A genetic disorder is a genetic problem caused by one or more
abnormalities in the genome. Most genetic disorders are quite rare and
affect one person in every several thousands or millions.
Genetic disorders may be hereditary, meaning that they are passed down from the parents' genes. In other genetic disorders, defects may be caused by new mutations or changes to the DNA. In such cases, the defect will only be passed down if it occurs in the germline.
A single-gene (or monogenic) disorder is the result of a single mutated gene. Over 6000 human diseases are caused by single-gene defects. Single-gene disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparental disomy, however, may affect inheritance patterns. The divisions between recessive and dominant types are not "hard and fast", although the divisions between autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, achondroplasia
is typically considered a dominant disorder, but children with two
genes for achondroplasia have a severe skeletal disorder of which
achondroplasics could be viewed as carriers. Sickle-cell anemia is also considered a recessive condition, but heterozygous carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition.
When a couple where one partner or both are sufferers or carriers of a
single-gene disorder wish to have a child, they can do so through in vitro fertilization, which enables preimplantation genetic diagnosis to occur to check whether the embryo has the genetic disorder.
Two copies of the gene must be mutated for a person to be affected by
an autosomal recessive disorder. An affected person usually has
unaffected parents who each carry a single copy of the mutated gene (and
are referred to as carriers). Two unaffected people who each carry one
copy of the mutated gene have a 25% risk with each pregnancy of having a
child affected by the disorder. Examples of this type of disorder are Albinism, Medium-chain acyl-CoA dehydrogenase deficiency, cystic fibrosis, sickle-cell disease, Tay-Sachs disease, Niemann-Pick disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such as wet versus dry earwax, are also determined in an autosomal recessive fashion.
X-linked dominant
X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern, with a prime example being X-linked hypophosphatemic rickets.
Males and females are both affected in these disorders, with males
typically being more severely affected than females. Some X-linked
dominant conditions, such as Rett syndrome, incontinentia pigmenti type 2, and Aicardi syndrome, are usually fatal in males either in utero
or shortly after birth, and are therefore predominantly seen in
females. Exceptions to this finding are extremely rare cases in which
boys with Klinefelter syndrome
(47,XXY) also inherit an X-linked dominant condition and exhibit
symptoms more similar to those of a female in terms of disease severity.
The chance of passing on an X-linked dominant disorder differs between
men and women. The sons of a man with an X-linked dominant disorder
will all be unaffected (since they receive their father's Y chromosome),
and his daughters will all inherit the condition. A woman with an
X-linked dominant disorder has a 50% chance of having an affected fetus
with each pregnancy, although in cases such as incontinentia pigmenti,
only female offspring are generally viable. In addition, although these
conditions do not alter fertility per se, individuals with Rett syndrome or Aicardi syndrome rarely reproduce.
X-linked recessive
X-linked recessive conditions are also caused by mutations in genes
on the X chromosome. Males are more frequently affected than females,
and the chance of passing on the disorder differs between men and women.
The sons of a man with an X-linked recessive disorder will not be
affected, and his daughters will carry one copy of the mutated gene. A
woman who is a carrier of an X-linked recessive disorder (XRXr)
has a 50% chance of having sons who are affected and a 50% chance of
having daughters who carry one copy of the mutated gene and are
therefore carriers. X-linked recessive conditions include the serious
diseases hemophilia A, Duchenne muscular dystrophy, and Lesch-Nyhan syndrome, as well as common and less serious conditions such as male pattern baldness and red-green color blindness. X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).
Y-linked
Y-linked disorders are caused by mutations on the Y chromosome.
These conditions may only be transmitted from the heterogametic sex
(e.g. male humans) to offspring of the same sex. More simply, this means
that Y-linked disorders in humans can only be passed from men to their
sons; females can never be affected because they do not possess
Y-allosomes.
Y-linked disorders are exceedingly rare but the most well-known
examples typically cause infertility. Reproduction in such conditions is
only possible through the circumvention of infertility by medical
intervention.
Mitochondrial
This type of inheritance, also known as maternal inheritance, applies to genes encoded by mitochondrial DNA.
Because only egg cells contribute mitochondria to the developing
embryo, only mothers can pass on mitochondrial DNA conditions to their
children. An example of this type of disorder is Leber's hereditary optic neuropathy.
It is important to stress that the vast majority of mitochondrial
disease (particularly when symptoms develop in early life) is actually
caused by an underlying nuclear gene defect, and most often follows
autosomal recessive inheritance.
Multiple genes
Genetic
disorders may also be complex, multifactorial, or polygenic, meaning
they are likely associated with the effects of multiple genes in
combination with lifestyles and environmental factors. Multifactorial
disorders include heart disease and diabetes.
Although complex disorders often cluster in families, they do not have a
clear-cut pattern of inheritance. This makes it difficult to determine a
person’s risk of inheriting or passing on these disorders. Complex
disorders are also difficult to study and treat, because the specific
factors that cause most of these disorders have not yet been identified.
Studies which aim to identify the cause of complex disorders can use
several methodological approaches to determine genotype-phenotype associations. One method, the genotype-first approach,
starts by identifying genetic variants within patients and then
determining the associated clinical manifestations. This is opposed to
the more traditional phenotype-first approach, and may identify causal
factors that have previously been obscured by clinical heterogeneity, penetrance, and expressivity.
On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian
diseases. But this does not mean that the genes cannot eventually be
located and studied. There is also a strong environmental component to
many of them (e.g., blood pressure).
Due to the wide range of genetic disorders that are known, diagnosis
is widely varied and dependent of the disorder. Most genetic disorders
are diagnosed at birth or during early childhood however some, such as Huntington's disease, can escape detection until the patient is well into adulthood.
The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depth family history,
it is possible to anticipate possible disorders in children which
direct medical professionals to specific tests depending on the disorder
and allow parents the chance to prepare for potential lifestyle
changes, anticipate the possibility of stillbirth, or contemplate termination. Prenatal diagnosis can detect the presence of characteristic abnormalities in fetal development through ultrasound, or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis.
Prognosis
Not
all genetic disorders directly result in death; however, there are no
known cures for genetic disorders. Many genetic disorders affect stages
of development, such as Down syndrome, while others result in purely physical symptoms such as muscular dystrophy. Other disorders, such as Huntington's disease,
show no signs until adulthood. During the active time of a genetic
disorder, patients mostly rely on maintaining or slowing the degradation
of quality of life and maintain patient autonomy. This includes physical therapy, pain management, and may include a selection of alternative medicine programs.
The treatment of genetic disorders is an ongoing battle with over
1800 gene therapy clinical trials having been completed, are ongoing, or
have been approved worldwide. Despite this, most treatment options revolve around treating the symptoms of the disorders in an attempt to improve patient quality of life.
Gene therapy refers to a form of treatment where a healthy gene
is introduced to a patient. This should alleviate the defect caused by a
faulty gene or slow the progression of disease. A major obstacle has
been the delivery of genes to the appropriate cell, tissue, and organ
affected by the disorder. How does one introduce a gene into the
potentially trillions of cells which carry the defective copy? This
question has been the roadblock between understanding the genetic
disorder and correcting the genetic disorder.
Cherry-red spot as seen in the retina in Tay–Sachs disease. The fovea's center appears bright red because it is surrounded by a whiter than usual area.
Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord.
The most common type, known as infantile Tay–Sachs disease, becomes
apparent around three to six months of age with the baby losing the
ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move. Death usually occurs in early childhood. Less commonly the disease may occur in later childhood or adulthood. These forms are generally milder in nature.
The treatment of Tay–Sachs disease is supportive in nature. This may involve multiple specialities as well as psychosocial support for the family. The disease is rare in the general population. In Ashkenazi Jews, French Canadians of southeastern Quebec, and Cajuns of southern Louisiana, the condition is more common. Approximately 1 in 3,600 Ashkenazi Jews at birth are affected.
The disease is named after Waren Tay, who in 1881 first described a symptomatic red spot on the retina of the eye; and Bernard Sachs, who described in 1887 the cellular changes and noted an increased rate of disease in Ashkenazi Jews. Carriers of a single Tay–Sachs allele are typically normal. It has been hypothesized that being a carrier may confer protection from another condition such as tuberculosis, explaining the persistence of the allele in certain populations. Researchers are looking at gene therapy or enzyme replacement therapy as possible treatments.
Signs and symptoms
Tay–Sachs
disease is typically first noticed in infants around 6 months old
displaying an abnormally strong response to sudden noises or other
stimuli, known as the "startle response". There may also be listlessness
or muscle stiffness (hypertonia). The disease is classified into
several forms, which are differentiated based on the onset age of neurologicalsymptoms.
Infantile Tay–Sachs disease.Infants with Tay–Sachs disease appear to develop normally for the first six months after birth. Then, as neurons become distended with gangliosides, a relentless deterioration of mental and physical abilities begins. The child may become blind, deaf, unable to swallow, atrophied, and paralytic. Death usually occurs before the age of four.
Juvenile Tay–Sachs disease. Juvenile Tay–Sachs disease is
rarer than other forms of Tay–Sachs, and usually is initially seen in
children between two and ten years old. People with Tay–Sachs disease
develop cognitive and motor skill deterioration, dysarthria, dysphagia, ataxia, and spasticity. Death usually occurs between the age of five to fifteen years.
Adult/Late-Onset Tay–Sachs disease. A rare form of this
disease, known as Adult-Onset or Late-Onset Tay–Sachs disease, usually
has its first symptoms during the 30s or 40s. In contrast to the other
forms, late-onset Tay–Sachs disease is usually not fatal as the effects
can stop progressing. It is frequently misdiagnosed. It is characterized
by unsteadiness of gait and progressive neurological deterioration. Symptoms of late-onset Tay–Sachs – which typically begin to be seen in adolescence or early adulthood – include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly a schizophrenia-like psychosis. People with late-onset Tay–Sachs may become full-time wheelchair users in adulthood.
Until the 1970s and 1980s, when the disease's molecular genetics
became known, the juvenile and adult forms of the disease were not
always recognized as variants of Tay–Sachs disease. Post-infantile
Tay–Sachs was often misdiagnosed as another neurological disorder, such
as Friedreich's ataxia.
Genetics
Tay–Sachs disease is inherited in the autosomal recessive pattern, depicted above.
The HEXA gene is located on the long (q) arm of human chromosome 15, between positions 23 and 24.
Tay–Sachs disease is an autosomal recessive genetic disorder, meaning that when both parents are carriers,
there is a 25% risk of giving birth to an affected child with each
pregnancy. The affected child would have received a mutated copy of the
gene from each parent.
Tay–Sachs results from mutations in the HEXAgene on chromosome 15, which encodes the alpha-subunit of beta-N-acetylhexosaminidase A, a lysosomalenzyme. By 2000, more than 100 different mutations had been identified in the human HEXA gene. These mutations have included single base insertions and deletions, splice phase mutations, missense mutations, and other more complex patterns. Each of these mutations alters the gene's protein product (i.e., the enzyme), sometimes severely inhibiting its function. In recent years, population studies and pedigree analysis have shown how such mutations arise and spread within small founder populations. Initial research focused on several such founder populations:
Ashkenazi Jews. A four base pair insertion in exon 11 (1278insTATC) results in an altered reading frame for the HEXA
gene. This mutation is the most prevalent mutation in the Ashkenazi
Jewish population, and leads to the infantile form of Tay–Sachs disease.
Cajuns.
The same 1278insTATC mutation found among Ashkenazi Jews occurs in the
Cajun population of southern Louisiana. Researchers have traced the
ancestry of carriers from Louisiana families back to a single founder
couple – not known to be Jewish – who lived in France in the 18th
century.
French Canadians.
Two mutations, unrelated to the Ashkenazi/Cajun mutation, are absent in
France but common among French Canadians living in eastern Quebec and
Acadians from the Province of New Brunswick. Pedigree analysis suggests
the mutations were uncommon before the late 17th century.
In the 1960s and early 1970s, when the biochemical basis of Tay–Sachs disease was first becoming known, no mutations had been sequenced directly for genetic diseases. Researchers of that era did not yet know how common polymorphisms
would prove to be. The "Jewish Fur Trader Hypothesis," with its
implication that a single mutation must have spread from one population
into another, reflected the knowledge at the time. Subsequent research,
however, has proven that a large variety of different HEXA
mutations can cause the disease. Because Tay–Sachs was one of the first
genetic disorders for which widespread genetic screening was possible,
it is one of the first genetic disorders in which the prevalence of compound heterozygosity has been demonstrated.
Compound heterozygosity ultimately explains the disease's
variability, including the late-onset forms. The disease can potentially
result from the inheritance of two unrelated mutations in the HEXA
gene, one from each parent. Classic infantile Tay–Sachs disease results
when a child has inherited mutations from both parents that completely
stop the biodegradation of gangliosides.
Late onset forms occur due to the diverse mutation base – people with
Tay–Sachs disease may technically be heterozygotes, with two differing HEXA mutations that both inactivate, alter, or inhibit enzyme activity. When a patient has at least one HEXA
copy that still enables some level of hexosaminidase A activity, a
later onset disease form occurs. When disease occurs because of two
unrelated mutations, the patient is said to be a compound heterozygote.
Heterozygous carriers (individuals who inherit one mutant allele)
show abnormal enzyme activity but manifest no disease symptoms. This
phenomenon is called dominance; the biochemical reason for wild-type alleles' dominance over nonfunctional mutant alleles in inborn errors of metabolism comes from how enzymes function. Enzymes are proteincatalysts
for chemical reactions; as catalysts, they speed up reactions without
being used up in the process, so only small enzyme quantities are
required to carry out a reaction. Someone homozygous for a nonfunctional
mutation in the enzyme-encoding gene has little or no enzyme activity,
so will manifest the abnormal phenotype.
A heterozygote (heterozygous individual) has at least half of the
normal enzyme activity level, due to expression of the wild-type allele.
This level is normally enough to enable normal function and thus
prevent phenotypic expression.
Pathophysiology
Tay–Sachs disease is caused by insufficient activity of the enzyme hexosaminidase A. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down sphingolipids.
When hexosaminidase A is no longer functioning properly, the lipids
accumulate in the brain and interfere with normal biological processes.
Hexosaminidase A specifically breaks down fatty acid
derivatives called gangliosides; these are made and biodegraded rapidly
in early life as the brain develops. Patients with and carriers of
Tay–Sachs can be identified by a simple blood test that measures hexosaminidase A activity.
The hydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A; the third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate-specific cofactor for the enzyme. Deficiency in any one of these proteins leads to ganglioside storage, primarily in the lysosomes of neurons. Tay–Sachs disease (along with AB-variant GM2-gangliosidosis and Sandhoff disease)
occurs because a mutation inherited from both parents deactivates or
inhibits this process. Most Tay–Sachs mutations probably do not directly
affect protein functional elements (e.g., the active site). Instead, they cause incorrect folding (disrupting function) or disable intracellular transport.
Diagnosis
In patients with a clinical suspicion for Tay–Sachs disease, with any age of onset, the initial testing involves an enzyme assay to measure the activity of hexosaminidase in serum, fibroblasts, or leukocytes.
Total hexosaminidase enzyme activity is decreased in individuals with
Tay-Sachs as is the percentage of hexosaminidase A. After confirmation
of decreased enzyme activity in an individual, confirmation by molecular
analysis can be pursued. All patients with infantile onset Tay–Sachs disease have a "cherry red" macula in the retina, easily observable by a physician using an ophthalmoscope. This red spot is a retinal area that appears red because of gangliosides in the surrounding retinal ganglion cells. The choroidal circulation is showing through "red" in this foveal region where all retinal ganglion cells are pushed aside to increase visual acuity.
Thus, this cherry-red spot is the only normal part of the retina; it
shows up in contrast to the rest of the retina. Microscopic analysis of
the retinal neurons shows they are distended from excess ganglioside
storage. Unlike other lysosomal storage diseases (e.g., Gaucher disease, Niemann–Pick disease, and Sandhoff disease), hepatosplenomegaly (liver and spleen enlargement) is not seen in Tay–Sachs.
Prevention
Three main approaches have been used to prevent or reduce the incidence of Tay–Sachs:
Prenatal diagnosis.
If both parents are identified as carriers, prenatal genetic testing
can determine whether the fetus has inherited a defective gene copy from
both parents. Chorionic villus sampling (CVS), the most common form of prenatal diagnosis, can be performed between 10 and 14 weeks of gestation. Amniocentesis is usually performed at 15–18 weeks. These procedures have risks of miscarriage of 1% or less.
Preimplantation genetic diagnosis. By retrieving the mother's eggs for in vitro fertilization,
it is possible to test the embryo for the disorder prior to
implantation. Healthy embryos are then selected and transferred into the
mother's womb, while unhealthy embryos are discarded. In addition to
Tay–Sachs disease, preimplantation genetic diagnosis has been used to
prevent cystic fibrosis and sickle cell anemia among other genetic disorders.
Mate selection. In Orthodox Jewish circles, the organization Dor Yeshorim
carries out an anonymous screening program so that carrier couples for
Tay–Sachs and other genetic disorders can avoid marriage.
Management
As of 2010 there was no treatment that addressed the cause of Tay–Sachs disease or could slow its progression; people receive supportive care to ease the symptoms and extend life by reducing the chance of contracting infections. Infants are given feeding tubes when they can no longer swallow. In late-onset Tay–Sachs, medication (e.g., lithium for depression) can sometimes control psychiatric symptoms and seizures, although some medications (e.g., tricyclic antidepressants, phenothiazines, haloperidol, and risperidone) are associated with significant adverse effects.
Outcomes
As of 2010, even with the best care, children with infantile Tay–Sachs disease usually die by the age of 4.
Children with the juvenile form are likely to die from the ages 5-15,
while those with the adult form will probably not be affected.
Epidemiology
Founder effects occur when a small number of individuals from a larger population
establish a new population. In this illustration, the original
population is on the left with three possible founder populations on the
right. Two of the three founder populations are genetically distinct
from the original population.
Ashkenazi Jews have a high incidence of Tay–Sachs and other lipid storage diseases. In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier. The disease incidence is about 1 in every 3,500 newborn among Ashkenazi Jews. French Canadians and the Cajun community of Louisiana have an occurrence similar to the Ashkenazi Jews. Irish Americans have a 1 in 50 chance of being a carrier. In the general population, the incidence of carriers as heterozygotes is about 1 in 300. The incidence is approximately 1 in 320,000 newborns in the general population in United States.
Three general classes of theories have been proposed to explain
the high frequency of Tay–Sachs carriers in the Ashkenazi Jewish
population:
Heterozygote advantage.
When applied to a particular allele, this theory posits that mutation
carriers have a selective advantage, perhaps in a particular
environment.
Reproductive compensation.
Parents who lose a child because of disease tend to "compensate" by
having additional children to replace them. This phenomenon may maintain
and possibly even increase the incidence of autosomal recessive
disease.
Founder effect. This hypothesis states that the high incidence of the 1278insTATC chromosomes is the result of an elevated allele frequency that existed by chance in an early founder population.
Tay–Sachs disease was one of the first genetic disorders for which
epidemiology was studied using molecular data. Studies of Tay–Sachs
mutations using new molecular techniques such as linkage disequilibrium and coalescence analysis have brought an emerging consensus among researchers supporting the founder effect theory.
History
Waren Tay and Bernard Sachs, two physicians, described the disease's progression and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar symptoms.
Both Tay and Sachs reported their first cases among Ashkenazi
Jewish families. Tay reported his observations in 1881 in the first
volume of the proceedings of the British Ophthalmological Society, of
which he was a founding member.
By 1884, he had seen three cases in a single family. Years later,
Bernard Sachs, an American neurologist, reported similar findings when
he reported a case of "arrested cerebral development" to other New York
Neurological Society members.
Sachs, who recognized that the disease had a familial basis, proposed that the disease should be called amaurotic familial idiocy. However, its genetic basis was still poorly understood. Although Gregor Mendel
had published his article on the genetics of peas in 1865, Mendel's
paper was largely forgotten for more than a generation – not
rediscovered by other scientists until 1899. Thus, the Mendelian model
for explaining Tay–Sachs was unavailable to scientists and doctors of
the time. The first edition of the Jewish Encyclopedia, published in 12 volumes between 1901 and 1906, described what was then known about the disease:
It is a curious fact that amaurotic family idiocy, a rare
and fatal disease of children, occurs mostly among Jews. The largest
number of cases has been observed in the United States—over thirty in
number. It was at first thought that this was an exclusively Jewish
disease because most of the cases at first reported were between Russian
and Polish Jews; but recently there have been reported cases occurring
in non-Jewish children. The chief characteristics of the disease are
progressive mental and physical enfeeblement; weakness and paralysis of
all the extremities; and marasmus, associated with symmetrical changes
in the macula lutea. On investigation of the reported cases, they found
that neither consanguinity nor syphilitic, alcoholic, or nervous
antecedents in the family history are factors in the etiology of the
disease. No preventive measures have as yet been discovered, and no
treatment has been of benefit, all the cases having terminated fatally.
Jewish immigration to the United States peaked in the period 1880–1924, with the immigrants arriving from Russia and countries in Eastern Europe; this was also a period of nativism
(hostility to immigrants) in the United States. Opponents of
immigration often questioned whether immigrants from southern and
eastern Europe could be assimilated into American society. Reports of
Tay–Sachs disease contributed to a perception among nativists that Jews
were an inferior race.
In 1969, Shintaro Okada and John S. O'Brien showed that Tay–Sachs
disease was caused by an enzyme defect; he also proved that Tay–Sachs
patients could be diagnosed by an assay of hexosaminidase A activity.
The further development of enzyme assays demonstrated that levels of
hexosaminidases A and B could be measured in patients and carriers,
allowing the reliable detection of heterozygotes. During the early
1970s, researchers developed protocols for newborn testing, carrier
screening, and pre-natal diagnosis. By the end of 1979, researchers had identified three variant forms of GM2 gangliosidosis, including Sandhoff disease and the AB variant of GM2-gangliosidosis, accounting for false negatives in carrier testing.
Society and culture
Since carrier testing for Tay–Sachs began in 1971, millions of
Ashkenazi Jews have been screened as carriers. Jewish communities
embraced the cause of genetic screening from the 1970s on. The success
with Tay–Sachs disease has led Israel to become the first country that offers free genetic screening and counseling for all couples and opened discussions about the proper scope of genetic testing for other disorders in Israel.
Because Tay–Sachs disease was one of the first autosomal recessive genetic disorders for which there was an enzyme assay test (prior to polymerase chain reaction testing methods), it was intensely studied as a model for all such diseases, and researchers sought evidence of a selective process. A continuing controversy is whether heterozygotes (carriers) have or had a selective advantage. The presence of four different lysosomal storage disorders in the Ashkenazi Jewish population suggests a past selective advantage for heterozygous carriers of these conditions."
This controversy among researchers has reflected three debates among geneticists at large:
Dominance versus overdominance.
In applied genetics (selective and agricultural breeding), this
controversy has reflected the century-long debate over whether dominance
or overdominance provides the best explanation for heterosis (hybrid vigor).
The classical/balance controversy. The classical hypothesis of genetic variability, often associated with Hermann Muller, maintains that most genes are of a normal wild type, and that most individuals are homozygous for that wild type, while most selection is purifying selection that operates to eliminate deleterious alleles. The balancing hypothesis, often associated with Theodosius Dobzhansky, states that heterozygosity will be common at loci, and that it frequently reflects either directional selection or balancing selection.
Enzyme replacement therapy
techniques have been investigated for lysosomal storage disorders, and
could potentially be used to treat Tay–Sachs as well. The goal would be
to replace the nonfunctional enzyme, a process similar to insulin injections for diabetes. However, in previous studies, the HEXA enzyme itself has been thought to be too large to pass through the specialized cell layer in the blood vessels that forms the blood–brain barrier in humans.
Researchers have also tried directly instilling the deficient enzyme hexosaminidase A into the cerebrospinal fluid (CSF) which bathes the brain. However, intracerebral neurons seem unable to take up this physically large molecule
efficiently even when it is directly by them. Therefore, this approach
to treatment of Tay–Sachs disease has also been ineffective so far.
Jacob sheep model
Tay–Sachs disease exists in Jacob sheep.
The biochemical mechanism for this disease in the Jacob sheep is
virtually identical to that in humans, wherein diminished activity of
hexosaminidase A results in increased concentrations of GM2 ganglioside
in the affected animal. Sequencing of the HEXA gene cDNA of affected Jacobs sheep reveal an identical number of nucleotides and exons as in the human HEXA gene, and 86% nucleotide sequence identity. A missense mutation (G444R) was found in the HEXA
cDNA of the affected sheep. This mutation is a single nucleotide change
at the end of exon 11, resulting in that exon's deletion (before
translation) via splicing. The Tay–Sachs model provided by the Jacob sheep is the first to offer promise as a means for gene therapy clinical trials, which may prove useful for disease treatment in humans.
Substrate reduction therapy
Other experimental methods being researched involve substrate reduction therapy,
which attempts to use alternative enzymes to increase the brain's
catabolism of GM2 gangliosides to a point where residual degradative
activity is sufficient to prevent substrate accumulation. One experiment has demonstrated that using the enzyme sialidase
allows the genetic defect to be effectively bypassed, and as a
consequence, GM2 gangliosides are metabolized so that their levels
become almost inconsequential. If a safe pharmacological treatment can
be developed – one that increases expression of lysosomal sialidase in
neurons without other toxicity – then this new form of therapy could
essentially cure the disease.
Another metabolic therapy under investigation for Tay–Sachs disease uses miglustat. This drug is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyzes the first step in synthesizing glucose-based glycosphingolipids like GM2 ganglioside.
Increasing β-hexosaminidase A activity
As
Tay–Sachs disease is a deficiency of β-hexosaminidase A, by getting a
substance that increases its activity, people affected will not be
deteriorating as fast or not at all. While for infantile Tay–Sachs
disease, there is no β-hexosaminidase A so then the treatment would be
ineffective. However, for people affected by Late-Onset Tay–Sachs
disease, they still have β-hexosaminidase A. The drug Pyrimethamine has been shown to increase activity of β-hexosaminidase A.
However, the increased levels of β-hexosaminidase A still fall far
short of the desired "10% of normal HEXA", above which the phenotypic
symptoms begin to disappear.
Cord blood transplant
This
is a harsh procedure, which involves killing the patient's blood system
with chemo and administering cord blood. This procedure has been done
before, with several people surviving the infantile form, to age 8 and
on. Cord blood is immature, so it easily accepts its new host without
rejecting it. As to date, the two hospitals that do this procedure are
the University of Minnesota and Duke Medical Center.
Critics criticize its harsh nature, and that it is unapproved. It
is also hard for it to cross the blood-brain barrier. The earlier
treatment starts, the better. It is often very pricey, with $25000 per
unit. Adults will need many units of cord blood.
CF is inherited in an autosomal recessive manner. It is caused by the presence of mutations in both copies of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Those with a single working copy are carriers and otherwise mostly normal. CFTR is involved in production of sweat, digestive fluids, and mucus. When the CFTR is not functional, secretions which are usually thin instead become thick. The condition is diagnosed by a sweat test and genetic testing. Screening of infants at birth takes place in some areas of the world.
There is no known cure for cystic fibrosis. Lung infections are treated with antibiotics which may be given intravenously, inhaled, or by mouth. Sometimes, the antibiotic azithromycin is used long term. Inhaled hypertonic saline and salbutamol may also be useful. Lung transplantation may be an option if lung function continues to worsen. Pancreatic enzyme replacement and fat-soluble vitamin supplementation are important, especially in the young. Airway clearance techniques such as chest physiotherapy have some short-term benefit, but long-term effects are unclear. The average life expectancy is between 42 and 50 years in the developed world. Lung problems are responsible for death in 80% of people with cystic fibrosis.
CF is most common among people of Northern European ancestry and affects about one out of every 3,000 newborns. About one in 25 people is a carrier. It is least common in Africans and Asians. It was first recognized as a specific disease by Dorothy Andersen in 1938, with descriptions that fit the condition occurring at least as far back as 1595. The name "cystic fibrosis" refers to the characteristic fibrosis and cysts that form within the pancreas.
Signs and symptoms
Health problems associated with cystic fibrosis
The main signs and symptoms of cystic fibrosis are salty-tasting skin, poor growth, and poor weight gain despite normal food intake, accumulation of thick, sticky mucus, frequent chest infections, and coughing or shortness of breath. Males can be infertile due to congenital absence of the vas deferens. Symptoms often appear in infancy and childhood, such as bowel obstruction due to meconium ileus in newborn babies. As the children grow, they exercise to release mucus in the alveoli. Epithelial cells in the person have a mutated protein that leads to abnormally viscous mucus production.
The poor growth in children typically presents as an inability to gain
weight or height at the same rate as their peers, and is occasionally
not diagnosed until investigation is initiated for poor growth. The
causes of growth failure are multifactorial and include chronic lung
infection, poor absorption of nutrients through the gastrointestinal
tract, and increased metabolic demand due to chronic illness.
In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. Vitamin K is normally absorbed from breast milk,
formula, and later, solid foods. This absorption is impaired in some
cystic fibrosis patients. Young children are especially sensitive to
vitamin K malabsorptive disorders because only a very small amount of
vitamin K crosses the placenta, leaving the child with very low reserves
and limited ability to absorb vitamin K from dietary sources after
birth. Because factors II, VII, IX, and X (clotting factors) are vitamin
K–dependent, low levels of vitamin K can result in coagulation
problems. Consequently, when a child presents with unexplained bruising,
a coagulation evaluation may be warranted to determine whether an
underlying disease is present.
Lungs and sinuses
Respiratory infections in CF varies according to age.
Lung disease results from clogging of the airways due to mucus build-up, decreased mucociliary clearance, and resulting inflammation.
Inflammation and infection cause injury and structural changes to the
lungs, leading to a variety of symptoms. In the early stages, incessant
coughing, copious phlegm production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages, changes in the architecture of the lung, such as pathology in the major airways (bronchiectasis), further exacerbate difficulties in breathing. Other signs include coughing up blood (hemoptysis), high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks, such as bilevel positive airway pressure machines or ventilators. Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the three most common organisms causing lung infections in CF patients. In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis, in which the body's response to the common fungusAspergillus fumigatus causes worsening of breathing problems. Another is infection with Mycobacterium avium complex, a group of bacteria related to tuberculosis, which can cause lung damage and does not respond to common antibiotics. People with CF are susceptible to getting a pneumothorax.
Mucus in the paranasal sinuses
is equally thick and may also cause blockage of the sinus passages,
leading to infection. This may cause facial pain, fever, nasal drainage,
and headaches. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyps) due to inflammation from chronic sinus infections. Recurrent sinonasal polyps can occur in 10% to 25% of CF patients. These polyps can block the nasal passages and increase breathing difficulties.
Cardiorespiratory complications are the most common cause of
death (about 80%) in patients at most CF centers in the United States.
Gastrointestinal
Prior to prenatal and newborn screening, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (meconium). Meconium may completely block the intestines and cause serious illness. This condition, called meconium ileus, occurs in 5–10% of newborns with CF. In addition, protrusion of internal rectal membranes (rectal prolapse) is more common, occurring in as many as 10% of children with CF, and it is caused by increased fecal volume, malnutrition, and increased intra–abdominal pressure due to coughing.
The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas, an organ responsible for providing digestive juices that help break down food. These secretions block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis). The pancreatic ducts are totally plugged in more advanced cases, usually seen in older children or adolescents. This causes atrophy of the exocrine glands and progressive fibrosis.
The lack of digestive enzymes leads to difficulty absorbing
nutrients with their subsequent excretion in the feces, a disorder known
as malabsorption. Malabsorption leads to malnutrition and poor growth and development because of calorie loss. Resultant hypoproteinemia may be severe enough to cause generalized edema. Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K.
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF. It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional (e.g. ΔF508/ΔF508).
It occurs in 10% to 15% of patients with one "severe" and one "mild"
CFTR mutation where little CFTR activity still occurs, or where two
"mild" CFTR mutations exist. In these milder cases, sufficient pancreatic exocrine function is still present so that enzyme supplementation is not required.
Usually, no other GI complications occur in pancreas-sufficient
phenotypes, and in general, such individuals usually have excellent
growth and development. Despite this, idiopathic chronic pancreatitis
can occur in a subset of pancreas-sufficient individuals with CF, and
is associated with recurrent abdominal pain and life-threatening
complications.
Thickened secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the bile ducts, leading to liver damage. Over time, this can lead to scarring and nodularity (cirrhosis). The liver fails to rid the blood of toxins and does not make important proteins, such as those responsible for blood clotting. Liver disease is the third-most common cause of death associated with CF.
Endocrine
The pancreas contains the islets of Langerhans, which are responsible for making insulin, a hormone that helps regulate blood glucose. Damage of the pancreas can lead to loss of the islet cells, leading to a type of diabetes unique to those with the disease. This cystic fibrosis-related diabetes shares characteristics that can be found in type 1 and type 2 diabetics, and is one of the principal nonpulmonary complications of CF.
Vitamin D is involved in calcium and phosphate regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease osteoporosis in which weakened bones are more susceptible to fractures. In addition, people with CF often develop clubbing of their fingers and toes due to the effects of chronic illness and low oxygen in their tissues.
Infertility
Infertility
affects both men and women. At least 97% of men with cystic fibrosis
are infertile, but not sterile and can have children with assisted
reproductive techniques. The main cause of infertility in men with CF is congenital absence of the vas deferens (which normally connects the testes to the ejaculatory ducts of the penis), but potentially also by other mechanisms such as causing no sperm, abnormally shaped sperm, and few sperm with poor motility.
Many men found to have congenital absence of the vas deferens during
evaluation for infertility have a mild, previously undiagnosed form of
CF.
Around 20% of women with CF have fertility difficulties due to
thickened cervical mucus or malnutrition. In severe cases, malnutrition
disrupts ovulation and causes a lack of menstruation.
Causes
Cystic fibrosis has an autosomal recessive pattern of inheritance
CF is caused by a mutation in the genecystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, is a deletion (Δ signifying deletion) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein. This mutation accounts for two-thirds (66–70%) of CF cases worldwide and 90% of cases in the United States; however, over 1500 other mutations can produce CF. Although most people have two working copies (alleles) of the CFTR
gene, only one is needed to prevent cystic fibrosis. CF develops when
neither allele can produce a functional CFTR protein. Thus, CF is
considered an autosomal recessive disease.
The CFTR gene, found at the q31.2 locus of chromosome 7, is 230,000 base pairs long, and creates a protein that is 1,480 amino acids
long. More specifically, the location is between base pair 117,120,016
and 117,308,718 on the long arm of chromosome 7, region 3, band 1,
subband 2, represented as 7q31.2. Structurally, the CFTR is a type of gene known as an ABC gene.
The product of this gene (the CFTR protein) is a chloride ion channel
important in creating sweat, digestive juices, and mucus. This protein
possesses two ATP-hydrolyzingdomains, which allows the protein to use energy in the form of ATP. It also contains two domains comprising six alpha helices apiece, which allow the protein to cross the cell membrane. A regulatory binding site on the protein allows activation by phosphorylation, mainly by cAMP-dependent protein kinase. The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction. The majority of CFTR in the lung's passages is produced by rare ion-transporting cells that regulate mucus properties.
In addition, the evidence is increasing that genetic modifiers besides CFTR modulate the frequency and severity of the disease. One example is mannan-binding lectin, which is involved in innate immunity by facilitating phagocytosis of microorganisms. Polymorphisms
in one or both mannan-binding lectin alleles that result in lower
circulating levels of the protein are associated with a threefold higher
risk of end-stage lung disease, as well as an increased burden of
chronic bacterial infections.
Pathophysiology
The CFTR protein is a channel protein that controls the flow of H2O and Cl-
ions in and out of cells inside the lungs. When the CFTR protein is
working correctly, ions freely flow in and out of the cells. However,
when the CFTR protein is malfunctioning, these ions cannot flow out of
the cell due to a blocked channel. This causes cystic fibrosis,
characterized by the buildup of thick mucus in the lungs.
Several mutations in the CFTR
gene can occur, and different mutations cause different defects in the
CFTR protein, sometimes causing a milder or more severe disease. These
protein defects are also targets for drugs which can sometimes restore
their function. ΔF508-CFTR, which occurs in >90% of patients in the U.S., creates a protein that does not fold
normally and is not appropriately transported to the cell membrane,
resulting in its degradation. Other mutations result in proteins that
are too short (truncated) because production
is ended prematurely. Other mutations produce proteins that do not use
energy (in the form of ATP) normally, do not allow chloride, iodide, and
thiocyanate to cross the membrane appropriately, and degrade at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.
The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body.
The protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid.
This channel is primarily responsible for controlling the movement of
halogens from inside to outside of the cell; however, in the sweat
ducts, it facilitates the movement of chloride from the sweat duct into
the cytoplasm. When the CFTR protein does not resorb ions in sweat
ducts, chloride and thiocyanate released from sweat glands are trapped inside the ducts and pumped to the skin. Additionally hypothiocyanite, OSCN, cannot be produced by the immune defense system. Because chloride is negatively charged, this modifies the electrical potential inside and outside the cell that normally causes cations
to cross into the cell. Sodium is the most common cation in the
extracellular space. The excess chloride within sweat ducts prevents
sodium resorption by epithelial sodium channels and the combination of
sodium and chloride creates the salt, which is lost in high amounts in
the sweat of individuals with CF. This lost salt forms the basis for the
sweat test.
Most of the damage in CF is due to blockage of the narrow
passages of affected organs with thickened secretions. These blockages
lead to remodeling and infection in the lung, damage by accumulated
digestive enzymes in the pancreas, blockage of the intestines by thick
feces, etc. Several theories have been posited on how the defects in the
protein and cellular function cause the clinical effects. The most
current theory suggests that defective ion transport leads to
dehydration in the airway epithelia, thickening mucus. In airway
epithelial cells, the cilia exist in between the cell's apical surface
and mucus in a layer known as airway surface liquid (ASL). The flow of
ions from the cell and into this layer is determined by ion channels
such as CFTR. CFTR not only allows chloride ions to be drawn from the
cell and into the ASL, but it also regulates another channel called
ENac, which allows sodium ions to leave the ASL and enter the
respiratory epithelium. CFTR normally inhibits this channel, but if the
CFTR is defective, then sodium flows freely from the ASL and into the
cell. As water follows sodium, the depth of ASL will be depleted and the
cilia will be left in the mucous layer.
As cilia cannot effectively move in a thick, viscous environment,
mucociliary clearance is deficient and a buildup of mucus occurs,
clogging small airways.
The accumulation of more viscous, nutrient-rich mucus in the lungs
allows bacteria to hide from the body's immune system, causing repeated
respiratory infections. The presence of the same CFTR proteins in the
pancreatic duct and sweat glands in the skin also cause symptoms in
these systems.
Chronic infections
The
lungs of individuals with cystic fibrosis are colonized and infected by
bacteria from an early age. These bacteria, which often spread among
individuals with CF, thrive in the altered mucus, which collects in the
small airways of the lungs. This mucus leads to the formation of
bacterial microenvironments known as biofilms
that are difficult for immune cells and antibiotics to penetrate.
Viscous secretions and persistent respiratory infections repeatedly
damage the lung by gradually remodeling the airways, which makes
infection even more difficult to eradicate.
Over time, both the types of bacteria and their individual
characteristics change in individuals with CF. In the initial stage,
common bacteria such as S. aureus and H. influenzae colonize and infect the lungs. Eventually, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates. By 18 years of age, 80% of patients with classic CF harbor P. aeruginosa, and 3.5% harbor B. cepacia. Once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. Pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" Pseudomonas, which are rarely seen in people who do not have CF. Scientific evidences suggest the interleukin 17 pathway plays a key role in resistance and modulation of the inflammatory response during P. aeruginosa infection in CF.
In particular, interleukin 17-mediated immunity plays a double-edged
activity during chronic airways infection; on one side, it contributes
to the control of P. aeruginosa burden, while on the other, it propagates exacerbated pulmonary neutrophilia and tissue remodeling.
Infection can spread by passing between different individuals with CF. In the past, people with CF often participated in summer "CF camps" and other recreational gatherings. Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizers) was not sterilized between individual patients.
This led to transmission of more dangerous strains of bacteria among
groups of patients. As a result, individuals with CF are now routinely
isolated from one another in the healthcare setting, and healthcare
providers are encouraged to wear gowns and gloves when examining
patients with CF to limit the spread of virulent bacterial strains.
CF patients may also have their airways chronically colonized by filamentous fungi (such as Aspergillus fumigatus, Scedosporium apiospermum, Aspergillus terreus) and/or yeasts (such as Candida albicans); other filamentous fungi less commonly isolated include Aspergillus flavus and Aspergillus nidulans (occur transiently in CF respiratory secretions) and Exophiala dermatitidis and Scedosporium prolificans (chronic airway-colonizers); some filamentous fungi such as Penicillium emersonii and Acrophialophora fusispora are encountered in patients almost exclusively in the context of CF.
Defective mucociliary clearance characterizing CF is associated with
local immunological disorders. In addition, the prolonged therapy with
antibiotics and the use of corticosteroid treatments may also facilitate
fungal growth. Although the clinical relevance of the fungal airway
colonization is still a matter of debate, filamentous fungi may
contribute to the local inflammatory response and therefore to the
progressive deterioration of the lung function, as often happens with
allergic bronchopulmonary aspergillosis – the most common fungal
disease in the context of CF, involving a Th2-driven immune response to Aspergillus species.
Diagnosis and monitoring
The location of the CFTR gene on chromosome 7
Cystic fibrosis may be diagnosed by many different methods, including newborn screening, sweat testing, and genetic testing.
As of 2006 in the United States, 10% of cases are diagnosed shortly
after birth as part of newborn screening programs. The newborn screen
initially measures for raised blood concentration of immunoreactive trypsinogen.
Infants with an abnormal newborn screen need a sweat test to confirm
the CF diagnosis. In many cases, a parent makes the diagnosis because
the infant tastes salty. Immunoreactive trypsinogen levels can be increased in individuals who have a single mutated copy of the CFTR gene (carriers) or, in rare instances, in individuals with two normal copies of the CFTR gene. Due to these false positives, CF screening in newborns can be controversial.
Most U.S. states and countries do not screen for CF routinely at birth.
Therefore, most individuals are diagnosed after symptoms (e.g.
sinopulmonary disease and GI manifestations)
prompt an evaluation for cystic fibrosis. The most commonly used form
of testing is the sweat test. Sweat testing involves application of a
medication that stimulates sweating (pilocarpine). To deliver the medication through the skin, iontophoresis
is used, whereby one electrode is placed onto the applied medication
and an electric current is passed to a separate electrode on the skin.
The resultant sweat is then collected on filter paper or in a capillary
tube and analyzed for abnormal amounts of sodium and chloride. People
with CF have increased amounts of them in their sweat. In contrast,
people with CF have less thiocyanate and hypothiocyanite in their saliva and mucus (Banfi et al.). In the case of milder forms of CF, transepithelial potential difference measurements can be helpful. CF can also be diagnosed by identification of mutations in the CFTR gene.
People with CF may be listed in a disease registry that allows researchers and doctors to track health results and identify candidates for clinical trials.
Prenatal
Women who are pregnant or couples planning a pregnancy can have themselves tested for the CFTR
gene mutations to determine the risk that their child will be born with
CF. Testing is typically performed first on one or both parents and, if
the risk of CF is high, testing on the fetus is performed. The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant be tested to see if they are a carrier.
Because development of CF in the fetus requires each parent to pass on a mutated copy of the CFTR
gene and because CF testing is expensive, testing is often performed
initially on one parent. If testing shows that parent is a CFTR
gene mutation carrier, the other parent is tested to calculate the risk
that their children will have CF. CF can result from more than a
thousand different mutations. As of 2016, typically only the most common mutations are tested for, such as ΔF508
Most commercially available tests look for 32 or fewer different
mutations. If a family has a known uncommon mutation, specific screening
for that mutation can be performed. Because not all known mutations are
found on current tests, a negative screen does not guarantee that a
child will not have CF.
During pregnancy, testing can be performed on the placenta (chorionic villus sampling) or the fluid around the fetus (amniocentesis). However, chorionic villus sampling has a risk of fetal death of one in 100 and amniocentesis of one in 200; a recent study has indicated this may be much lower, about one in 1,600.
Economically, for carrier couples of cystic fibrosis, when comparing preimplantation genetic diagnosis
(PGD) with natural conception (NC) followed by prenatal testing and
abortion of affected pregnancies, PGD provides net economic benefits up
to a maternal age around 40 years, after which NC, prenatal testing, and
abortion have higher economic benefit.
Management
While
no cures for CF are known, several treatment methods are used. The
management of CF has improved significantly over the past 70 years.
While infants born with it 70 years ago would have been unlikely to live
beyond their first year, infants today are likely to live well into
adulthood. Recent advances in the treatment of cystic fibrosis have
meant that individuals with cystic fibrosis can live a fuller life less
encumbered by their condition. The cornerstones of management are the
proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. Pulmonary rehabilitation
as a management of CF continues throughout a person's life, and is
aimed at maximizing organ function, and therefore the quality of life.
At best, current treatments delay the decline in organ function. Because
of the wide variation in disease symptoms, treatment typically occurs
at specialist multidisciplinary centers and is tailored to the
individual. Targets for therapy are the lungs, gastrointestinal tract
(including pancreatic enzyme supplements), the reproductive organs (including assisted reproductive technology), and psychological support.
The most consistent aspect of therapy in CF is limiting and
treating the lung damage caused by thick mucus and infection, with the
goal of maintaining quality of life. Intravenous, inhaled,
and oral antibiotics are used to treat chronic and acute infections.
Mechanical devices and inhalation medications are used to alter and
clear the thickened mucus. These therapies, while effective, can be
extremely time-consuming.
Antibiotics
Many people with CF are on one or more antibiotics at all times, even when healthy, to prophylactically
suppress infection. Antibiotics are absolutely necessary whenever
pneumonia is suspected or a noticeable decline in lung function is seen,
and are usually chosen based on the results of a sputum analysis and
the person's past response. This prolonged therapy often necessitates
hospitalization and insertion of a more permanent IV such as a peripherally inserted central catheter or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin, colistin, and aztreonam is often given for months at a time to improve lung function by impeding the growth of colonized bacteria. Inhaled antibiotic therapy helps lung function by fighting infection,
but also has significant drawbacks such as development of antibiotic
resistance, tinnitus, and changes in the voice. Inhaled levofloxacin may be used to treat Pseudomonas aeruginosa in people with cystic fibrosis who are infected.
The early management of Pseudomonas aeruginosa infection is easier and
better, using nebulised antibiotics with or without oral antibiotics may
sustain its eradication up to 2 years.
Antibiotics by mouth such as ciprofloxacin or azithromycin are given to help prevent infection or to control ongoing infection. The aminoglycoside antibiotics (e.g. tobramycin) used can cause hearing loss, damage to the balance system in the inner ear or kidney failure with long-term use. To prevent these side-effects, the amount of antibiotics in the blood is routinely measured and adjusted accordingly.
All these factors related to the antibiotics use, the chronicity
of the disease, and the emergence of resistant bacteria demand more
exploration for different strategies such as antibiotic adjuvant therapy.
Other medication
Aerosolized medications that help loosen secretions include dornase alfa and hypertonicsaline. Dornase is a recombinant human deoxyribonuclease, which breaks down DNA in the sputum, thus decreasing its viscosity. Denufosol, an investigational drug, opens an alternative chloride channel, helping to liquefy mucus. Whether inhaled corticosteroids are useful is unclear, but stopping inhaled corticosteroid therapy is safe. There is weak evidence that corticosteroid treatment may cause harm by interfering with growth. Pneumococcal vaccination has not been studied as of 2014. As of 2014, there is no clear evidence from randomized controlled trials that the influenza vaccine is beneficial for people with cystic fibrosis.
Ivacaftor
is a medication taken by mouth for the treatment of CF due to a number
of specific mutations responsive to ivacaftor-induced CFTR protein
enhancement. It improves lung function by about 10%; however, as of 2014 it is expensive. The first year it was on the market, the list price was over $300,000 per year in the United States. In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor. In 2018, the FDA approved the combination ivacaftor/tezacaftor; the manufacturer announced a list price of $292,000 per year. Tezacaftor helps move the CFTR protein to the correct position on the cell surface, and is designed to treat people with the F508del mutation.
Several mechanical techniques are used to dislodge sputum and encourage its expectoration. One technique is chest physiotherapy
where a respiratory therapist percusses an individual's chest by hand
several times a day, to loosen up secretions. This "percussive effect"
can be administered also through specific devices that device chest wall oscillation or intrapulmonary percussive ventilator. Other methods such as biphasic cuirass ventilation,
and associated clearance mode available in such devices, integrate a
cough assistance phase, as well as a vibration phase for dislodging
secretions. These are portable and adapted for home use. Chest
physiotherapy is beneficial for short-term airway clearance.
Another technique is positive expiratory pressure physiotherapy
that consists of providing a back pressure to the airways during
expiration. This effect is provided by devices that consists of a mask
or a mouthpiece in which a resistance is applied only on the expiration
phase.
Operating principles of this technique seems to be the increase of gas
pressure behind mucus through collateral ventilation along with a
temporary increase in functional residual capacity preventing the early
collapse of small airways during exhalation.
As lung disease worsens, mechanical breathing support may become
necessary. Individuals with CF may need to wear special masks at night
to help push air into their lungs. These machines, known as bilevel positive airway pressure
(BiPAP) ventilators, help prevent low blood oxygen levels during sleep.
Non-invasive ventilators may be used during physical therapy to improve
sputum clearance. It is not known if this type of therapy has an impact on pulmonary exacerbations or disease progression. It is not known what role non-invasive ventilation therapy has for improving exercise capacity in people with cystic fibrosis. During severe illness, a tube may be placed in the throat (a procedure known as a tracheostomy) to enable breathing supported by a ventilator.
For children, preliminary studies show massage therapy may help people and their families' quality of life.
Some lung infections require surgical removal of the infected
part of the lung. If this is necessary many times, lung function is
severely reduced. The most effective treatment options for people with CF who have spontaneous or recurrent pneumothoraces is not clear.
Transplantation
Lung transplantation often becomes necessary for individuals with CF as lung function and exercise tolerance
decline. Although single lung transplantation is possible in other
diseases, individuals with CF must have both lungs replaced because the
remaining lung might contain bacteria that could infect the transplanted
lung. A pancreatic or liver transplant may be performed at the same
time to alleviate liver disease and/or diabetes.
Lung transplantation is considered when lung function declines to the
point where assistance from mechanical devices is required or someone's
survival is threatened.
Other aspects
Intracytoplasmic sperm injection can be used to provide fertility for men with cystic fibrosis
Newborns with intestinal obstruction typically require surgery,
whereas adults with distal intestinal obstruction syndrome typically do
not. Treatment of pancreatic insufficiency by replacement of missing
digestive enzymes allows the duodenum to properly absorb nutrients and
vitamins that would otherwise be lost in the feces. However, the best
dosage and form of pancreatic enzyme replacement is unclear, as are the
risks and long-term effectiveness of this treatment.
So far, no large-scale research involving the incidence of atherosclerosis and coronary heart disease
in adults with cystic fibrosis has been conducted. This is likely
because the vast majority of people with cystic fibrosis do not live
long enough to develop clinically significant atherosclerosis or
coronary heart disease.
Diabetes
is the most common nonpulmonary complication of CF. It mixes features
of type 1 and type 2 diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes. While oral antidiabetic drugs are sometimes used, the recommended treatment is the use of insulin injections or an insulin pump, and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended.
There is no strong evidence that people with cystic fibrosis can prevent osteoporosis by increasing their intake of vitamin D. Bisphosphonates taken by mouth or intravenously can be used to improve the bone mineral density in people with cystic fibrosis. When taking bisphosphates intravenously, adverse effects such as pain and flu-like symptoms can be an issue. The adverse effects of bisphosphates taken by mouth on the gastrointestinal tract are not known.
Poor growth may be avoided by insertion of a feeding tube for increasing food energy through supplemental feeds or by administration of injected growth hormone.
Sinus infections are treated by prolonged courses of antibiotics.
The development of nasal polyps or other chronic changes within the
nasal passages may severely limit airflow through the nose, and over
time reduce the person's sense of smell. Sinus surgery is often used to
alleviate nasal obstruction and to limit further infections. Nasal
steroids such as fluticasone are used to decrease nasal inflammation.
Female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. Male infertility caused by absence of the vas deferens may be overcome with testicular sperm extraction,
collecting sperm cells directly from the testicles. If the collected
sample contains too few sperm cells to likely have a spontaneous
fertilization, intracytoplasmic sperm injection can be performed. Third party reproduction is also a possibility for women with CF. Whether taking antioxidants affects outcomes is unclear.
Physical exercise is usually part of outpatient care for people with cystic fibrosis.
Aerobic exercise seems to be beneficial for aerobic exercise capacity,
lung function and health-related quality of life; however, the quality
of the evidence was poor.
Prognosis
The
prognosis for cystic fibrosis has improved due to earlier diagnosis
through screening and better treatment and access to health care. In
1959, the median age of survival of children with CF in the United
States was six months. In 2010, survival is estimated to be 37 years for women and 40 for men. In Canada, median survival increased from 24 years in 1982 to 47.7 in 2007. In the United States those born with CF in 2016 have an expected life expectancy of 47.7 when cared for in specialty clinics.
In the US, of those with CF who are more than 18 years old as of
2009, 92% had graduated from high school, 67% had at least some college
education, 15% were disabled, 9% were unemployed, 56% were single, and
39% were married or living with a partner.
Quality of life
Chronic
illnesses can be very difficult to manage. CF is a chronic illness that
affects the "digestive and respiratory tracts resulting in generalized
malnutrition and chronic respiratory infections". The thick secretions clog the airways in the lungs, which often cause inflammation and severe lung infections.
If it is compromised, it affects the quality of life (QOL) of someone
with CF and their ability to complete such tasks as everyday chores.
According to Schmitz and Goldbeck (2006), CF significantly increases
emotional stress on both the individual and the family, "and the
necessary time-consuming daily treatment routine may have further
negative effects on quality of life". However, Havermans and colleagues (2006) have shown that young
outpatients with CF who have participated in the Cystic Fibrosis
Questionnaire-Revised "rated some QOL domains higher than did their
parents".
Consequently, outpatients with CF have a more positive outlook for
themselves. Furthermore, many ways can improve the QOL in CF patients. Exercise is
promoted to increase lung function. Integrating an exercise regimen into
the CF patient’s daily routine can significantly improve QOL.
No definitive cure for CF is known, but diverse medications are used,
such as mucolytics, bronchodilators, steroids, and antibiotics, that
have the purpose of loosening mucus, expanding airways, decreasing
inflammation, and fighting lung infections, respectively.
Epidemiology
Mutation
Frequency worldwide
ΔF508
66%–70%
G542X
2.4%
G551D
1.6%
N1303K
1.3%
W1282X
1.2%
All others
27.5%
Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of European heritage.
In the United States, about 30,000 individuals have CF; most are
diagnosed by six months of age. In Canada, about 4,000 people have CF. Around 1 in 25 people of European descent, and one in 30 of Caucasian Americans, is a carrier of a CF mutation. Although CF is less common in these groups, roughly one in 46 Hispanics, one in 65 Africans, and one in 90 Asians carry at least one abnormal CFTR gene. Ireland has the world's highest prevalence of CF, at one in 1353.
Although technically a rare disease, CF is ranked as one of the
most widespread life-shortening genetic diseases. It is most common
among nations in the Western world. An exception is Finland, where only one in 80 people carries a CF mutation. The World Health Organization states, "In the European Union, one in 2000–3000 newborns is found to be affected by CF". In the United States, one in 3,500 children is born with CF.
In 1997, about one in 3,300 Caucasian children in the United States
was born with CF. In contrast, only one in 15,000 African American
children suffered from it, and in Asian Americans, the rate was even
lower at one in 32,000.
Cystic fibrosis is diagnosed in males and females equally. For
reasons that remain unclear, data have shown that males tend to have a
longer life expectancy than females, but recent studies suggest this gender gap may no longer exist perhaps due to improvements in health care facilities, while a recent study from Ireland identified a link between the female hormone estrogen and worse outcomes in CF.
The distribution of CF alleles varies among populations. The
frequency of ΔF508 carriers has been estimated at one in 200 in northern
Sweden, one in 143 in Lithuanians, and one in 38 in Denmark. No ΔF508
carriers were found among 171 Finns and 151 Saami people.
ΔF508 does occur in Finland, but it is a minority allele there. CF is
known to occur in only 20 families (pedigrees) in Finland.
Evolution
The ΔF508 mutation is estimated to be up to 52,000 years old.
Numerous hypotheses have been advanced as to why such a lethal mutation
has persisted and spread in the human population. Other common
autosomal recessive diseases such as sickle-cell anemia have been found to protect carriers from other diseases, an evolutionary trade-off known as heterozygote advantage. Resistance to the following have all been proposed as possible sources of heterozygote advantage:
Cholera: With the discovery that cholera toxin requires normal host CFTR proteins to function properly, it was hypothesized that carriers of mutant CFTR genes benefited from resistance to cholera and other causes of diarrhea. Further studies have not confirmed this hypothesis.
Typhoid: Normal CFTR proteins are also essential for the entry of Salmonella Typhi into cells, suggesting that carriers of mutant CFTR genes might be resistant to typhoid fever. No in vivo
study has yet confirmed this. In both cases, the low level of cystic
fibrosis outside of Europe, in places where both cholera and typhoid
fever are endemic, is not immediately explicable.
Diarrhea:
The prevalence of CF in Europe might be connected with the development
of cattle domestication. In this hypothesis, carriers of a single mutant
CFTR had some protection from diarrhea caused by lactose intolerance, prior to the appearance of the mutations that created lactose tolerance.
Tuberculosis: Another possible explanation is that carriers of the gene could have some resistance to TB. This hypothesis is based on the thesis that CFTR gene mutation carriers have insufficient action in one of their enzymes – arylsulphatase - which is necessary for Mycobacterium tuberculosis virulence. As M. tuberculosis
would use its host’s sources to affect the individual, and due to the
lack of enzyme it could not presents its virulence, being a carrier of CFTR mutation could provide resistance against tuberculosis.
CF is supposed to have appeared about 3,000 BC because of migration
of peoples, gene mutations, and new conditions in nourishment.
Although the entire clinical spectrum of CF was not recognized until
the 1930s, certain aspects of CF were identified much earlier. Indeed,
literature from Germany and Switzerland in the 18th century warned "Wehe dem Kind, das beim Kuß auf die Stirn salzig schmeckt, es ist verhext und muss bald sterben"
or "Woe to the child who tastes salty from a kiss on the brow, for he
is cursed and soon must die", recognizing the association between the
salt loss in CF and illness.
In 1938, Dorothy Hansine Andersen
published an article, "Cystic Fibrosis of the Pancreas and Its Relation
to Celiac Disease: a Clinical and Pathological Study", in the American Journal of Diseases of Children.
She was the first to describe the characteristic cystic fibrosis of
the pancreas and to correlate it with the lung and intestinal disease
prominent in CF.
She also first hypothesized that CF was a recessive disease and first
used pancreatic enzyme replacement to treat affected children. In 1952, Paul di Sant’Agnese discovered abnormalities in sweat electrolytes; a sweat test was developed and improved over the next decade.
The first linkage between CF and another marker (Paroxonase) was found in 1985 by Hans Eiberg, indicating that only one locus exists for CF. In 1988, the first mutation for CF, ΔF508 was discovered by Francis Collins, Lap-Chee Tsui, and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF.
Because mutations in the CFTR gene are typically small, classical genetics techniques had been unable to accurately pinpoint the mutated gene. Using protein markers, gene-linkage studies were able to map the mutation to chromosome 7. Chromosome-walking and -jumping techniques were then used to identify and sequence the gene. In 1989, Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children in Toronto
that discovered the gene responsible for CF. CF represents a classic
example of how a human genetic disorder was elucidated strictly by the
process of forward genetics.
Research
Gene therapy
Gene therapy
has been explored as a potential cure for CF. Results from clinical
trials have shown limited success as of 2016, and using gene therapy as
routine therapy is not suggested. A small study published in 2015 found a small benefit.
The focus of much CF gene therapy research is aimed at trying to place a normal copy of the CFTR gene into affected cells. Transferring the normal CFTR
gene into the affected epithelium cells would result in the production
of functional CFTR protein in all target cells, without adverse
reactions or an inflammation response. To prevent the lung
manifestations of CF, only 5–10% the normal amount of CFTR gene
expression is needed.
Multiple approaches have been tested for gene transfer, such as
liposomes and viral vectors in animal models and clinical trials.
However, both methods were found to be relatively inefficient treatment
options,
mainly because very few cells take up the vector and express the gene,
so the treatment has little effect. Additionally, problems have been
noted in cDNA recombination, such that the gene introduced by the
treatment is rendered unusable.
There has been a functional repair in culture of CFTR by CRISPR/Cas9 in
intestinal stem cell organoids of cystic fibrosis patients.
Phage therapy
Phage therapy is being studied for multidrug resistant bacteria in people with CF.
Small molecules
A number of small molecules that aim at compensating various mutations of the CFTR gene are under development. One approach is to develop drugs that get the ribosome to overcome the stop codon
and synthesize a full-length CFTR protein. About 10% of CF results from
a premature stop codon in the DNA, leading to early termination of
protein synthesis and truncated proteins. These drugs target nonsense mutations such as G542X, which consists of the amino acid glycine
in position 542 being replaced by a stop codon. Aminoglycoside
antibiotics interfere with protein synthesis and error-correction. In
some cases, they can cause the cell to overcome a premature stop codon
by inserting a random amino acid, thereby allowing expression of a
full-length protein.
The aminoglycoside gentamicin has been used to treat lung cells from CF patients in the laboratory to induce the cells to grow full-length proteins. Another drug targeting nonsense mutations is ataluren, which is undergoing Phase III clinical trials as of October 2011.
