Paroxysmal kinesogenic choreoathetosis
Encyclopedia
Wikipedia Article
Paroxysmal kinesigenic choreathetosis, (PKC) also called Paroxysmal Kinesigenic Dyskinesia (PKD) is a hyperkinetic movement disorder
characterized by attacks of involuntary movements, which are triggered by sudden voluntary movements. The number of attacks can range from up to twenty times per day, to more than twenty times per day, with attacks increasing during puberty and decreasing in a person’s 20's to 30's. Involuntary movements can take many forms such as ballism, chorea
or dystonia
and usually only affect one side of the body or one limb in particular. This rare disorder only affects about 1 in 150,000 people with PKD accounting for 86.8% of all the types of paroxysmal dyskinesias
and occurs more often in males than females. There are two types of PKD, primary and secondary. Primary PKD can be further broken down into familial and sporadic. Familial PKD, which means the individual has a family history of the disorder, is more common, but sporadic cases are also seen. Secondary PKD can be caused by many other medical conditions such as multiple sclerosis (MS)
, stroke
, pseudohypoparathyroidism
, hypocalcemia
, hypoglycemia
, hyperglycemia
, central nervous system
trauma, or peripheral nervous system
trauma. PKD has also been linked with The ICCA Syndrome
, in which patients have afebrile
seizures as children and then develop paroxysmal choreoathetosis later in life. This phenomenon is actually quite common, with about 42% of individuals with PKD reporting a history of afebrile seizures as a child.
, naming it paroxysmal kinesigenic choreoathetosis. Finally in a review in 1995 Demirkiran and Jankovic
stated the disease should be called paroxysmal kinesigenic dyskinesia instead, pointing out that the attacks could manifest as any form of dyskinesia, not just choreoathetosis.
. The study also found that patients with familial PKD exhibit symptoms that follow the diagnostic criteria closely, while sporadic PKD individuals may deviate slightly. Prior to criteria for diagnosis being set out, many patients with PKD were often diagnosed with some form of epilepsy
. Unlike epilepsy, as shown, patients with PKD do not lose consciousness during attacks. In addition, individuals with PKD generally have normal postictal
neurologic exams. However, many patients also experience an aura
, similar to those experienced with epilepsy, preceding their attacks. Some patients describe it as a tingling sensation
in the affected limb or “butterflies in their stomach.” Some individuals also have precipitants, such as stress and anxiety that make it more likely for attacks to occur.
The above diagnostic criteria also set PKD apart from the other paroxysmal dyskinesias, which include paroxysmal nonkinesigenic dyskinesia
(PNKD) and paroxysmal exercise-induced dyskinesia
(PED). While PKD attacks last less than one minute, PNKD attacks last a few minutes to a few hours, and as the name suggests, the attacks do not occur because of a sudden voluntary movement like PKD. Additionally, PKD can almost always be managed with drug therapy, while PNKD is not as responsive to anticonvulsants. PED, on the other hand, separates itself from PKD in that it is caused by prolonged exercise. Attacks from PED will cease soon after exercise is stopped.
, a benzodiazepine
. Other categories of drugs have also been used, such as dopamine
affecting drugs like Levodopa or Tetrabenazine
. Individuals with the disorder can also modify their behavior to lessen their attacks without the influence of drug therapy. For example, decreasing stress to avoid precipitants can help patients decrease the number of attacks. In addition, avoiding any sudden movements can also prevent an attack. In order to prevent an attack, some individuals use their auras as a warning, while others purposefully perform slow gestures or movements prior to a triggering movement. Many, if not most, individuals end up growing out of the attacks with age, even without medicinal therapy, but some patients will go back to having attacks after a period of remission. In regards to secondary PKD, treatment of the primary condition can lessen the PKD attacks in those individuals.
of PKD is not fully explained. A few mechanisms have been suggested thus far:
Multiple methods are being used to study the potential brain abnormalities of individuals with PKD compared with “normal” individuals. These methods include SPECT studies, fMRI
studies, and diffusion tensor imaging. The main problem with many of the studies concerned with the pathophysiology of the disorder is the small sample size. Because the studies normally only include about 7-10 patients with PKD, the results cannot be generalized to the entire population of patients. However, the studies do bring up possibilities for further study.
. However, the literature does state that although this could be a cause of PKD, it could also be a result of PKD. Another SPECT study showed an increase in the cerebral blood flow in the left posterior thalamus
in a PKD patient during an attack. The researchers also subtracted the ictal from the postictal scans, and saw increased blood flow in the thalamus. They ultimately suggested that hyperactive blood flow in this area could be causing the pathophysiology of PKD. This study, however, was only performed on one patient, and would need to be replicated many more times in order to be generalized to the population of PKD patients. Other SPECT studies have been cited showing hyperactivity in the basal ganglia.
and the bilateral putamen
had increased ALFF in PKD patients. The researchers concluded that the hyperactivity in these regions suggested that there is a dysfunction in the basal ganglia-thalamo-cortical circuit in PKD. This circuit is part of the motor control circuit in the brain, making it a reasonable place for abnormality in a movement disorder, but again, researchers are still unsure of the role these differences they found play in the disease pathology.
. In one study researchers found that some of the patients had abnormalities in their thalamus. However, this does not prove that all patients have abnormalities in their thalamus. Other cases are cited, including a patient who developed a similar paroxysmal dyskinesia after a thalamic infarction
, implicating that an abnormality in the thalamus of individuals could contribute to PKD. It is not fully known, however, what role a thalamic abnormality plays in the disease pathophysiology.
gene on chromosome 16 was identified as the cause of the disease. The researchers looked at the genetics of eight families with strong histories of PKD. They employed whole genome sequencing
, along with Sanger sequencing to identify the gene that was mutated in these families. The mutations in this gene included a nonsense mutation
identified in the genome
of one family and an insertion mutation
identified in the genome of another family. The researchers then confirmed this gene as the cause of PKD when it was not mutated in the genome of 1000 control
patients. The mechanism of how PRRT2 causes PKD still requires further investigation. However, researchers suggest it may have to do with PRRT2's expression in the basal ganglia, and the expression of an associated protein, SNAP25, in the basal ganglia as well.
Paroxysmal kinesigenic choreathetosis, (PKC) also called Paroxysmal Kinesigenic Dyskinesia (PKD) is a hyperkinetic movement disorder
Movement disorder
Movement disorders include:* Akathisia * Akinesia * Associated Movements * Athetosis...
characterized by attacks of involuntary movements, which are triggered by sudden voluntary movements. The number of attacks can range from up to twenty times per day, to more than twenty times per day, with attacks increasing during puberty and decreasing in a person’s 20's to 30's. Involuntary movements can take many forms such as ballism, chorea
Choreia
Choreia may refer to:*Choreia , ancient Greek dance*Choreia , medical disorder involving involuntary movement...
or dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
and usually only affect one side of the body or one limb in particular. This rare disorder only affects about 1 in 150,000 people with PKD accounting for 86.8% of all the types of paroxysmal dyskinesias
Paroxysmal dyskinesia
The paroxysmal dyskinesias are a group of rare movement disorders characterized by attacks of hyperkinesis with intact consciousness.-Types:* Paroxysmal kinesogenic choreoathetosis* Paroxysmal nonkinesogenic dyskinesia* Paroxysmal exercise-induced dystonia...
and occurs more often in males than females. There are two types of PKD, primary and secondary. Primary PKD can be further broken down into familial and sporadic. Familial PKD, which means the individual has a family history of the disorder, is more common, but sporadic cases are also seen. Secondary PKD can be caused by many other medical conditions such as multiple sclerosis (MS)
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, pseudohypoparathyroidism
Pseudohypoparathyroidism
Pseudohypoparathyroidism is a condition associated primarily with resistance to the parathyroid hormone. Patients have a low serum calcium and high phosphate, but the parathyroid hormone level is actually appropriately high...
, hypocalcemia
Hypocalcaemia
In medicine, hypocalcaemia is the presence of low serum calcium levels in the blood, usually taken as less than 2.1 mmol/L or 9 mg/dl or an ionized calcium level of less than 1.1 mmol/L or 4.5 mg/dL. It is a type of electrolyte disturbance...
, hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
, hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
, central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
trauma, or peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
trauma. PKD has also been linked with The ICCA Syndrome
The ICCA Syndrome
The ICCA Syndrome .The ICCA syndrome is a neurological genetic disorder with an autosomal dominant mode of inheritance...
, in which patients have afebrile
Normal human body temperature
Normal human body temperature, also known as normothermia or euthermia, is a concept that depends upon the place in the body at which the measurement is made, and the time of day and level of activity of the person...
seizures as children and then develop paroxysmal choreoathetosis later in life. This phenomenon is actually quite common, with about 42% of individuals with PKD reporting a history of afebrile seizures as a child.
History of Discovery
A movement disorder similar to PKD was first mentioned in research literature in 1940 by Mount and Reback. They described a disorder consisting of attacks of involuntary movements but unlike PKD, the attacks lasted minutes to hours and were found to be caused by alcohol, or caffeine intake. They named it paroxysmal dystonic choreoathetosis. Kertesz later described another new movement disorder in 1967. He described a disorder that was induced by sudden movements, and responded to anticonvulsantsAnticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
, naming it paroxysmal kinesigenic choreoathetosis. Finally in a review in 1995 Demirkiran and Jankovic
Joseph Jankovic
Joseph Jankovic, M.D. is a neurologist currently practicing at the Department of Neurology at Baylor College of Medicine in Houston, Texas.Dr. Jankovic has served as the principal investigator on over a hundred clinical trials and his pioneering research on drugs for Parkinsonian disorders and...
stated the disease should be called paroxysmal kinesigenic dyskinesia instead, pointing out that the attacks could manifest as any form of dyskinesia, not just choreoathetosis.
Diagnosis
Paroxysmal kinesigenic dyskinesia is diagnosed using a strict set of guidelines. These criteria were studied and confirmed by Bruno et al. in a study of 121 individuals with PKD.The age at onset is between 1 and 20 years old. The attacks of involuntary movements last less than one minute and have a known trigger, usually a sudden voluntary movement. For example, if a PKD patient stands up or begins walking after being sedentary for a period of time, or a person goes from a walk to a run, it can trigger an attack. Persons with PKD do not lose consciousness during attacks and have a full memory of the entire attack. Lastly, people with the disorder have a good response to medication and are usually prescribed anticonvulsantsAnticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
. The study also found that patients with familial PKD exhibit symptoms that follow the diagnostic criteria closely, while sporadic PKD individuals may deviate slightly. Prior to criteria for diagnosis being set out, many patients with PKD were often diagnosed with some form of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. Unlike epilepsy, as shown, patients with PKD do not lose consciousness during attacks. In addition, individuals with PKD generally have normal postictal
Postictal state
The postictal state is the altered state of consciousness that a person enters after experiencing a seizure. It usually lasts between 5 and 30 minutes, but sometimes longer in the case of larger or more severe seizures and is characterized by drowsiness, confusion, nausea, hypertension, headache or...
neurologic exams. However, many patients also experience an aura
Aura (symptom)
An aura is a perceptual disturbance experienced by some migraine sufferers before a migraine headache, and the telltale sensation experienced by some people with epilepsy before a seizure. It often manifests as the perception of a strange light, an unpleasant smell or confusing thoughts or...
, similar to those experienced with epilepsy, preceding their attacks. Some patients describe it as a tingling sensation
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
in the affected limb or “butterflies in their stomach.” Some individuals also have precipitants, such as stress and anxiety that make it more likely for attacks to occur.
The above diagnostic criteria also set PKD apart from the other paroxysmal dyskinesias, which include paroxysmal nonkinesigenic dyskinesia
Paroxysmal Nonkinesigenic Dyskinesia
Paroxysmal Nonkinesigenic Dyskinesia is an episodic movement disorder first described by Mount and Reback in 1940 under the name "Familial paroxysmal choreoathetosis"...
(PNKD) and paroxysmal exercise-induced dyskinesia
Paroxysmal exercise-induced dystonia
Paroxysmal exercise-induced dystonia or PED is a rare neurological disorder characterized by sudden, transient, involuntary movements, often including repetitive twisting motions and painful posturing triggered by exercise or other physical exertion...
(PED). While PKD attacks last less than one minute, PNKD attacks last a few minutes to a few hours, and as the name suggests, the attacks do not occur because of a sudden voluntary movement like PKD. Additionally, PKD can almost always be managed with drug therapy, while PNKD is not as responsive to anticonvulsants. PED, on the other hand, separates itself from PKD in that it is caused by prolonged exercise. Attacks from PED will cease soon after exercise is stopped.
Treatment
Almost all patients respond positively to antiepileptic (anticonvulsant) drugs. One of the drugs most often mentioned in the literature is carbamazepineCarbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, a benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
. Other categories of drugs have also been used, such as dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
affecting drugs like Levodopa or Tetrabenazine
Tetrabenazine
Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorder and is marketed under the trade names Nitoman in Canada and Xenazine in New Zealand and some parts of Europe, and is also available in the USA as an orphan drug. On August 15, 2008 the U.S...
. Individuals with the disorder can also modify their behavior to lessen their attacks without the influence of drug therapy. For example, decreasing stress to avoid precipitants can help patients decrease the number of attacks. In addition, avoiding any sudden movements can also prevent an attack. In order to prevent an attack, some individuals use their auras as a warning, while others purposefully perform slow gestures or movements prior to a triggering movement. Many, if not most, individuals end up growing out of the attacks with age, even without medicinal therapy, but some patients will go back to having attacks after a period of remission. In regards to secondary PKD, treatment of the primary condition can lessen the PKD attacks in those individuals.
Pathophysiology
Currently the pathophysiologyPathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
of PKD is not fully explained. A few mechanisms have been suggested thus far:
- GABAGamma-aminobutyric acidγ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
dysregulation - Abnormal breakdown of dopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in the basal gangliaBasal gangliaThe basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas... - Dysfunction of the substantia nigraSubstantia nigraThe substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
- A form of epilepsy
Multiple methods are being used to study the potential brain abnormalities of individuals with PKD compared with “normal” individuals. These methods include SPECT studies, fMRI
Functional magnetic resonance imaging
Functional magnetic resonance imaging or functional MRI is a type of specialized MRI scan used to measure the hemodynamic response related to neural activity in the brain or spinal cord of humans or other animals. It is one of the most recently developed forms of neuroimaging...
studies, and diffusion tensor imaging. The main problem with many of the studies concerned with the pathophysiology of the disorder is the small sample size. Because the studies normally only include about 7-10 patients with PKD, the results cannot be generalized to the entire population of patients. However, the studies do bring up possibilities for further study.
SPECT Studies
In a study by Joo et al., the researchers performed interictal studies, meaning they scanned the patient's brain between attacks to find an underlying abnormality, rather than ictal scans, which look at the abnormalities that present themselves during an attack. The researchers found interictally decreased cerebral blood flow in the posterior parts of the bilateral caudate nucleusCaudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
. However, the literature does state that although this could be a cause of PKD, it could also be a result of PKD. Another SPECT study showed an increase in the cerebral blood flow in the left posterior thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
in a PKD patient during an attack. The researchers also subtracted the ictal from the postictal scans, and saw increased blood flow in the thalamus. They ultimately suggested that hyperactive blood flow in this area could be causing the pathophysiology of PKD. This study, however, was only performed on one patient, and would need to be replicated many more times in order to be generalized to the population of PKD patients. Other SPECT studies have been cited showing hyperactivity in the basal ganglia.
fMRI Studies
In a study by Zhou et al., the researchers performed fMRI studies on PKD patients, and analyzed the differences between the amplitude low frequency fluctuations (ALFF) of the patients. They found that the left postcentral gyrusPostcentral gyrus
The lateral postcentral gyrus is a prominent structure in the parietal lobe of the human brain and an important landmark. It is the location of primary somatosensory cortex, the main sensory receptive area for the sense of touch...
and the bilateral putamen
Putamen
The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...
had increased ALFF in PKD patients. The researchers concluded that the hyperactivity in these regions suggested that there is a dysfunction in the basal ganglia-thalamo-cortical circuit in PKD. This circuit is part of the motor control circuit in the brain, making it a reasonable place for abnormality in a movement disorder, but again, researchers are still unsure of the role these differences they found play in the disease pathology.
Diffusion Tensor Imaging
Diffusion tensor imaging (DTI) displays physical alterations in the brain that may not be seen on regular MRIMagnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
. In one study researchers found that some of the patients had abnormalities in their thalamus. However, this does not prove that all patients have abnormalities in their thalamus. Other cases are cited, including a patient who developed a similar paroxysmal dyskinesia after a thalamic infarction
Infarction
In medicine, infarction refers to tissue death that is caused by a local lack of oxygen due to obstruction of the tissue's blood supply. The resulting lesion is referred to as an infarct.-Causes:...
, implicating that an abnormality in the thalamus of individuals could contribute to PKD. It is not fully known, however, what role a thalamic abnormality plays in the disease pathophysiology.
Genetics of Disease
Paroxysmal kinesigenic dyskinesia has been shown to be inherited in an autosomal dominant fashion. In 2011 , the PRRT2PRRT2
Proline-rich transmembrane protein 2 is a protein that in humans is encoded by the PRRT2 gene.PRRT2 encodes a proline-rich transmembrane protein. It has been shown to be the cause of paroxysmal kinesigenic dyskinesia.-External links:*...
gene on chromosome 16 was identified as the cause of the disease. The researchers looked at the genetics of eight families with strong histories of PKD. They employed whole genome sequencing
Full genome sequencing
Full genome sequencing , also known as whole genome sequencing , complete genome sequencing, or entire genome sequencing, is a laboratory process that determines the complete DNA sequence of an organism's genome at a single time...
, along with Sanger sequencing to identify the gene that was mutated in these families. The mutations in this gene included a nonsense mutation
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
identified in the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
of one family and an insertion mutation
Insertion (genetics)
In genetics, an insertion is the addition of one or more nucleotide base pairs into a DNA sequence. This can often happen in microsatellite regions due to the DNA polymerase slipping...
identified in the genome of another family. The researchers then confirmed this gene as the cause of PKD when it was not mutated in the genome of 1000 control
Scientific control
Scientific control allows for comparisons of concepts. It is a part of the scientific method. Scientific control is often used in discussion of natural experiments. For instance, during drug testing, scientists will try to control two groups to keep them as identical and normal as possible, then...
patients. The mechanism of how PRRT2 causes PKD still requires further investigation. However, researchers suggest it may have to do with PRRT2's expression in the basal ganglia, and the expression of an associated protein, SNAP25, in the basal ganglia as well.
See also
- Paroxysmal dyskinesiaParoxysmal dyskinesiaThe paroxysmal dyskinesias are a group of rare movement disorders characterized by attacks of hyperkinesis with intact consciousness.-Types:* Paroxysmal kinesogenic choreoathetosis* Paroxysmal nonkinesogenic dyskinesia* Paroxysmal exercise-induced dystonia...
- Paroxysmal nonkinesogenic dyskinesia
- Paroxysmal exercise-induced dystoniaParoxysmal exercise-induced dystoniaParoxysmal exercise-induced dystonia or PED is a rare neurological disorder characterized by sudden, transient, involuntary movements, often including repetitive twisting motions and painful posturing triggered by exercise or other physical exertion...