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ICD 10 code
Bartter syndrome E26.8
Gitelman syndrome E83.4
The disease
Bartter syndrome and Gitelman syndrome are associated as they both concern
hereditary changes in the ability of the kidneys to control the salt balance in
the body. The syndromes are closely related but symptoms vary widely. There
are four types of Bartter syndrome. The most serious forms of the syndrome
are associated with serious symptoms requiring intensive medical
interventions. However, most people with Gitelman syndrome and some
people with the milder forms of Bartter syndrome are not significantly
affected by their conditions.
Occurrence
Bartter and Gitelman syndromes are equally rare, with an incidence of one or
two per 100,000 inhabitants, indicating that there are between 100 and 200
individuals with the disease in Sweden. Bartter syndrome and Gitelman
syndrome are found all over the world.
Cause
The cause of Bartter and Gitelman syndromes is a mutation in one of the
genes controlling the production of (coding for) certain proteins which form a
constituent part of ion channels. These ion channels manage the transport of
sodium, potassium and chloride ions across cell membranes. (See figure 1.)
Bartter syndrome is divided into types 1, 2, 3 and 4 depending on the protein
which is affected. Genes mutated in Bartter syndrome types 1, 2, 3 and 4
are SLC12A1 (15q15-21), KCNJ1 (11q21-25), CLCNKB (1p36)
and BSND (1p32.1) respectively. People with types 2 and 4 have similar
symptoms and are described together in the”Symptoms” section. The same
applies to types 1 and 3, which also resemble each other. The protein affected
in Bartter type 4 also plays a role in the development of the inner ear, so a
child with this type of the disease is born deaf.
The kidneys have many functions. They remove impurities from the blood,
regulate blood pressure and maintain balances in the body’s levels of water,
salts and trace elements. Each kidney is made up of approximately one million
functional units named nephrons. A nephron consists of a network of blood
capillaries (glomerulus, plural glomeruli) and a system of tubules. The
glomeruli filter blood so that blood cells and blood proteins remain in the
blood vessels while most of the fluid, containing salts and trace elements, is
released into the tubules. Primary urine is processed in the tubules, where all
products not treated as impurities are reabsorbed by the blood vessels. (See
figure 2.) If tubules did not function, an adult would need to excrete
approximately one hundred litres of urine per day and salt levels in the body
would become uncontrolled, with life-threatening consequences.
Figure 2: Cross-section of the kidney.
Sodium and potassium are essential elements for the body. One important
function of the kidneys is to ensure that excessive amounts of sodium are not
released into the urine since sodium levels regulate fluid levels in the body.
The hormones renin and aldosterone help by ensuring that sodium is
reabsorbed from primary urine while potassium is excreted in urine.
Potassium causes urine to be acidic, which makes the blood more alkaline
(with raised pH levels). Levels of other substances in the body, including
calcium and magnesium, are also controlled by the tubules of the kidneys.
How much of these substances is retained, or lost in the urine, is regulated by
sodium levels.
In both Bartter and Gitelman syndromes the ability to reabsorb sodium from
primary urine is impaired, as mid-portions of tubules do not function
normally. To some extent this is compensated for by increased production of
renin and aldosterone, hormones which cause the latter portion of the tubules
to absorb more sodium and excrete more potassium and acid in the urine. The
consequence is that blood pH levels tend to rise and the kidneys’ ability to
concentrate urine becomes impaired. Both diseases are characterised by
varying degrees of potassium deficiency, excessive thirst, raised urine
production and elevated blood pH levels. Calcium and magnesium balances
are also affected.
Recently it has becomes possible to identify how different types of Bartter and
Gitelman syndromes are associated with the impaired functionality of specific
proteins in the kidneys. It is now also possible to identify the genetic
mutations which cause changes in specific proteins.
The cause of the delayed motor and cognitive development of many children
with Bartter syndrome, particularly type 4, is not fully understood. One
possible cause is that the protein affected plays a role in the nervous system.
In addition, a difficult neonatal period may negatively influence a child’s
future development.
Heredity
The inheritance pattern of both Bartter syndrome and Gitelman syndrome is
autosomal recessive. This means that both parents are healthy carriers of a
mutated gene. When two healthy carriers have a child, there is a 25 per cent
risk that the child will inherit the mutated genes (one from each parent), in
which case he or she will have the disease. In 50 per cent of cases the child
inherits only one mutated gene (from one parent only) and, like both parents,
will be a healthy carrier of the mutated gene. In 25 per cent of cases the child
will not have the disease and will not be a carrier of the mutated gene.
Symptoms
In Bartter syndrome types 2 and 4, symptoms present at birth, indicating a
severe form of the disease. In types 1 and 3 symptoms usually manifest during
early childhood and in isolated cases may be scarcely noticeable. Not every
individual with Gitelman syndrome experiences symptoms. When symptoms
do manifest, they usually do so in the teens.
Children with these syndrome types have impaired pre-natal kidney function.
Reduced kidney function results in increased urine production, leading in turn
to excessive amounts of amniotic fluid. Birth is often premature, which in
itself is associated with increased risks to the child. During the first days and
weeks of life, the child loses excessive amounts of fluid and salts. If these
fluids and salts are not replaced there is a risk of cardiac arrhythmia or serious
dehydration.
Anomalies in fluid and salt balances are life-long, causing children and adults
with the syndrome to urinate and drink excessively. In some people,
especially those with Bartter syndrome type 4, there is a risk that the kidneys’
ability to remove impurities from the blood will gradually decline, leading to
renal insufficiency. Renal insufficiency may start in the neonatal period or
during early childhood; it may be moderate or so severe that the child requires
dialysis or a kidney transplant. The severity of renal insufficiency determines
the severity of the associated conditions, which include restricted growth,
anaemia and calcium imbalances.
The impaired ability to concentrate urine leads to excessive thirst and a risk of
dehydration. Dehydration can cause constipation or feverish episodes. In type
2, the child often has elevated levels of calcium in the urine, which many
cause calcification in the kidneys. This has a negative effect on kidney
function.
In type 4, cognitive and motor development are primarily affected. They result
in the child learning to stand, walk and talk later than other children. In this
type of the disease the child is deaf from birth.
Growth is often impaired and it is common for children with types 2 and 4 to
be short as adults, particularly if they develop renal failure.
The most common symptoms are increased thirst and urine production.
Children often wish to drink large quantities at frequent intervals throughout
the day. They urinate excessively, which increases the risk of dehydration.
Signs are constipation, feelings of sickness, vomiting and elevated body
temperature. Many children also crave salt.
Gitelman syndrome
Adults with the condition may be affected by swollen and tender joints as a
result of chondrocalcinosis (false gout), caused by the deposit of calcium
crystals in the joints.
Diagnosis
Bartter and Gitelman syndromes are associated with potassium deficiency and
elevated pH levels in the blood. Urine contains high concentrations of sodium
and potassium. Levels of hormones renin and aldosterone are often elevated.
A DNA analysis can usually confirm the diagnosis.
Carrier diagnosis, pre-natal diagnosis and embryo diagnosis are all possible if
the mutation in the family has been identified.
Bartter syndrome types 2 och 4
Blood and urine levels of potassium, sodium and chloride are abnormal, with
high levels in the urine and low levels in the blood. Abnormal levels can be
measured during the neonatal period. The exception occurs in type 2, where
potassium levels in the blood may be extremely high during the first week of
life. Calcium levels in urine can also be high, mainly in type 2. Already in the
neonatal period auditory tests can establish that a child with type 4 is deaf.
The presence of calcium deposits in the kidneys can be established with the
help of an ultrasound examination. Renal insufficiency is diagnosed with the
help of blood tests and clearance tests. (A creatinine clearance test is used to
help evaluate the rate and efficiency of kidney filtration.)
People with types 1 and 3 of the syndrome show the same abnormal values in
blood and urine as people with types 2 and 4, but symptoms present later.
Increased amounts of calcium are excreted in the urine, although renal failure
occurs only in exceptional cases. The excretion of calcium seldom causes
calcium deposits or kidney stones.
Gitelman syndrome
Treatment/interventions
Bartter syndrome types 2 and 4
In the neonatal period it is essential to replace fluids and salts which have
been lost in the urine and to monitor the child carefully to ensure that neither
serious dehydration nor salt imbalance occurs. Apart from breast milk,
additional fluid is given either intravenously, or via a thin tube through the
nose directly into the stomach. It is usually necessary to give supplementary
sodium and potassium. Initially, they are often given intravenously, but
subsequently are administered by mouth several times a day. Appropriate
dosage causes no side effects while a potentially life-threatening salt
imbalance is prevented.
Neonates with type 2 may, at times during the first week of life, have
extremely high levels of potassium and may require medication to reduce the
risk of serious cardiac arrhythmia. After this period these children require
daily potassium supplements.
In order to stimulate the child’s development and help compensate for loss of
function, some children with type 4 require early habilitation. It is important
the child has contact with a habilitation team with expertise in auditory
impairments as well as knowledge of the way deafness affects interaction
with, and participation in, community and social life. A habilitation team
includes professionals with special expertise in how disability affects
everyday life, health and development. Help is available within the medical,
educational, psychological, social and technical fields. Measures may include
assessments, treatment, assistance with choice of aids, information about
disabilities and counselling. It also includes information on support offered by
the local authority, and advice on adapting accommodation and other
environments. The family may also need help in coordinating different forms
of assistance.
Habilitation plans are based on existing needs. For children with type 4, a
functioning form of communication is a priority, as this is a pre-condition for
the child’s successful development.
People with types 1 and 3 require daily potassium supplements. Many also
require additional sodium, and they are at risk of dehydration if they do not
drink sufficient fluids. As with other patients with Barrter syndrome, it is not
always possible to maintain normal levels of potassium. For that reason it is
important that people with types 1 and 3 contact medical services if affected
by gastrointestinal problems or are at risk of dehydration.
Gitelman syndrome
Others
Many people with Bartter or Gitelman syndromes crave salty foods and are
encouraged to eat foods containing large amounts of sodium and potassium. If
required, advice on appropriate nutrition can be provided by a dietician.
Practical advice
Extreme or prolonged bouts of physical activity are inadvisable for individuals
with Bartter and Gitelman syndromes.
Resource personnel
Paediatricians
Physician
HRF, The Swedish Hearing Loss Association, Gävlegatan 16, Box 6605, SE-
113 84 Stockholm, Sweden. Tel: +46 8 457 55 00, text telephone: +46 8 457
55 01, fax: +46 8 457 55 03, email: hrf@hrf.se, www.hrf.se.
Information material
An information leaflet on Bartter syndrome and Gitelman syndrome
summarising the information in this database text is available free of charge
from the customer service department of the Swedish National Board of
Health and Welfare (in Swedish only, article number 2011-11-23). Address:
SE-120 88 Stockholm. Tel: +46 75 247 38 80, fax: +46 35 19 75 29,
email: publikationsservice@socialstyrelsen.se. Postage will be charged for
bulk orders.
Literature
Bartter FC, Pronove P, Gill R, MacCardle RC. Hyperplasia of the
juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis.
A new syndrome. Am J Med 1962; 33: 811-828.
Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by
hypokalemia and hypomagnesemia. Tran Assoc Am Physicians 1966; 79:
221-235.
Knoers NV, Levtchenko EN. Gitelman syndrome. Orphanet J Rare Dis 2008;
3: 22.
Database references
OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim
Search: bartter syndrome, gitelman syndrome
Document information
The Swedish Information Centre for Rare Diseases produced and edited this
information material.
The medical experts who wrote the draft of this material are Associate
Professor Tryggve Nevéus and Associate Professor Gianni Celsi, Uppsala
University Children’s Hospital.
Date of publication: 2012-06-19
Version: 1.0
Publication date of the Swedish version: 2011-12-29
For enquiries contact The Swedish Information Centre for Rare Diseases, The
Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30
Gothenburg, Sweden. Tel: +46 31 786 55 90, email:ovanligadiagnoser@gu.se.
Contact
The Swedish Information Centre for Rare Diseases