CASE REPORT

Gitelman syndrome: novel mutation and long-term follow-up

Aditi Sinha • Petr Lnenicka • Biswanath Basu •

Ashima Gulati • Pankaj Hari • Arvind Bagga

Received: 22 May 2011 / Accepted: 13 September 2011 / Published online: 4 October 2011

� Japanese Society of Nephrology 2011

Abstract We report a case of Gitelman syndrome pre-

senting with fatigue, paresthesias, weakness of limbs and

neck muscles since 2.5 years of age. Investigations showed

hypokalemia and hypomagnesemia with urinary magne-

sium wasting. Genetic analysis revealed the presence of a

novel homozygous mutation in the SLC12A3 gene

(c.2879_2883?9ins14bp, p.Val 960 Glu fsx12). Manage-

ment with potassium and magnesium supplements and

spironolactone resulted in a significant improvement in

symptoms. Over a follow-up of 11 years, the patient

showed satisfactory growth and physical development.

Keywords Hypokalemia � Hypomagnesemia �SLC12A3 gene

Introduction

Gitelman syndrome (OMIM 263800) is an autosomal

recessive renal tubular disorder characterized by hypo-

magnesemia, hypokalemic metabolic alkalosis and normal

blood pressure, with modestly increased blood levels of

renin and aldosterone [1, 2]. The condition is secondary to

inactivating mutations of the SLC12A3 gene that encodes

the thiazide-sensitive sodium chloride cotransporter

(NCCT) in the distal convoluted tubules. Most patients

have mild symptoms and the diagnosis is delayed to late

childhood or adulthood [1–3]. The occurrence of symptoms

in early childhood is rare, and information on the long-term

outcome of Gitelman syndrome is limited [4–7]. We report

a 6-year-old girl with Gitelman syndrome, with novel

homozygous mutation of the SLC12A3 gene, who was

followed up for 11 years.

Case report

A 6-year-old girl was referred for evaluation of polyuria,

nocturnal enuresis and intermittent weakness of lower

limbs since 2.5 years of age. The child tired easily and

complained of intermittent limb weakness. While she could

attend school normally, she could not participate in active

sports. She was admitted twice, at 3- and 5-years of age,

with muscle cramps and severe weakness of muscles of the

neck. There was intermittent history of paresthesias of the

neck and limbs. There was no history of seizures, syncope,

vertigo, palpitations, hematuria and use of diuretics or

laxatives. On examination, the blood pressure was

96/56 mmHg, pulse rate 78/min and respiratory rate

20/min. The height was 109.5 cm and weight was 16 kg, at

25th and 3rd percentile, respectively [8]. The muscle tone,

power and deep tendon reflexes were normal.

Blood levels of potassium ranged between 2.4 and

2.7 mEq/L, sodium 133–139 mEq/L, chloride 97–99 mEq/L,

venous pH 7.43–7.58, bicarbonate 20–22 mEq/L, magnesium

1.4–1.5 mg/dL (normal 1.7–2.4 mg/dL), urea 38 mg/dL and

creatinine 0.4 mg/dL. Urinalysis was normal and there was no

glucosuria or abnormal proteinuria. The levels of urinary

potassium were 70–180 mEq/L, sodium 50–117 mEq/L and

chloride 60–109 mEq/L. The urinary calcium excretion

A. Sinha (&) � B. Basu � A. Gulati � P. Hari � A. Bagga

Division of Pediatric Nephrology, Department of Pediatrics,

All India Institute of Medical Sciences,

New Delhi 110029, India

e-mail: aditisinha4@rediffmail.com

P. Lnenicka

Institute of Biology and Medical Genetics of the 1st Faculty of

Medicine of Charles University and General Teaching Hospital,

Prague, Czech Republic

123

Clin Exp Nephrol (2012) 16:306–309

DOI 10.1007/s10157-011-0542-x

ranged between 6 and 30 mg/dL and calcium to creatinine

ratio was normal (0.03–0.18 mg/mg). The fractional excre-

tion of magnesium was 12.6% (normal\5%).

After overnight fasting, a thiazide test was performed by

estimation of serum and urinary electrolytes and creatinine

at baseline and over 4 h, following administration of oral

hydrochlorothiazide at a dose of 1 mg/kg [9]. The maximal

fractional excretion of chloride was 2.42%, similar to the

baseline value of 1.84%, suggesting a diagnosis of Gitel-

man syndrome. Plasma renin activity (1.33 ng/ml/h) and

blood levels of aldosterone (29.3 ng/dL), thyroxine and

thyroid-stimulating hormone were normal. Ultrasonogra-

phy of the abdomen showed normal kidneys with no

evidence of renal stones or nephrocalcinosis.

Family history was remarkable for third-degree parental

consanguinity (Fig. 1). A 9-year-old sister, with similar

symptoms since 4 years of age and with evaluation sug-

gesting hypokalemic metabolic alkalosis, had died recently

in a road traffic accident. Sequencing of the SLC12A3 gene

was carried out in the index case and her parents, and

compared to the reference genomic sequence (Genomic

sequence NC 000016; http://www.ncbi.nlm.nih.gov/gene/

6559). The analysis showed a novel homozygous mutation

of the SLC12A3 gene, in the form of an insertion of 14 base

pairs into the junction of exon 24 and intron 24

(c.2879_2883 ? 9ins14bp, p.Val 960 Glu fsx12) (Fig. 2).

This mutation is expected to lead to the substitution of

valine by glutamic acid at amino acid 960 (p.960Val[Glu)

and a frameshift changing the amino acid sequence

downstream of amino acid 960 and introducing an abnor-

mal stop codon at position 971 (Fig. 3). This change may

also lead to misprocessing of the junction of exon 24 and

intron 24. Either action may result in the production of a

non-functional protein.

The parents showed the above mutation in heterozygous

form. Sequencing also revealed 3 known polymorphisms

(c.122A[G, p.Ala122Ala; c.791C[G, p.Ala264Gly and

c.2952 C[T, p.Ile984Ile) in the patient.

Based on the clinical, biochemical features and muta-

tional analysis, the patient was diagnosed as Gitelman

syndrome. She was treated with supplements of potassium

(2–3 mEq/kg/day), magnesium (as oral magnesium sul-

phate, 0.7–1.2 mEq/kg/day) and indomethacin (1 mg/kg/day).

While there was symptomatic improvement, the patient

complained of tiredness after prolonged activity, and

hypokalemia and hypomagnesemia persisted. Over the next

2 years, the doses of potassium and magnesium supple-

ments were maintained at 3.5 and 1 mEq/kg/day respec-

tively. In view of persistent hypokalemia, the patient also

received treatment with spironolactone without a signifi-

cant increase in the level of serum potassium. She con-

tinued to attend regular school but was unable to participate

in active sports. Menarche was attained at 14 years.

At last follow-up, 11 years after diagnosis, the 17-year-

old remains asymptomatic apart from tiredness after pro-

longed activity. Her present height and weight are 145 cm

(25th percentile) and 53 kg (80th percentile) respectively,

and the sexual maturity rating is stage 5. The blood

level of sodium is 137 mEq/L, potassium 3.4 mEq/L,

pH 7.38, bicarbonate 22 mEq/L, creatinine 0.7 mg/dL,

urea 34 mg/dL and magnesium 1.4 mEq/L. Current medi-

cations include indomethacin and supplements of potas-

sium and magnesium.

Discussion

The diagnosis of Gitelman syndrome in this patient was

based on clinical and biochemical features, and confirmed

by the presence of a homozygous mutation in the SLC12A3

gene [2]. During a follow-up of 11 years, physical growth

and development were normal. The chief concern during

management was an inability to maintain normal levels of

serum magnesium and potassium, resulting in episodic

muscle weakness and feeling of tiredness.

The presentation of Gitelman syndrome is heterogeneous

in terms of age at presentation, clinical features and severity

of biochemical abnormalities. Most patients are diagnosed in

late childhood, beyond 6 years of age, or adulthood during

routine investigation or when evaluated for cramps, fatigue,

paresthesias and tetany [2]. A subgroup of patients have early

onset of symptoms including tetany, paralysis, seizures,

rhabdomyolysis, growth retardation and arrhythmias [7, 9].

The mild nature of clinical and laboratory abnormalities in

our patient likely represent a milder phenotype, which may

Fig. 1 Pedigree chart showing third-degree parental consanguinity.

An elder sibling with similar presentation died in an accident

Clin Exp Nephrol (2012) 16:306–309 307

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explain absence of overt alkalosis and normal levels of

plasma renin and aldosterone. In comparison with Bartter

syndrome, the degree of volume contraction and the asso-

ciated stimulation of the renin-angiotensin-aldosterone

axis in Gitelman syndrome are mild, and plasma aldosterone

levels might remain within normal range.

Data on long-term follow-up of patients diagnosed in

early childhood is limited. Bettinelli et al. [4] reported a

6-year-old girl with Gitelman syndrome, who was followed

for 14 years. At 20 years of age, the growth and develop-

ment were satisfactory and magnesium supplementation

reduced the risk of symptoms such as tetany. Satisfactory

physical growth has been reported following correction of

electrolyte abnormalities in a case series of children with

Gitelman syndrome [5]. Correction of biochemical abnor-

malities in the present patient also resulted in significant

clinical improvement. At the end of follow-up of 11 years,

she is intermittently symptomatic but has shown satisfac-

tory physical growth.

More than 180 mutations throughout the SLC12A3 gene

have been identified in Gitelman syndrome (Human Gene

Mutation Database, http://www.hgmd.cf.ac.uk). Most are

missense mutations; nonsense, frameshift and splice-site

mutations are less frequent. The condition is genetically

heterogeneous and no hotspots are identified, although

some mutations are more commonly reported in certain

ethnic groups [10]. There is limited evidence of a geno-

type-phenotype correlation, with considerable phenotypic

variability even within families having the same mutations

[10]. A proportion of patients show only a single mutation

in the heterozygous state, instead of being compound het-

erozygous or homozygous for such mutations [11, 12].

Although the mutation in the present case is not previously

reported, its presence in the homozygous state in a patient

with characteristic clinical and biochemical features sup-

ports the diagnosis of Gitelman syndrome. It is likely that

the present mutation resulted in a significant loss of NCCT

channel activity leading to an early onset of symptoms.

Fig. 2 Electrophoregram demonstrating the sequence of base pair at

the junction of the exon 24 and intron 24 of SLC12A3 gene. Arrowson the figure indicate (1) the first base of a 14-base pair length

insertion mutation that introduces a frameshift mutation, (2) the first

base after the frameshift insertion, and (3) the end of the mutated exon

24. The vertical strip denotes the end of the non-mutated exon. The

sequence of the reference normal exon is annotated below the mutated

sequence

308 Clin Exp Nephrol (2012) 16:306–309

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Confirmation of the pathogenicity of this mutation requires

transcript analysis and functional studies.

The present report adds to the experience of manage-

ment of Gitelman syndrome presenting in early childhood.

The patient showed the presence of a novel mutation,

which was considered pathogenic. Long-term potassium

and magnesium supplementation resulted in improvement

of clinical symptoms and normal physical growth.

References

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Fig. 3 Figure showing expected effect of mutation on protein

synthesis. The upper panel depicts the amino acid sequence generated

by translation of the normal nucleotide sequence at the junction of

exon 24 and intron 24. Normally, the amino acid chain is terminated

at position 1030 due to the presence of a stop codon. Mutation

between nucleotides guanine and thymine (indicated by the arrowpointing upwards in the upper panel) results in the insertion of 14

nucleotides (shown as the underlined sequence in the lower panel).This is expected to result in a frameshift mutation, with the

introduction of a stop codon at position 971

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