimicked pseudohypoaldosteronism but with initial hypertension, which had not been described in BS. Her subsequent genetic study confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1 compatible with Type II BS.

No MeSH data available.


Related in: MedlinePlus

(a) Sequencing analysis of KCNJ1 gene: genomic DNA was used for polymerase chain reactions (PCRs) of KCNJ1 gene Exons 1–5 and the adjacent introns. The PCR products were purified and then sequenced using the BigDye Terminator v1.1 Cycle Sequencing Kit (Appliedbiosystems) and run on an Applied Biosystems 377 Genetic analyzer. The data were collected and analysed using Applied Biosystems sequencing analysis software. The heterozygous alleles were resolved by cloning the PCR products into TOPO vectors, sequencing of multiple clones were performed. Results of genetic study of the index patient confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1. One heterozygous G-A mutation, was identified in Exon 5 of KCNJ1 (GAA-AAA), resulted in amino acid change from glutamic acid to lysine at codon 151 (E151K), Glu151Lys. Another heterozygous in-frame deletion of 12 nucleotides, which caused in-frame deletion of four amino acids (ANHT) from codon 116 to 119. These two mutations were located in the channel core regions and were highly suggestive of altering the channel properties resulting in BS in the affected patient. (b) Mother: heterozygous in-frame deletion of 12 nucelotides resulting in deletion of four amino acids (ANHT) from codon 116 to 119 was identified. Wild-type sequence was at codon 151. Because of such large in-frame deletion of four amino acids, this mutation is considered to be deleterious. Father: a heterozygous mutation at codon 151 was found (GAA-AAA) and resulted in amino acid change from glutamic acid to lysine (E151K). Wild-type sequence was at codon 116–119. In E151K missense mutation, among mammal species, the amino acid at codon 151 is highly conserved with either E or D and both are negatively charged residues. The mutation changes it to a positively charged residue. It is very likely to be deleterious. Population screening showed that the mutation E151K was not found in the screening of 160 chromosomes in the population. Such observations indicated that E151K is not a polymorphism in our population and supports that this is a disease-related mutation.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4400504&req=5

fig2: (a) Sequencing analysis of KCNJ1 gene: genomic DNA was used for polymerase chain reactions (PCRs) of KCNJ1 gene Exons 1–5 and the adjacent introns. The PCR products were purified and then sequenced using the BigDye Terminator v1.1 Cycle Sequencing Kit (Appliedbiosystems) and run on an Applied Biosystems 377 Genetic analyzer. The data were collected and analysed using Applied Biosystems sequencing analysis software. The heterozygous alleles were resolved by cloning the PCR products into TOPO vectors, sequencing of multiple clones were performed. Results of genetic study of the index patient confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1. One heterozygous G-A mutation, was identified in Exon 5 of KCNJ1 (GAA-AAA), resulted in amino acid change from glutamic acid to lysine at codon 151 (E151K), Glu151Lys. Another heterozygous in-frame deletion of 12 nucleotides, which caused in-frame deletion of four amino acids (ANHT) from codon 116 to 119. These two mutations were located in the channel core regions and were highly suggestive of altering the channel properties resulting in BS in the affected patient. (b) Mother: heterozygous in-frame deletion of 12 nucelotides resulting in deletion of four amino acids (ANHT) from codon 116 to 119 was identified. Wild-type sequence was at codon 151. Because of such large in-frame deletion of four amino acids, this mutation is considered to be deleterious. Father: a heterozygous mutation at codon 151 was found (GAA-AAA) and resulted in amino acid change from glutamic acid to lysine (E151K). Wild-type sequence was at codon 116–119. In E151K missense mutation, among mammal species, the amino acid at codon 151 is highly conserved with either E or D and both are negatively charged residues. The mutation changes it to a positively charged residue. It is very likely to be deleterious. Population screening showed that the mutation E151K was not found in the screening of 160 chromosomes in the population. Such observations indicated that E151K is not a polymorphism in our population and supports that this is a disease-related mutation.

Mentions: We describe a pre-term baby girl born at 35 weeks of gestation with birth weight 2.26 kg, Apgar Score 6 at 1 min and 9 at 5 min. The parents' marriage was non-consanguious and both were Chinese. The pregnancy was complicated by polyhydramnios detected since 28 weeks of gestation. After birth, she started feeding with usual infant formula (SMT™) and passed urine nine times per day. She developed several episodes of shallow breathing and apnoea at 24 h of life. These attacks were associated with oxygen desaturation and bradycardia but responded readily to tactile stimulation. Her oral feeding was poorly tolerated. To supplement her milk feeding, she was given intravenous fluid at 150 mL/day, with sodium concentration of 25 mmol/L and intravenous antibiotics were started empirically after sepsis work-up. The blood test revealed a serum sodium of 124 mmol/L (normal: 136–145 mmol/L) and potassium 6.8 mmol/L (normal: 3.5–5.1 mmol/L), urea 6.4 mmol/L (normal: 1.4–6.8 mmol/L) and creatinine 78 μmol/L (normal: 21–75 μmol/L). She was not oedematous. Her lowest serum sodium dropped to 113 mmol/L on Day 4, chloride 86 mmol/L (normal: 95–105 mmol/L) and bicarbonate 18 mmol/L (normal: 22–29 mmol/L). Her fluid intake, urine output and body weight in the initial few days of life are summarized in Table 1. Despite severe salt wasting and a weight loss of 14% within the first week, her blood pressure measured via intra-arterial line with good tracing was high for a premature baby at around 80/50 mmHg (Figure 1). She had a high urine output which ranged from 7.4–10 mL/kg/h and urine osmolality was low at 145–237 mosmol/kg. Urine sodium excretion ranged from 47 to 91 mmol/L, with increased fractional excretion of urinary sodium to 4–11%. Her morning cortisol was 556 nmol/L (normal spot cortisol at 7–10 am: 171–538 nmol/L), 17αOH progesterone was 3.2 nmol/L (normal: 0.5–20 nmol/L), aldosterone >3330 pmol/L (normal: <444 pmol/L) and plasma renin activity was extremely high such that it was out of the usual range for measurement in our laboratory. A random spot urine calcium creatinine ratio was 3.8 mmol/mmol Cr (normal: <0.7 mmol/mmol Cr). Serum magnesium was 0.69 mmol/L (normal: 0.62–0.91 mmol/L). Cranial ultrasound (USG) on Day 4 did not show any intra-cranial lesions or cerebral oedema. USG kidney on Day 19 showed bilateral nephrocalcinosis. She was treated with an NaCl supplement. Her serum sodium increased to 132 mmol/L by Day 8 of life but her serum potassium slowly dropped to a lowest of 2.6 mmol/L on Day 10 with increased transtubular potassium gradient at 6.9. Genetic study confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1 compatible with Type II Bartter syndrome (BS) (Figure 2a and b). The baby inherited an E151K missense mutation from her father and an in-frame deletion of four amino acids (ANHT) from her mother. Her condition was stabilized with sodium supplement at 10 mmol/kg/day, potassium supplement at 3.4 mmol/kg/day and indomethacin at 1.5 mg/kg/day. Her blood pressure slowly dropped back to the 90th percentile without any treatment. Her estimated glomerular filtration rate by Schwartz formula at 2 weeks of life was 33.3 mL/min/1.73 m2 (normal for age).


Paradoxical hypertension and salt wasting in Type II Bartter syndrome.

Chan WK, To KF, Tong JH, Law CW - Clin Kidney J (2012)

(a) Sequencing analysis of KCNJ1 gene: genomic DNA was used for polymerase chain reactions (PCRs) of KCNJ1 gene Exons 1–5 and the adjacent introns. The PCR products were purified and then sequenced using the BigDye Terminator v1.1 Cycle Sequencing Kit (Appliedbiosystems) and run on an Applied Biosystems 377 Genetic analyzer. The data were collected and analysed using Applied Biosystems sequencing analysis software. The heterozygous alleles were resolved by cloning the PCR products into TOPO vectors, sequencing of multiple clones were performed. Results of genetic study of the index patient confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1. One heterozygous G-A mutation, was identified in Exon 5 of KCNJ1 (GAA-AAA), resulted in amino acid change from glutamic acid to lysine at codon 151 (E151K), Glu151Lys. Another heterozygous in-frame deletion of 12 nucleotides, which caused in-frame deletion of four amino acids (ANHT) from codon 116 to 119. These two mutations were located in the channel core regions and were highly suggestive of altering the channel properties resulting in BS in the affected patient. (b) Mother: heterozygous in-frame deletion of 12 nucelotides resulting in deletion of four amino acids (ANHT) from codon 116 to 119 was identified. Wild-type sequence was at codon 151. Because of such large in-frame deletion of four amino acids, this mutation is considered to be deleterious. Father: a heterozygous mutation at codon 151 was found (GAA-AAA) and resulted in amino acid change from glutamic acid to lysine (E151K). Wild-type sequence was at codon 116–119. In E151K missense mutation, among mammal species, the amino acid at codon 151 is highly conserved with either E or D and both are negatively charged residues. The mutation changes it to a positively charged residue. It is very likely to be deleterious. Population screening showed that the mutation E151K was not found in the screening of 160 chromosomes in the population. Such observations indicated that E151K is not a polymorphism in our population and supports that this is a disease-related mutation.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400504&req=5

fig2: (a) Sequencing analysis of KCNJ1 gene: genomic DNA was used for polymerase chain reactions (PCRs) of KCNJ1 gene Exons 1–5 and the adjacent introns. The PCR products were purified and then sequenced using the BigDye Terminator v1.1 Cycle Sequencing Kit (Appliedbiosystems) and run on an Applied Biosystems 377 Genetic analyzer. The data were collected and analysed using Applied Biosystems sequencing analysis software. The heterozygous alleles were resolved by cloning the PCR products into TOPO vectors, sequencing of multiple clones were performed. Results of genetic study of the index patient confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1. One heterozygous G-A mutation, was identified in Exon 5 of KCNJ1 (GAA-AAA), resulted in amino acid change from glutamic acid to lysine at codon 151 (E151K), Glu151Lys. Another heterozygous in-frame deletion of 12 nucleotides, which caused in-frame deletion of four amino acids (ANHT) from codon 116 to 119. These two mutations were located in the channel core regions and were highly suggestive of altering the channel properties resulting in BS in the affected patient. (b) Mother: heterozygous in-frame deletion of 12 nucelotides resulting in deletion of four amino acids (ANHT) from codon 116 to 119 was identified. Wild-type sequence was at codon 151. Because of such large in-frame deletion of four amino acids, this mutation is considered to be deleterious. Father: a heterozygous mutation at codon 151 was found (GAA-AAA) and resulted in amino acid change from glutamic acid to lysine (E151K). Wild-type sequence was at codon 116–119. In E151K missense mutation, among mammal species, the amino acid at codon 151 is highly conserved with either E or D and both are negatively charged residues. The mutation changes it to a positively charged residue. It is very likely to be deleterious. Population screening showed that the mutation E151K was not found in the screening of 160 chromosomes in the population. Such observations indicated that E151K is not a polymorphism in our population and supports that this is a disease-related mutation.
Mentions: We describe a pre-term baby girl born at 35 weeks of gestation with birth weight 2.26 kg, Apgar Score 6 at 1 min and 9 at 5 min. The parents' marriage was non-consanguious and both were Chinese. The pregnancy was complicated by polyhydramnios detected since 28 weeks of gestation. After birth, she started feeding with usual infant formula (SMT™) and passed urine nine times per day. She developed several episodes of shallow breathing and apnoea at 24 h of life. These attacks were associated with oxygen desaturation and bradycardia but responded readily to tactile stimulation. Her oral feeding was poorly tolerated. To supplement her milk feeding, she was given intravenous fluid at 150 mL/day, with sodium concentration of 25 mmol/L and intravenous antibiotics were started empirically after sepsis work-up. The blood test revealed a serum sodium of 124 mmol/L (normal: 136–145 mmol/L) and potassium 6.8 mmol/L (normal: 3.5–5.1 mmol/L), urea 6.4 mmol/L (normal: 1.4–6.8 mmol/L) and creatinine 78 μmol/L (normal: 21–75 μmol/L). She was not oedematous. Her lowest serum sodium dropped to 113 mmol/L on Day 4, chloride 86 mmol/L (normal: 95–105 mmol/L) and bicarbonate 18 mmol/L (normal: 22–29 mmol/L). Her fluid intake, urine output and body weight in the initial few days of life are summarized in Table 1. Despite severe salt wasting and a weight loss of 14% within the first week, her blood pressure measured via intra-arterial line with good tracing was high for a premature baby at around 80/50 mmHg (Figure 1). She had a high urine output which ranged from 7.4–10 mL/kg/h and urine osmolality was low at 145–237 mosmol/kg. Urine sodium excretion ranged from 47 to 91 mmol/L, with increased fractional excretion of urinary sodium to 4–11%. Her morning cortisol was 556 nmol/L (normal spot cortisol at 7–10 am: 171–538 nmol/L), 17αOH progesterone was 3.2 nmol/L (normal: 0.5–20 nmol/L), aldosterone >3330 pmol/L (normal: <444 pmol/L) and plasma renin activity was extremely high such that it was out of the usual range for measurement in our laboratory. A random spot urine calcium creatinine ratio was 3.8 mmol/mmol Cr (normal: <0.7 mmol/mmol Cr). Serum magnesium was 0.69 mmol/L (normal: 0.62–0.91 mmol/L). Cranial ultrasound (USG) on Day 4 did not show any intra-cranial lesions or cerebral oedema. USG kidney on Day 19 showed bilateral nephrocalcinosis. She was treated with an NaCl supplement. Her serum sodium increased to 132 mmol/L by Day 8 of life but her serum potassium slowly dropped to a lowest of 2.6 mmol/L on Day 10 with increased transtubular potassium gradient at 6.9. Genetic study confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1 compatible with Type II Bartter syndrome (BS) (Figure 2a and b). The baby inherited an E151K missense mutation from her father and an in-frame deletion of four amino acids (ANHT) from her mother. Her condition was stabilized with sodium supplement at 10 mmol/kg/day, potassium supplement at 3.4 mmol/kg/day and indomethacin at 1.5 mg/kg/day. Her blood pressure slowly dropped back to the 90th percentile without any treatment. Her estimated glomerular filtration rate by Schwartz formula at 2 weeks of life was 33.3 mL/min/1.73 m2 (normal for age).

Bottom Line: We report a low birth weight newborn baby who presented with repeated apnoea shortly after birth as well as hyponatraemia, hypochloraemia, hyperkalaemia and metabolic acidosis.Her biochemical features mimicked pseudohypoaldosteronism but with initial hypertension, which had not been described in BS.Her subsequent genetic study confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1 compatible with Type II BS.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, Queen Elizabeth Hospital, Hong Kong SAR, China.

ABSTRACT
Ante/neonatal Bartter syndrome (BS) is a rare hereditary disorder. It is characterized by renal salt wasting, hypokalaemic metabolic alkalosis, high renin and aldosterone but normal blood pressure. We report a low birth weight newborn baby who presented with repeated apnoea shortly after birth as well as hyponatraemia, hypochloraemia, hyperkalaemia and metabolic acidosis. Her biochemical features mimicked pseudohypoaldosteronism but with initial hypertension, which had not been described in BS. Her subsequent genetic study confirmed two novel heterozygous mutations in the Exon 5 of KCNJ1 compatible with Type II BS.

No MeSH data available.


Related in: MedlinePlus