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Gitelman Syndrome

Familial Hypokalemia Hypomagnesemia

Gitelman's syndrome (GS) is an inherited condition that features low levels of magnesium and potassium in the serum and low levels of calcium in the urine. The inheritance pattern is autosomal recessive.


Presentation

Gitelman syndrome is a genetic condition that affects the renal tubules, leading to hypomagnesemia, hypokalemia and hypocalciuria, as well as acid-base imbalance (metabolic alkalosis). Although Gitelman syndrome was previously thought to be a milder form of a tubular transport disorder ascribed to Bartter syndrome, it is now recognized as a distinct medical entity that should not be confused with Bartter's syndrome [1] [2] [3] [4].

Gitelman syndrome is characterized by a wide variety of symptoms; not all patients experience the full spectrum. Diarrhea, vomiting and tetany, as a result of significant hypomagnesemia related to fluid loss, are some of the reported symptoms. Paresthesias may be described, as well as weakness and fatigue that discourages the individuals from engaging in physical activity. However, there have been cases reported that do not display serious symptoms; a young adult has been described in the literature as exhibiting only leg cramps, weakness, vomiting, and malaise [5]. Growth is hindered only in cases of profound hypomagnesemia and hypokalemia [6].

Some Gitelman syndrome patients may also report swollen, burning and tender joints; this is attributed to the chondrocalcinosis that may accompany the rest of the symptoms. Some isolated reports have described neurological symptoms such as ataxia, visual impairment and vertigo as well. As for the cardiovascular system, although Gitelman syndrome causes ventricular arrhythmias, they only rarely result in any considerable symptomatology, with only a few patients experiencing cardiac arrest [7] [8]. Patients are usually hypotensive.

Weakness
  • His mother had more slight symptoms of weakness than him with mild hypokalemia and hypocalciuria. Mild hypomagnesemia was also observed in his sister with occasional weakness.[ncbi.nlm.nih.gov]
  • In spite of being a rare disorder, GS has to be considered in children with developmental delay and muscle weakness. With adequate treatment, GS patients have an excellent prognosis.[ncbi.nlm.nih.gov]
  • Paresthesias may be described, as well as weakness and fatigue that discourages the individuals from engaging in physical activity.[symptoma.com]
  • Patients with Gitelman syndrome are usually diagnosed by chance or present with muscular weakness, constipation, or tetanies due to hypokalemia and hypomagnesemia.[ncbi.nlm.nih.gov]
  • We report a case of Gitelman syndrome presenting with fatigue, paresthesias, weakness of limbs and neck muscles since 2.5 years of age. Investigations showed hypokalemia and hypomagnesemia with urinary magnesium wasting.[ncbi.nlm.nih.gov]
Fatigue
  • Clinical signs are mostly secondary to chronic hypokalemia and include dizziness, fatigue, constipation and weakness. Patients can also present with muscle cramps, tetany, fatigue and convulsions due to severe metabolic alkalosis or hypomagnesemia.[ncbi.nlm.nih.gov]
  • We report a case of Gitelman syndrome presenting with fatigue, paresthesias, weakness of limbs and neck muscles since 2.5 years of age. Investigations showed hypokalemia and hypomagnesemia with urinary magnesium wasting.[ncbi.nlm.nih.gov]
  • The clinical spectrum is wide and usually characterized by chronic fatigue, cramps, muscle weakness and paresthesiae. We describe a case of a 43 year-old male patient with early onset of knee arthritis and no other symptoms.[ncbi.nlm.nih.gov]
  • Gitelman syndrome is the most common renal tubulopathy, recently exhibiting a dramatic rise of incidence in Asia.A 50-year-old woman presented with vomiting, fatigue and quadriparesis.[ncbi.nlm.nih.gov]
  • A 22-year male presented with severe episodic fatigue involving all limbs associated with episodes of sinking, palpitations, salt craving, increased thirst and frequent micturition hampering his routine daily activities.[ncbi.nlm.nih.gov]
Chest Discomfort
  • Both probands have normal or lower blood pressure, weakness and numbness of lower extremities, muscular soreness, and occasional palpitations and chest discomfort. Proband A wearies easily and Proband B has occasional joint numbness and pain.[ncbi.nlm.nih.gov]
Recurrent Urinary Tract Infection
  • The reason for their impaired renal function was not clear, but one participant had a history of recurrent urinary tract infections in the years following childbirth, necessitating pelvic floor surgery.[doi.org]
Euthyroid
  • Thyrotoxic periodic paralysis was included in the differential diagnosis, but evolved into euthyroid state, persisting with severe hypokalemia, which led to be diagnosed as Gitelman syndrome.[ncbi.nlm.nih.gov]
Low Back Pain
  • back pain: an exploration of the impact of a patient-centered website , Patient Educ Couns , 2009 , vol. 77 (pg. 27 - 32 ) 9 Online health information seeking in the context of the medical consultation in Switzerland , Qual Health Res , 2010 , vol. 20[academic.oup.com]
Long Arm
  • GS is caused by an inactivating mutation in the SLC12A3 gene, which is located on the long arm of chromosome 16 (16q13) and encodes a thiazide-sensitive sodium chloride cotransporter (NCCT).[ncbi.nlm.nih.gov]
Heel Pain
  • We report a case that has Gitelman syndrome (GS) and familial Mediterranean fever (FMF) presenting with recurrent arthritis of right knee and heel pain. Investigations showed hypokalemia and hypomagnesemia with urinary magnesium wasting.[ncbi.nlm.nih.gov]
Visual Impairment
  • Some isolated reports have described neurological symptoms such as ataxia, visual impairment and vertigo as well.[symptoma.com]
Red Eye
  • A 62-year-old woman with painful red eyes and sicca syndrome presented at the ophthalmological department. The diagnostic evaluation identified a Sjögren syndrome with early endophthalmitis as the reason for the red eyes.[ncbi.nlm.nih.gov]
Psychomotor Retardation
  • Here we describe a case of GS presenting in infancy with hypokalemia and psychomotor retardation. We present an 18-month-old boy who presented with psychomotor retardation and failure to thrive.[ncbi.nlm.nih.gov]
Vertigo
  • Some isolated reports have described neurological symptoms such as ataxia, visual impairment and vertigo as well.[symptoma.com]
  • Despite symptoms including presyncope, vertigo, ataxia, and blurred vision, few data have been accumulated regarding formal cardiac evaluation for patients with Gitelman's syndrome. 3 We report a case of Gitelman's syndrome in a patient presenting with[nejm.org]
  • These symptoms include blurred vision, vertigo, and an impaired ability to coordinate voluntary movements (ataxia). A study from Yale indicated that Gitelman and Bartter syndrome have significant impact to quality of life (Cruz D et al., 2001).[rarediseases.org]
  • In earlier clinical reports additional symptoms, such as ataxia, vertigo, and blurred vision have been reported. Cruz and colleagues have challenged the generally shared idea that GS is a mild disorder [ 3 ].[ncbi.nlm.nih.gov]
Papilledema
  • She had bilateral papilledema, and right abducens palsy. CSF examination demonstrated high pressure (over 320 mmH(2)O) with normal cytochemistry. Brain MRI was normal.[ncbi.nlm.nih.gov]
  • […] report a case of Gitelman syndrome (GS) in a dizygotic twin who presented at 12 years of age with growth delay, metabolic alkalosis, hypomagnesemia and hypokalemia with inappropriate kaliuresis, and idiopathic intracranial hypertension with bilateral papilledema[ncbi.nlm.nih.gov]
Resting Tremor
  • tremor R arm Cramps Occasional Occasional leg cramps Occasional Polydipsia Drank   7 L/day, now 2 L 1 L daily, more with sport Yes (on diuretic) Vomiting During pregnancy During pregnancy During pregnancy Comorbidities Osteoarthritis IHD Hypertension[doi.org]
Encephalopathy
  • We believe that the findings are due to alteration of respiratory chain function secondary to the metabolic derangement and hence have a similar imaging appearance as encephalopathy related to mitochondrial cytopathy or metabolic encephalopathy.[ncbi.nlm.nih.gov]

Workup

A detailed medical history, clinical examination and symptomatology, as well as laboratory testing are all used to diagnose Gitelman syndrome. Laboratory blood abnormalities include:

Although low serum magnesium and urine calcium had been regarded as a necessary part of the Gitelman syndrome diagnosis, a 2004 study reported two families with a valid diagnosis of Gitelman syndrome (corroborated by genetic tests), with women presenting with hypokalemia but normal urine calcium and serum magnesium [9]. The female patients of these families were also found to exhibit less severe hypokalemia and were generally asymptomatic. Patients with Gitelman syndrome tend to respond to diuretics, which suggests that the syndrome mainly affects the distal tubules. Genetic testing to confirm a diagnosis can be performed, if indicated. The gene involved is the SLC12A3 gene, encoding for the thiazide-sensitive NaCl cotransporter (NCC); the majority of patients affected by Gitelman syndrome exhibit SLC12A3 mutations. Genetic counseling is available for families affected by Gitelman syndrome.

Differential diagnosis should include Bartter's syndrome, laxative abuse and chronic vomiting. Other diagnostic modalities, such as electrocardiography or joint magnetic resonance imaging scans (MRI) can be employed depending on the symptoms reported by each individual.

Hypouricemia
  • A 6-year-old Caucasian girl was admitted via the Emergency department for vomiting, and initial laboratory investigations found hyponatremia, hypokalemia, metabolic acidosis with normal anion gap, hypophosphatemia, and hypouricemia.[ncbi.nlm.nih.gov]

Treatment

  • Male patients tend to experience more severe symptoms and poor treatment effect.[ncbi.nlm.nih.gov]
  • Mean blood potassium levels increased from 2.8 0.3, 3.5 0.5 and 3.2 0.3 before treatment to 3.2 0.5, 3.7 0.6 and 3.7 0.3 mmol/l with treatment in groups with two (P 0.003), one and no mutated alleles respectively.[ncbi.nlm.nih.gov]
  • Body growth improves with treatment and close follow-up.[ncbi.nlm.nih.gov]
  • However, evidence supporting these treatment options is limited to case series studies.[ncbi.nlm.nih.gov]
  • Furthermore, this case suggests the potential use of thiazide diuretics in the treatment of calcineurin-induced hypertension.[ncbi.nlm.nih.gov]

Prognosis

  • In general, the long-term prognosis of GS is excellent.[ncbi.nlm.nih.gov]
  • We present a short statured boy with a clear history of familial short stature, normal growth and a final height prognosis within the target height range. However, routine laboratory studies led to the diagnosis of Gitelman syndrome.[ncbi.nlm.nih.gov]
  • Prognosis To date, there is no evidence that GS affects life expectancy. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management.[ncbi.nlm.nih.gov]

Etiology

  • Loss of function of mutated solute carrier family 12 member 3 (SLC12A3) gene is the most frequent etiology for Gitelman syndrome (GS), which is mainly manifested by hypokalemia, hypomagnesemia and hypocalciuria.[ncbi.nlm.nih.gov]
  • However, etiological investigations were inconclusive and the patient was discharged with potassium chloride and phosphorus supplementation.[ncbi.nlm.nih.gov]
  • Etiology GS is caused by biallelic inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive sodium-chloride cotransporter NCC expressed in the apical membrane of cells lining the distal convoluted tubule.[orpha.net]
  • Dear Editor, Hypokalemia is one of the most common electrolyte abnormalities which etiology can be unclear and the incorrect diagnosis can result in the wrong treatment.[revistanefrologia.com]

Epidemiology

  • Summary Epidemiology Gitelman syndrome (GS) prevalence is estimated at 1 to 10 per 40,000 and potentially higher in Asia. GS is arguably the most frequent inherited tubulopathy.[orpha.net]
  • Familial aggregation and genetic epidemiology of blood pressure.[dx.doi.org]
  • Summary Epidemiology To date, only one large pedigree with 18 affected individuals has been reported in the literature.[orpha.net]
  • Disease name and synonyms Gitelman syndrome Gitelman's syndrome Familial hypokalemia-hypomagnesemia Definition and epidemiology Gitelman syndrome (GS) (OMIM 263800), also referred to as familial hypokalemia-hypomagnesemia, is an autosomal recessive salt-losing[ncbi.nlm.nih.gov]
Sex distribution
Age distribution

Pathophysiology

  • KEYWORDS: Acid–base; Electrolytes; Gitelman syndrome; Pathophysiology; Potassium[ncbi.nlm.nih.gov]
  • Acquired Gitelman syndrome (GS) associated with Sjögren syndrome (SS) is rare, and the test to determine the pathophysiological state of acquired GS in patients with primary SS has not been reported previously.[ncbi.nlm.nih.gov]
  • We review the molecular pathophysiology of Gitelman syndrome and related tubular disorders and discuss management in pregnancy.[scholars.northwestern.edu]
  • By taking the quite heterogeneous presentations and the apparently different pathophysiologies as the basis, the applicability of the physiologic classification has been tested.[journals.lww.com]
  • A pathophysiological and clinical uptodate. Endocrine 2012;41:53–[clinlabnavigator.com]

Prevention

  • Hypomagnesemia is corrected with magnesium chloride (magnesium sulfate or oxide are avoided to prevent diarrhea) [ 7, 11 ]. Conclusion GS can present as early as two years of age.[jmedicalcasereports.biomedcentral.com]
  • It is therefore important to monitor patients and try to correct the potassium and magnesium disturbances to prevent acute exacerbations and progression 9.[f1000research.com]
  • Genetics), Clinical DNA Testing and DNA Banking - Marshfield, WI, USA TAT : 3-5 weeks price : 990.00 Gitelman Syndrome via the SLC12A3 Gene method(s): Sequencing, Next Gen PreventionGenetics (Prevention Genetics), Clinical DNA Testing and DNA Banking[genetests.org]

References

Article

  1. Geven WB, Willem JL, Schroder CH. Study of the path physiology of Bartter/Gitelman's syndrome. Attempt of classification-role of renal magnesium depletion. Magnesium B. 1994;16:29–36.
  2. Bettinelli A, Bianchetti MG, Girardin E. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. Pediatr J. 1992;120:38–43.
  3. Simon DB, Nelson-Williams C, Bia MJ. Gitelman's variant of Bartters syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet. 1996;12:24–30.
  4. Gladziwa U, Schwarz R, Gitter AH. Chronic hypokalaemia of adults: Gitelman's syndrome is frequent but classical Bartter's syndrome is rare. Nephrol Dial Transplant. 1995;10:1607–1613.
  5. M Gjata, M Tase, A Gjata, and Zh Gjergji. Gitelman's Syndrome (Familial hypokalemia-hypomagnesemia). Hippokratia. 2007 Jul-Sep; 11(3): 150–153.
  6. Riveira-Munoz E, Chang Q, Godefroid N, Hoenderop JG, Bindels RJ, Dahan K, Devuyst O. Belgian network for study of gitelman syndrome. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J Am Soc Nephrol. 2007;1:1271–1283.
  7. Foglia PEG, Bettineli A, Tosetto C, Cortesi C, Crosazzo L, Edefonti A, Bianchetti MG. Cardiac work up in primary hypokalemia-hypomagnesemia (Gitelman syndrome) Nephrol Dial Transplant. 2004;19:1398–1402.
  8. Scognamiglio R, Negut C, Calò LA. Aborted sudden cardiac death in two patients with Bartter's/Gitelman's syndromes. Clin Nephrol. 2007;67:193–197.
  9. Lin SH, Cheng NL, Hsu YJ, Halperin ML. Intrafamiliar phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter. Am J Kidney Dis. 2004;43:304–312.

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Last updated: 2019-07-11 21:31