Related Terms

• AHI1, CEP290, cerebellar vermis agenesis-hyperpnea-episodic eye moves-ataxia-retardation, cerebellar vermis aplasia, cerebellarparenchymal disorder IV, cerebello-oculo-renal syndrome 1 (CORS1), cerebelloparenchymal disorder IV (CPD4), cerebelloparenchymal disorder IV familial, chorioretinal coloboma-Joubert syndrome, COACH, Dekaban-Arima syndrome, hyperpnea-episodic abnormal eye movement, JBTS1, Joubert-Boltshauser syndrome, kidneys-cystic retinal aplasia Joubert syndrome, NPHP1, polydactyly-Joubert syndrome, retinal aplastic-cystic kidneys-Joubert syndrome, Senior-Løken syndrome, TMEM67(MKS3), Varadi-Papp syndrome, vermis aplasia, vermis cerebellar agenesis.

Background

• Joubert syndrome and related disorders (JSRD) are a spectrum of disorders that have some, but not all, features in common. Joubert syndrome is a rare genetic condition that affects the cerebellar vermis, which is found between the left and right hemispheres of the cerebellum and controls balance and coordination. In Joubert syndrome, the cerebellar vermis is absent or underdeveloped and the brain stem is malformed. These brain abnormalities are called the "molar tooth sign," because the structures look like a molar tooth on a magnetic resonance imaging (MRI) scan. The most common features of the disorder are ataxia (a lack of muscle control), hyperpnea (an abnormal breathing pattern characterized by rapid breathing), sleep apnea, intellectual disabilities, and involuntary eye and tongue movements. Other abnormalities, such as extra fingers or toes, a cleft lip or palate, tongue abnormalities, and seizures, may occur. The syndrome was first identified by pioneering pediatric neurologist Marie Joubert in Montreal.

• Most cases of Joubert syndrome occur in individuals with no family history of the disorder. These cases are caused by a spontaneous genetic mutation in the egg, sperm cells, or developing embryo. In some cases, Joubert syndrome is inherited, or passed down among family members. Joubert syndrome is more likely to occur in consanguineous families, in which the parents are closely related and the faulty gene runs in the family. When Joubert syndrome is inherited, it follows an autosomal recessive pattern of inheritance.

• The prevalence of Joubert syndrome is unknown, but more than 200 cases have been reported in people of Algerian, Belgian, Dutch, French Canadian, German, Indian, Italian, Japanese, Laotian, Moroccan, Portuguese, Spanish, Swedish, Swiss, and Turkish origin. Males are twice as likely to have Joubert syndrome as females, for unknown reasons.

• There is no cure for Joubert syndrome. Treatment aims to reduce symptoms and prevent complications. Prognosis depends on the severity of damage to the cerebellar vermis. Some people with Joubert syndrome are only mildly affected while others are more severely affected.

Risk Factors

• Joubert syndrome may be inherited, or passed down among family members, so the only known risk factor is a family history of the disorder. However, most cases of Joubert syndrome occur in individuals with no family history of the disorder. These cases are caused by a spontaneous genetic mutation in the egg, sperm cells, or developing embryo. Joubert syndrome is more likely to occur in consanguineous families, in which the parents are closely related and the faulty gene runs in the family. When Joubert syndrome is inherited, it follows an autosomal recessive pattern of inheritance. Males are twice as likely to have Joubert syndrome as females, for unknown reasons.

• The likelihood of parents who carry the altered gene having a child with Joubert syndrome or any of the Joubert syndrome-related disorders is one in four, or 25%, in each pregnancy that they share.

• The prevalence of Joubert syndrome is unknown, but more than 200 cases have been reported in people of Algerian, Belgian, Dutch, French Canadian, German, Indian, Italian, Japanese, Laotian, Moroccan, Portuguese, Spanish, Swedish, Swiss, and Turkish origin.

Causes

• Random occurrence: Joubert syndrome and related disorders (JSRD) are a spectrum of disorders that have some, but not all, features in common. JSRD describes conditions that share the "molar tooth sign" and the clinical features of Joubert syndrome but also have other manifestations that may represent a distinct syndrome. Most cases of JSRD occur in individuals with no family history of the disorder. These cases are likely the result of a spontaneous mutation in the egg, sperm cells, or developing embryo.

• Genetic mutation: Four causative genes that appear to account for no more than 10% of cases of Joubert syndrome each include NPHP1, CEP290, AHI1, and TMEM67 (MKS3); other causative genes are unknown.

• Autosomal recessive inheritance: Although rare, JSRD may be inherited as an autosomal recessive trait, meaning that a person must inherit two copies of the defective gene, one from each parent, for the disorder to occur. Individuals who inherit only one copy of the defective gene generally have no symptoms and are called carriers, because they may pass on the disorder to their children. Joubert syndrome is more likely to occur in consanguineous families, in which the parents are closely related and the faulty gene runs in the family.

• If one parent is a carrier, then each child has a 50% chance of inheriting one defective gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two defective genes, a 50% chance of inheriting only one defective gene, and a 25% chance of inheriting neither defective gene. Therefore, if both parents are carriers, about one out of four children will have Joubert syndrome.

Signs and Symptoms

• General: Joubert syndrome and related disorders (JSRD) are a spectrum of disorders that have some, but not all, features in common. Joubert syndrome is a rare genetic condition that affects the cerebellar vermis, the part of the brain that controls balance and coordination and is located between the left and right sides of the brain. In Joubert syndrome, the cerebellar vermis is absent or underdeveloped and the brain stem is malformed. These brain abnormalities are called the "molar tooth sign," because these structures look like a molar tooth on a magnetic resonance imaging (MRI) scan. The most common features of the disorder are ataxia (a lack of muscle control), hyperpnea (an abnormal breathing pattern characterized by rapid breathing), sleep apnea, intellectual disabilities, and involuntary eye and tongue movements. Joubert syndrome may be diagnosed while the fetus is in the womb, using ultrasound to look at the brain, or soon after birth. Some symptoms of Joubert disease appear to be progressive, such as kidney disease, but others, such as a lack of muscle control, may simply delay the child's ability to reach certain developmental milestones.

• Brain: A key feature of Joubert syndrome and some related disorders is the absence or underdevelopment of the cerebellar vermis, the part of the brain that regulates balance and coordination. In some people with Joubert syndrome, the brain stem, a brain region involved in regulating heart and breathing functions, is also malformed. When the brain is imaged, as though looking down through the top of the head, these brain abnormalities may resemble a molar tooth. These brain abnormalities are likely the cause of problems with balance and coordination (ataxia). Ataxia associated with Joubert syndrome does not appear to be progressive and may simply delay the child's ability to reach certain developmental milestones.

• Breathing: People with Joubert syndrome and some with related disorders tend to have hyperpnea (rapid breathing or panting) and tend to pause between breaths (called apnea), which may be related to the brain abnormalities characteristic of this syndrome. When breathing is rapid, it may be three times as fast as normal breathing. Periods of apnea may last for up to 90 seconds. Rapid breathing is more likely to occur during periods of wakefulness, while apnea is more likely to occur during sleep. These breathing abnormalities may cause sudden death, or coma may occur in newborns with Joubert syndrome. Breathing tends to become more normal after the first year of life.

• Cognitive function: Cognitive abilities in people with Joubert syndrome may vary from normal to severely impaired. Although developmental delays and intellectual disabilities are common, some individuals with these syndromes have attended college. Individuals with Joubert syndrome and some with related disorders may experience speech apraxia, which may result in an inability to coordinate between speech comprehension and verbal communication. People with Joubert syndrome tend to have sociable personalities but may display behavioral problems, including hyperactivity, aggressiveness, and temper tantrums.

• Eyes: People with Joubert syndrome tend to have nystagmus (rapid involuntary eye movements). Other eye symptoms may include problems with the optic nerve or retina, which is located in the back of the eye and sends information to the brain via the optic nerve. In some cases, coloboma (a split iris, i.e., a gap in part of the structures of the eye) may also be observed. This gap may result in a keyhole-shaped iris and tends to occur more frequently in males. Blindness can occur in individuals whose optic nerve or retina is affected.

• Face: People with Joubert syndrome tend to have a characteristic facial appearance that includes a large head, prominent forehead, high and rounded eyebrows, low-set ears, and droopy eyelids. Their mouths may hang open and appear oval in shape. The tongue may stick out of the mouth and quiver. These distinctive facial features may become less noticeable with age.

• Kidney disease: People with Joubert syndrome may have progressive kidney disease, characterized by the development of cysts. These cysts replace normal kidney tissue, cause the kidney to become enlarged, and lead to loss of kidney function.

• Muscular weakness: People with Joubert syndrome tend to have poor muscle tone and muscular weakness.

• Other: There have been reports of deformities of the hands, feet, and mouth in people with Joubert syndrome. Some people with Joubert syndrome experience seizures.

Types of the Disease

• Joubert syndrome and related disorders (JSRD) are a spectrum of disorders that have some, but not all, features in common. The fundamental feature of the "molar tooth sign," seen on specific views of a brain scan, is a critical step in making a diagnosis of Joubert syndrome. Other features, such as kidney problems, eye or retinal changes, and liver problems, are likely to be specific to certain JSRD subgroups, including Joubert syndrome, Dekaban-Arima syndrome, Senior-Løken syndrome, Varadi-Papp syndrome, and COACH.

• Joubert syndrome: Joubert syndrome is a rare genetic condition that affects the cerebellar vermis, the part of the brain that controls balance and coordination and is found between the left and right sides of the brain. In Joubert syndrome, the cerebellar vermis is absent or underdeveloped, and the brain stem is malformed. These brain abnormalities are called the "molar tooth sign," because these structures look like a molar tooth on a magnetic resonance imaging (MRI) scan. The most common features of the disorder are ataxia (a lack of muscle control), hyperpnea (an abnormal breathing pattern characterized by rapid breathing), sleep apnea, intellectual disabilities, and involuntary eye and tongue movements. Other abnormalities, such as extra fingers or toes, a cleft lip or palate, tongue abnormalities, and seizures, may occur. Four causative genes, which appear to account for no more than 10% of cases of Joubert syndrome each, are NPHP1, CEP290, AHI1, and TMEM67 (MKS3); other causative genes are unknown.

• Dekaban-Arima syndrome: Dekaban-Arima syndrome is a related disorder with visual deficiency and renal insufficiency that is characterized by an abnormality in the cerebellar vermis, a part of the brain. Symptoms associated with this disorder may include developmental delays, intellectual disabilities, and breakdown of the retina, which may lead to blindness. Some children may demonstrate repeated eye rubbing, poking, and pressing (symptoms of severe visual impairment); decreased kidney function; hypotonia (decreased muscle tone); and short stature and poor growth. Dekaban-Arima syndrome is passed down from parents to offspring as an autosomal recessive trait, meaning that an individual must inherit a copy of the defective gene from each parent in order for the condition to occur. The likelihood of having a child with Dekaban-Arima syndrome for parents who carry the altered gene is one in four, or 25%, in each pregnancy that they share. To date, no genes known to be specifically responsible for Dekaban-Arima syndrome have been identified. However, it is possible that mutations in the CEP290 gene, one of the three genes identified for JSRD thus far, may cause Dekaban-Arima syndrome in some children. However, this gene is not the cause in many individuals with JSRD, and the genetics of these disorders remains complex and unknown.

• Senior-Løken syndrome: Senior-Løken syndrome is a disorder with a combination of nephronophthisis with retinal dystrophy. Symptoms of Senior-Løken syndrome include renal insufficiency, particularly juvenile nephronophthisis. Initial symptoms of nephronophthisis include increased thirst, urination, and sometimes anemia and breakdown of the retina, which may lead to blindness. Reduced ability to see well in low-light conditions (e.g., at night) may be one of the first indications of retinal dystrophy. Senior-Løken syndrome is passed down from parents to offspring as an autosomal recessive trait, meaning that an individual must inherit a copy of the defective gene from each parent in order for the condition to occur. The likelihood of having a child born with Senior-Løken syndrome for parents who carry the altered gene involved is one in four, or 25%, in each pregnancy that they share. A number of genes responsible for Senior-Løken syndrome have been identified, and some of these genes are altered in those individuals who have associated features of a cerebellar malformation and developmental delays. Three such genes associated with Joubert syndrome and complications of retinal dystrophy and nephronophthisis are NPHP1, AHI1, and CEP290. However, these do not explain all cases of Senior-Løken syndrome, and the genetics of these disorders remains complex and unknown.

• Varadi-Papp syndrome: Varadi-Papp syndrome, a related disorder, is a type of oral-facial-digital (OFD) disorder characterized by an abnormality in the cerebellar vermis, a part of the brain. Individuals diagnosed with Varadi-Papp syndrome traditionally exhibit the following features: cleft lip or palate; anomalies of the tongue, such as nodules or benign tumors; oral frenula (extra strands of tissue between the gums, and in the tongue and mouth); abnormalities in teeth, particularly tooth shape and tooth enamel hypoplasia; facial abnormalities, including abnormalities in the region of the eyes, which may include epicanthal folds (prominent folds of skin over the central corners of the eye), squinting, strabismus (paralysis of the ocular muscles), or hypertelorism (wide-spaced eyes); and polydactyly (extra fingers and toes), especially of central digits (with a Y-shaped metacarpal bone in the hands), and duplicated great toes. Other symptoms include extra digits on the pinkie side of the hand; a variety of brain malformations, such as an underdeveloped cerebellar vermis (called hypoplasia) or complete lack of the cerebellar vermis (called aplasia or agenesis), which may be indicated by the "molar tooth" sign found on axial views on an MRI scan; developmental delays and intellectual disabilities; and short stature and poor growth. Varadi-Papp syndrome is passed from parent to offspring as an autosomal recessive trait, meaning that an individual must inherit a copy of the defective gene from both parents in order for the condition to occur. The likelihood of having a child born with this condition for parents who carry the gene involved is one in four, or 25%, in each pregnancy that they share. To date, no genes known to be responsible specifically for Varadi-Papp syndrome have been identified. Although three genes are known to cause JSRD, none of these has been associated with the features of Varadi-Papp syndrome.

• Cogan-type congenital oculomotor apraxia (Cogan-type OMA): Cogan-type congenital oculomotor apraxia (Cogan-type OMA) is a related disorder. OMA refers to a specific eye movement caused by an abnormality in the cerebellar vermis, a part of the brain, because of which it is difficult for children to track objects smoothly. Their eyes may appear to jump, with jerky movements. Symptoms are congenital (present from birth). Cogan-type OMA is believed to be passed down from parents to offspring as an autosomal recessive trait, meaning that an individual must inherit a copy of the defective gene from both parents in order for the condition to occur. The likelihood of having a child born to parents who carry the altered gene involved is one in four, or 25%, in each pregnancy that they share. One gene for this disorder has been identified, NPHP1, but it is unclear whether this gene is altered only in those individuals who have associated features of nephronophthisis, a cerebellar malformation, or both. It is likely that alterations in other genes also may cause this condition.

• COACH: COACH is a related disorder characterized by an abnormality in the cerebellar vermis, a part of the brain. The name COACH is a mnemonic that stands for the different characteristics of the disorder: cerebellar vermis hypoplasia/aplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Patients diagnosed with COACH traditionally exhibit the following features: hypoplasia (underdevelopment) or aplasia/agenesis (complete lack) of the cerebellar vermis, usually indicated by the "molar tooth" sign found on an axial view of an MRI scan; developmental delays or intellectual disabilities; difficulty coordinating voluntary muscle movements; ataxia (uncoordinated movements); coloboma (a malformation of the retina or other regions of the eye); abnormalities of the liver, including hepatic fibrosis, which have delayed onset or progress slowly; and hypotonia (decreased muscle tone). COACH syndrome is passed down from parents to offspring as an autosomal recessive trait, meaning that an individual must inherit a copy of the defective gene from both parents in order for the condition to occur. The likelihood of having a child born with COACH for parents who carry the altered gene involved is one in four, or 25%, in each pregnancy that they share. To date, no genes have been identified that cause COACH syndrome specifically. It is likely that alterations in multiple genes may cause this condition.

Diagnosis

• General: To diagnose Joubert syndrome and related disorders (JSRD), a physical exam and thorough family history should be completed. If JSRD is suspected, diagnosis may be possible in the womb. A positive diagnosis is based on the presence of the characteristic brain abnormality; however, not all fetuses or infants will display all symptoms of the disorder. Interview questions should focus on attainment of developmental milestones such as sitting and walking. A clinician should also look for characteristic facial features, which include a large head, prominent forehead, high and rounded eyebrows, low-set ears, and droopy eyelids. Patients' mouths may hang open and appear oval in shape. The tongue may stick out of the mouth and quiver. Also apparent may be involuntary eye movements, breathing abnormalities, muscular weakness, and lack of coordination.

• Imaging: The diagnosis of Joubert syndrome may be aided by the use of imaging studies including X-rays, computed tomography (CT), and magnetic resonance imaging (MRI). A CT scan is a noninvasive imaging technique that uses a series of X-rays to build a picture of the inside of the body. MRI is a noninvasive imaging technique that uses magnetic and radio waves to create an image of tissues within the body. A CT or MRI scan of the brain may assess the presence or absence of the cerebellar vermis, the part of the brain responsible for balance and coordination. The abnormally small brain stem in JSRD may resemble a molar tooth and is called the "molar tooth sign."

• Genetic testing: Although information is limited regarding what genetic mutations cause Joubert syndrome, genetic testing may be available to determine whether an individual has certain forms of the syndrome. Genetic testing may also be able to determine whether a developing fetus has certain forms of the disorder. Four causative genes, which appear to account for no more than 10% of cases of Joubert syndrome each, are NPHP1, CEP290, AHI1, and TMEM67 (MKS3); other causative genes are unknown.

Complications

• Coordination and development: Because of abnormalities in the cerebellar vermis, people with Joubert syndrome often have problems with balance and coordination (called ataxia). People with Joubert syndrome may also have delayed development of overall motor and speech skills. Problems with coordination and development depend on how severely the brain is affected in this condition.

• Coma: Breathing abnormalities characteristic of Joubert syndrome and some related disorders may cause coma in young people with this disorder.

• Kidney failure: People with Joubert syndrome may experience kidney failure caused by progressively worsening cystic kidney disease, which is caused by the accumulation of cysts in kidney tissue. Cysts are small fluid-filled sacs that grow in the middle, or medulla, of the kidney. They replace normal kidney tissue, cause the kidney to become enlarged, and lead to loss of kidney function.

• Seizures: Some people with Joubert syndrome and some related disorders experience seizures.

• Sudden death: Breathing abnormalities characteristic of Joubert syndrome may cause sudden death, especially in young people with the disorder.

Treatment

• General: There is no cure for Joubert syndrome. Instead, treatment aims to reduce symptoms and prevent complications. People with Joubert syndrome should be regularly examined by an ophthalmologist (eye specialist), neurologist (nerve specialist), respiratory specialist, and geneticist. Early in life, people with Joubert syndrome should be closely monitored for breathing problems. A decreased life span has been seen in many patients.

• Adaptive equipment: Special equipment is also available for individuals with Joubert syndrome and related disorders. Wheelchairs, walkers, and braces may help individuals to perform daily tasks. Many people with Joubert syndrome can operate a wheelchair on their own and can move around without much difficulty. There are also motorized wheelchairs available if the conventional type is not appropriate or if the chair is for a child. A walker is a piece of equipment usually made out of light metal, with four adjustable legs. Some people with Joubert syndrome can walk but have poor balance and may fall, so a walker may be helpful to them. Because of the fine motor problems often associated with Joubert syndrome, individuals may have a hard time using eating utensils. Eating utensils specially designed for individuals with fine motor problems are available, as are special grips and handles for everyday objects that may make activities of daily living more accessible.

• Behavioral therapy: Behavioral therapy is available to help people with Joubert syndrome improve their communication and social skills as well as their learning abilities and adaptive behaviors. Therapy may also help reduce negative behaviors, such as aggression, temper tantrums, and hyperactivity. For instance, dialectical behavior therapy may be used to teach behavioral skills to help a person tolerate stress, regulate emotions, and improve relationships with others. Evidence suggests that behavioral therapy is most effective if it is started early in life.

• Corrective lenses: Individuals with Joubert syndrome who have vision problems may benefit from corrective lenses or glasses for conditions such as nearsightedness. However, neither glasses nor corrective lenses can improve optic atrophy, which is common in Joubert syndrome.

• Dialysis: When the kidneys begin to fail, patients can undergo various types of dialysis to restore the filtering function of the kidneys. In hemodialysis, a patient's blood is circulated into an external filter and cleaned. The filtered blood is then returned to the body. In peritoneal dialysis, a fluid containing dextrose is introduced into the abdomen through a tube. This solution absorbs the wastes in the body and is then removed.

• Drugs: Medications may be prescribed for people with Joubert syndrome who experience seizures. Anticonvulsants, also known as antiepileptic drugs, such as phenytoin (Dilantin®), are used to treat seizures. U.S. Food and Drug Administration (FDA) approval usually requires that 50% of the patient treatment group saw at least a 50% improvement in the rate of epileptic seizures. About 20% of patients with epilepsy continue to have breakthrough epileptic seizures despite the optimal anticonvulsant treatment. Most side effects are mild and dose related and may often be avoided or minimized by the use of the smallest effective dosage. Some side effects include mood changes, drowsiness, or unsteady gait. Some anticonvulsant medications have idiosyncratic side effects that cannot be predicted by dose, including drug rashes, hepatitis (liver toxicity), or aplastic anemia. Safety includes the consideration of teratogenicity (the effects of medications on fetal development) when women with epilepsy become pregnant.

• Education: People with Joubert syndrome who have intellectual disabilities are required by law to have access to education that is tailored to their specific strengths and weaknesses. According to the Individuals with Disabilities Education Act, all children with disabilities must receive free and appropriate education. This law states that staff members of the patient's school must consult with the patient's parents or caregivers to design and write an individualized education plan based on the child's needs. The school faculty must document the child's progress in order to ensure that the child's needs are being met.

• Educational programs vary among patients depending on the child's specific learning disabilities. In general, most experts believe that children with disabilities should be educated alongside their nondisabled peers. The idea is that nondisabled students will help the patient learn appropriate behavioral, social, and language skills. Therefore, some Joubert syndrome patients are educated in mainstream classrooms. Others attend public schools but take special education classes. Still others attend specialized schools that are equipped to teach children with disabilities.

• Occupational therapy: Patients with Joubert syndrome may benefit from occupational therapy. During sessions, a therapist helps the child learn skills needed to perform basic daily tasks, such as eating, dressing, and communicating with others. Some patients work with therapists who specialize in disorders and disabilities. Parents and caregivers can ask their child's pediatrician for recommended therapists.

• Physical therapy: Patients with Joubert syndrome may benefit from seeing a physical therapist. A physical therapist may be able to help patients maintain muscle tone, strength, and flexibility by having them perform various exercises.

• Sleep apnea treatment: Lifestyle changes, which include avoiding alcohol and medications that cause drowsiness, weight loss, and using mouthpieces and breathing devices, or surgery are used to treat sleep apnea.

• Speech-language therapy: Some patients with Joubert syndrome may benefit from speech-language therapy because individuals often develop communication skills more slowly than normal. During speech-language therapy, a qualified speech-language professional (SLP) works with the patient on a one-to-one basis, in a small group, or in a classroom, to help the patient improve speech, language, and communication skills. Programs are tailored to the patient's individual needs. Speech pathologists use a variety of exercises to improve the patient's communication skills. Exercises typically start off simple and become more complex as therapy continues. For instance, the therapist may ask the patient to name objects, tell stories, or explain the purpose of an object.

• Transplantation: Some patients who experience kidney failure may undergo kidney transplantation. An individual with end-stage renal disease may receive a healthy kidney either from a living donor or from a deceased donor. Kidneys that are transplanted into patients with Joubert syndrome do not tend to develop cysts. However, transplantation is associated with complications, including infection and the possibility of rejection of the new organ. To reduce the chance of rejection, patients may need to take immunosuppressant drugs, such as tacrolimus, mycophenolate, prednisone, cyclosporine, rapamycin, or azathioprine. Cyclosporine, considered a breakthrough immunosuppressant when it was first developed in the 1980s, ironically causes kidney toxicity and may result in drug-related damage to the newly transplanted kidney.

Integrative Therapies

• Currently there is limited scientific evidence on the use of integrative therapies for the treatment or prevention of Joubert syndrome.

Prevention

• There are no known means of preventing Joubert syndrome. Although information is limited regarding the genetic mutations that cause Joubert syndrome, genetic testing may be available to determine whether an individual or a developing fetus has certain types of the syndrome. A decreased life span has been seen in many patients.

• Medications may be prescribed for people with Joubert syndrome who experience seizures.

Author Information

• This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

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