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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2016  |  Volume : 27  |  Issue : 4  |  Page : 832-835
Gitelman syndrome, familial seizures, and demyelinating neuropathy: Rare association may be due to sodium potassium cotransporter genes

Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

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Date of Web Publication5-Jul-2016

How to cite this article:
Singh R K, Bhoi S K, Kalita J, Misra U K. Gitelman syndrome, familial seizures, and demyelinating neuropathy: Rare association may be due to sodium potassium cotransporter genes. Saudi J Kidney Dis Transpl 2016;27:832-5

How to cite this URL:
Singh R K, Bhoi S K, Kalita J, Misra U K. Gitelman syndrome, familial seizures, and demyelinating neuropathy: Rare association may be due to sodium potassium cotransporter genes. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2023 Jan 29];27:832-5. Available from: https://www.sjkdt.org/text.asp?2016/27/4/832/185287
To the Editor

Rare association of different diseases in patient may point to the genetic basis of their association. Often the genetic diseases manifest early in life but not always, and therefore may be missed, especially in elderly patients. We managed a patient with the rare association of familial seizures, neuropathy, and nephropathy. We report this patient and suggest the possible cause of such association.

A 61-year-old patient was admitted with weakness and paresthesia all four limbs for 25 days and respiratory difficulty for three days. Tingling sensation first involved lower limbs followed by upper limbs within three days. Weakness started from the third day of illness in the lower limb followed by the upper limbs.

The patient became bed bound by the 13 th day of illness. He developed bulbar dysfunction from the 7 th day of illness and breathlessness for the last three days. He had five to six loose stools daily for a week prior to this illness. He had a history of one generalized tonic-clonic seizure at the age of one year, but there was no recurrence. There was a history of tonic-clonic seizure in his two daughters and a son out of five children. On examination, his pulse rate was 126/min and blood pressure (BP) 110/70 mm Hg. Single breath count was four and respiratory rate was 32/min. He was conscious, oriented and there was no pallor, icterus, clubbing, and edema. Chest and cardiac examination was normal. Abdomen was distended (due to gasses). Meningeal signs were absent, and there were bilateral facial, 9 th and 10 th cranial nerve palsy. Fundus and extraocular movements were normal. Muscle tone was decreased in all four limbs with generalized areflexia. The lower limb muscle power was grade 1 on a Medical Research Council (MRC) and upper limb grade 2 to 3. Sensory examination revealed impaired fine touch, joint position and vibration sensations below hip and elbow, and pain and temperature impairment below knee and elbow. Autonomic disturbance was evidenced by the loss of sinus arrhythmia, wide fluctuations in pulse and blood pressure, and recurrent bowel disturbance. He was put on ventilator support on the 25 th day of illness because of hypoxia (PaO 2 58 mm Hg), hypercarbia (PaCO 2 51 mm Hg), and alkalosis (pH 7.48). On the 26 th day of illness, he developed fever of 39°C with abdominal distension, loose stool, and gastric hemorrhage which persisted for two weeks. It subsided after treatment with broad spectrum antibiotics. Weakness progressed for another three weeks, and his power deteriorated to grade 1 in in all four limbs, and he was unable to close his eyes. Intravenous immunoglobulin (IVIg) was started on the 50 th day of illness followed by oral prednisolone 40 mg daily from the 65 th day of illness. He had persistent hypokalemia and alkalosis and was treated with spironolactone 50 mg twice daily and IV and oral potassium. Tracheostomy was done and he was gradually weaned from ventilator on the 90 th day of illness. His hemoglobin was 11.1 g/dL and white cell count 14000/mm 3 , with 91% polymorphs. Erythrocyte sedimentation rate was 71 mm for 1 st h. Blood sugar was 92 mg/dL, serum creatinine 0.9 mg/dL, serum glutamic oxaloacetic transaminase was 54 U/L, serum glutamate pyruvate transaminase 153 U/L, serum bilirubin 1 mg/dL, serum protein 5 g/dL, serum albumin 3 g/dL, and alkaline phosphatase 186 U/L. Routine urine examination revealed 1+ protein and pH of 6. Anti-nuclear antibody was positive, anti-dsDNA was negative, and antineutrophil cytoplasmic antibodies screen and antiphospholipid antibodies were absent. Serum electrophoresis and bone marrow examination were normal. His 24 h urinary evaluation revealed: protein 1.2 g, potassium: 95 mmol/day, chloride 1016 mmol/day, calcium 275 mg/day, and serum magnesium was 1.8 mg/dL.

Cerebrospinal fluid (CSF) revealed 136 mg/ dL protein and 10 cells/mm 3 . Nerve conduction study was performed on the 23 rd day of illness and revealed median motor nerve conduction velocity of 39.3 m/s (terminal latency 12.1 ms, F response 52.3 ms), ulnar motor nerve conduction velocity was 34.7 m/s (terminal latency 8.2 ms, F wave was not recordable). Peroneal motor conduction and median, ulnar, and sural nerve sensory conduction were unrecordable. The compound muscle action potential amplitudes were small, and there was no conduction block. The serum and urinary electrolytes [Table 1] and arterial blood gas trends [Figure 1] are presented.
Figure 1: Arterial blood gasses trend.

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Table 1: Laboratory reports.

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The presentation of this patient is noteworthy. He presented with persistent hypokalemia, metabolic and respiratory alkalosis, hypomagnesemia, and hypocalciuria which are consistent with Gitelman syndrome (GS). This patient also had a rare association with demyelinating neuropathy evidenced by electro-diagnostic findings (prolonged distal latency, slow nerve conduction velocity, and prolonged F-wave latency in median and ulnar nerves) with albuminocytological dissociation in CSF. The third rare association was a history of seizure in childhood. This patient also had a history of seizures in three of his five children suggesting an autosomal dominant inheritance. Search for a secondary cause of renal tubular dysfunction such as autoimmune disorder, toxic or metabolic abnormality, and paraproteinemia were negative excluding the basis of renal dysfunction, seizures, and demyelinating neuropathy. In the literature, we could not get a similar case.

Demyelinating neuropathy with GS has been reported in a 41-year-old male with four days history of weakness and limb paresthesia, his serum K + was 2.6 mEq/L, serum magnesium 1.7 mg/dL, with mild metabolic alkalosis. [1] Quadriparesis persisted in spite of correction of hypokalemia to 4 mEq/L. Nerve conduction study and albuminocytological dissociation were consistent with demyelinating neuropathy. Follow-up after 30 months revealed persistent hypomagnesemia (1.5 mg/dL) and hypocalciuria (<90 mg/day, normal 100-300 mg/day). [1]

In our patient, the arterial blood gas analysis revealed a pH of 7.48, PaCO 2 of 33.4 mm Hg, and HCO 3 of 24.9 mEq/L. For PCO 2 at 33.4 mm Hg, the expected HCO 3 concentration would be 21.7 mEq/L in the case of chronic respiratory alkalosis and 23.7 mEq/L in the case of acute respiratory alkalosis. HCO 3 at 24.9 mEq/L in our patient indicates mixed metabolic and respiratory alkalosis. In our patient, metabolic alkalosis was accompanied by respiratory alkalosis because the patient had respiratory failure and was on artificial ventilation for about three months. CO 2 retention and washout resulted in compensation and led to a mixed picture in arterial blood gas analysis.

Based on the clinical and laboratory data, we treated the patient with IVIg and corticosteroid considering the possibility of subacute inflammatory demyelinating neuropathy as the weakness had progressed over four weeks but the progression was <8 weeks which is needed for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). The patient showed mild improvement over three months, but recovery was not temporally related to IVIg or prednisolone treatment. Much of the improvement was evident after control of sepsis, gastric hemorrhage, and control of recurrent diarrheal attacks by antibiotic therapy.

Diuretic sensitive cotransport of cations with chloride is mediated by cation chloride cotransporters, a large gene family comprising of several genes, Na-Cl, Na-K-2Cl, and KCl cotransporters in addition to two related transporters of unknown functions. [2] These cotransporters perform a variety of physiological functions that differ in tissue distribution and cellular localization. Renal-specific NaCl cotransporter (NCC) and Na-K-2Cl (NK CC2) are involved in GS and Bartter syndrome, respectively. KCl cotransporter may be involved in demyelinating peripheral nerve neuropathies linked to chromosome 15q14. Characterization of mice with spontaneous and targeted mutations of several cation chloride cotransporters have provided insight into physiological and pathological role of several mutations of this gene family. Na-K-2Cl cotransporter and NK CC1 are involved in pain perception, hearing, salivation, spermatogenesis, and maintenance of extracellular fluid volume. Targeted deletion of the neuronal-specific K-Cl cotransporter KCC2 generates mice with seizures and suggests the pivotal role of this transporter in modulating neuronal excitability. Comparison of human and murine phenotypes associated with loss-of-function mutations in cationchloride cotransporters provides an opportunity for detailed physiological and morphological analysis of the tissues involved and learning about the mechanisms in seemingly unrelated and diverse clinical associations.

In a study, 25 out of 65 patients with CIDP had secondary CIDP and included diabetes mellitus in 16, POEMS in four (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), monoclonal gammopathy of undetermined significance in two, myeloma in one, lymphoma in one, and malignancy in one patient. Of the total patients with CIDP, 38.5% of patients had secondary CIDP which was associated with progressive course, less demyelinating features, and worse prognosis but no association with GS or seizure disorder was found. [3]

In another study by Misra et al, eight out of 37 patients with CIDP have atypical clinical features; however, their electrodiagnostic features and response to treatment are not different from typical CIDP and no such association like our case was found. [4]

The present patient had a unique association of GS, seizures, and peripheral nerve dysfunction which could be due to abnormality of NaK-Cl cotransporter genes. Further studies are needed to characterize these patients.

Conflict of interest: None declared.

   References Top

Saroja AO, Naik KR, Khanpet MS. Uncommon dyselectrolytemia complicating Guillain-Barré syndrome. J Neurosci Rural Pract 2013;4:328-30.  Back to cited text no. 1
[PUBMED]  Medknow Journal  
Delpire E, Mount DB. Human and murine phenotypes associated with defects in cationchloride cotransport. Annu Rev Physiol 2002;64:803-43.  Back to cited text no. 2
Wadwekar V, Kalita J, Misra UK. Does the chronic inflammatory demyelinating polyradiculoneuropathy due to secondary cause differ from primary? Neurol India 2011;59:664-8.  Back to cited text no. 3
[PUBMED]  Medknow Journal  
Misra UK, Kalita J, Yadav RK. A comparison of clinically atypical with typical chronic inflammatory demyelinating polyradiculoneuropathy. Eur Neurol 2007;58: 100-5.  Back to cited text no. 4

Correspondence Address:
Dr. U K Misra
Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.185287

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