Type-5 Bartter syndrome presenting with metabolic seizure in adulthood
- 1 Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Science—Bhopal, Bhopal, Madhya Pradesh, India
- 2 Nephrology, All India Institute of Medical Science—Bhopal, Bhopal, Madhya Pradesh, India
- 3 Pulmonary Medicine, All India Institute of Medical Science—Bhopal, Bhopal, Madhya Pradesh, India
- Correspondence to Dr Abhishek Goyal; avi784@gmail.com
Abstract
Bartter syndrome is a very rare and heterogeneous disease with variable age of onset and symptom severity. Genotypically they have inherited disorders of the thick ascending limb in the renal tubular system, which manifest phenotypically as electrolyte imbalance due to loss of sodium, chloride and potassium. Gain of function mutations in the calcium-sensing receptor has been described in some patients with Bartter’s syndrome (type-5 Bartter syndrome or autosomal dominant hypocalcaemia with Bartter syndrome) associated with hypocalcaemia and hypercalciuria differentiating it from Gitelman syndrome. This phenotype has been reported to present in adulthood with metabolic abnormalities. We present a case of a middle-aged woman who presented with metabolic seizures and on evaluation was found to have profound electrolyte abnormalities which were corrected with supplements and led to the resolution of symptoms.
Background
Bartter syndrome is a genetic disorder causing salt wasting and hypokalaemic metabolic alkalosis, hypercalciuria with nephrocalcinosis, mild hypomagnesaemia and increased urinary prostaglandin excretion with normal or low blood pressure. It presents mostly antenatally or in neonates but presentation in old age is reported and so its possibility should be kept in mind even in adults.1
Case presentation
A 59-year-old woman presented with an episode of seizure to a hospital where on evaluation for aetiology of seizure, hyponatraemia was detected. Serum sodium on presentation was 129, imaging of the brain was normal. Patient was managed with normal saline and increased salt intake and discharged after 7 days on antiepileptics. Patient reported generalised weakness and fatigue at home and was brought to our hospital for evaluation of same. On reviewing the history, patient revealed that she had easy fatigability, tiredness and weakness for last 5–6 years for which she sought medical attention in 2016 and was evaluated. Patients’ evaluation was unremarkable other than bilateral upper lobe fibrosis of lungs. Patient was counselled and put on symptomatic treatment. Examination of the patient revealed a lean-built woman with a weight of 41 kg and height of 150 cm. body mass index (BMI) was 18.22 kg/m². Patients’ vital signs were normal. Blood pressure was 100/60 mm Hg.
Investigations
Laboratory analysis revealed normal haemogram, normal renal function and a normal thyroid profile. Liver function test revealed mild transaminitis and hypoalbuminemia. Electrolye analysis revealed hypokalaemia, hyponatraemia, hypocalcaemia, hypomagnesaemia and hypophosphatemia (table 1). Arterial blood gas analysis suggested metabolic alkalosis (pH of 7.48 and bicarbonate of 32 mEq/L). During the evaluation of the cause of dyselectrolaemia, patient denied any history of current or remote diuretic use. Urinary electrolytes were analysed (table 2). Urinary potassium was 120 mEq/g of creatinine excreted. Transtubular potassium gradient was 25. 52, suggesting urinary potassium loss. Twenty-four hours of urinary calcium was 344 mg/day. Serum vitamin D and serum parathyroid hormone levels were normal. Urinary chloride was 110 mmol/L. Our patient gave a history of dryness of mouth and in view of upper lobe fibrosis patient was evaluated for Sjogrens’ syndrome. Anti-nuclear antibody (ANA) was negative by both ELISA and immunofluorescence method. Anti-Ro and Anti-La both were negative. Nail-fold capillaroscopy was done that was unremarkable, and lip mucosal biopsy was done that was normal. Examination by an otorhinolaryngologist revealed normal audiometry. Echocardiography of the patient was done which revealed severe TR, moderate MR and severe pulmonary arterial hypertension (PAH). Ejection fraction was 55%.
Serum electrolytes
| Parameter | 7 February | 8 February | 9 February | 10 February |
| Potassium (mmol/L) | 2.5 | 2.8 | 3.8 | 4.2 |
| Calcium (mg/dL) | 7.8 | 8.09 | 8.56 | 9.1 |
| Magnesium (mg/dL) | 0.64 | 1.15 | 1.76 | 2.0 |
| Phosphorus (mg/dL) | 1.21 | 3.1 | ||
| Sodium (mmol/L) | 133 | 137 | 136 | 135 |
| Urea (mg/dL) | 21 | 18 | ||
| Creatinine (mg/dL) | 0.8 | 0.7 | ||
| Albumin (g/dL) | 2.9 | 2.7 | ||
| Uric acid (mg/dL) | 4.2 |
Twenty-four hours of urinary concentration of electrolytes on 9 February 2019
| Sodium | Potassium | Calcium | Creatinine | Magnesium |
| 169 mmol/day | 72.6 mmol/day | 344 mg/dL | 632.5 mg/dL | 5.6 mg/dL |
Differential diagnosis
The main differential diagnoses other than Bartter syndrome were Gitelman syndrome and Sjogrens’ syndrome. The former was ruled out by relative hypercalciuria and the later by negative immunological and histopathological workup for Sjogrens’ syndrome. Among the subtypes of Bartter syndrome types 3 and 5 usually presented in adulthood but type 3 never presents with hypocalcaemia.
Treatment
Patient was put on potassium, calcium and magnesium supplements in hospital and patient was improved. Patient was discharged on diuretics (torsemide/spironolactone combination), ramipril, calcium and magnesium supplements.
Outcome and follow-up
Patient reported significant improvement in her general condition. On follow-up, her electrolytes came back to normal range. Diuretics were gradually tapered to torsemide 5 mg once daily (OD). Repeated echocardiography of the patient after 1 month of electrolyte replacement revealed mild tricuspi regurgitation (TR) and mild mitral regurgitation (MR). Patient is back to her daily routine work and is in good functional state following our department every 3 months.
Discussion
Bartter syndrome, originally described by Bartter and colleagues2, represents a set of closely related, genetic renal tubular disorders characterised by hypokalaemia, hypochloraemia, metabolic alkalosis and hyper-reninemia with normal blood pressure.1
Bartter syndrome has been classified on the basis of underlying genetic defect into five types.
Type 1—antenatal Bartter syndrome: mutation in Solute Carrier Family 12 Member 1 (SLC12A1), the sodium–chloride–potassium cotransporter gene.
Type 2—antenatal/neonatal Bartter syndrome: results from mutations in ROMK gene.
Type 3—classic Bartter syndrome: caused by mutation of the chloride voltage-gated channel Kb gene (CLCNKB), which encodes the CLC-Kb chloride channel involved in NaCl reabsorption in renal tubule.
Type 4—Bartter syndrome with sensorineural deafness: due to loss of function mutation in Bartter syndrome, infantile with sensorineural deafness (BSND), which encodes an essential beta subunit for CLC chloride channels.
Type 5—Bartter syndrome is also referred to autosomal dominant hypocalcaemia (also called autosomal dominant hypoparathyroidism) and results from a gain-of-function mutation in the calcium-sensing receptor(CaSR) gene.3 4 In parathyroid gland, this results in a downward ‘resetting’ of the normal range for serum calcium. As a result, a lower-than-normal serum calcium concentration inhibits parathyroid hormone release, resulting in hypocalcaemia.
The CaSR is also expressed in the basolateral membrane of the thick ascending limb where it is involved in the regulation of renal calcium transport and sodium chloride reabsorption. Activation of the CaSR blunts potassium efflux through the renal outer medullary potassium channel (ROMK) channel and also may reduce activity of the Na-K-2Cl cotransporter.3 5 Urinary calcium excretion is normal or high, since calcium reabsorption in the thick ascending limb requires normal sodium chloride reabsorption at this site. Some patients have gain-of-function mutations in the CaSR that are severe enough to produce mild to moderate renal sodium chloride wasting, which leads to volume contraction and increased aldosterone and renin levels.
Our patient had hypokalaemia, metabolic alkalosis, hypomagnesaemia and hypocalcaemia in the presence of hypercalciuria, which categorise her into type-5 Bartter phenotype.
The clinical features of the Bartter syndrome include muscle weakness, fatigue, tetany, paraesthesia, polydipsia, polyuria, orthostatic hypotension. The most common features in adults include fatigue, proximal muscle weakness and tetany.6 Bartter syndrome differs from Gitelman syndrome in the presence of hypercalciuria. Nephrocalcinosis and nephrolithiasis are usually seen after long duration of metabolic abnormalities. Treatment is aimed at inhibition of renin-angiotensin aldosterone axis and potassium supplements.
Our patient had hypokalaemia, metabolic alkalosis, elevated 24 hours of urinary calcium levels with normal blood pressure and hypomagnesaemia. Hypomagnesaemia has been reported in 20% of patients with Bartter syndrome.2 No other causative factors such as use of diuretics, amphotericin B, cisplatin, aminoglycosides and autoimmune disease such as Sjogrens’ syndrome could be identified for acquired Bartter syndrome (BS).
On reviewing the literature, very few cases of adult-onset Bartter have been reported. Cases of acquired type-5 Bartter syndrome have been reported in literature as a result of gentamicin and other aminoglycosides exposure but our patient did not have any exposure to aminoglycosides.7 An adulthood presentation has been reported in Bartter syndrome as a phenotypic variation also.8
Our patients’ echocardiography done during hospital stay revealed moderate mitral regurgitation, severe tricuspid regurgitation and severe pulmonary arterial hypertension. After a month’s electrolyte replacement, this mitral regurgitation resolved, which could be because of it being secondary to hypomagnesaemia and hence improving with magnesium supplements.
Patient’s perspective
I approached AIIMS Bhopal on 7 February 2019 morning with my wife. It was highly stressful for my family as she was not tolerating oral food. She was admitted and received true care and recovered back to her routine life. We thank all the doctors who were part of her treating team.
Learning points
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Bartter syndrome can present in adults also and is not exclusively seen in children.
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Hyponatraemia, hypokalaemia and metabolic alkalosis are common to both Bartter and Gitelman syndromes and cannot differentiate between them.
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Serum hypocalcaemia and relative hypercalciuria along with nephrocalcinosis and nephrolithiasis are the manifestations that differentiate type-5 Bartter from Gitelman syndrome.
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Metabolic abnormalities especially if multiple should be investigated thoroughly for an underlying cause and targeted therapy.
Footnotes
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Contributors AH: preparation of the manuscript, patient care and review of the literature. MA: patient care and review of the literature. AG: preparation of the manuscript and patient care, provided consent on behalf of other authors. AKK: patient care.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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