Machado-Joseph disease
Encyclopedia
Machado–Joseph disease or Spinocerebellar ataxia type 3 (SCA3) is a rare autosomal, dominantly inherited
neurodegenerative disease that causes progressive cerebellar ataxia
, which results in a lack of muscle control
and coordination
of the upper
and lower extremities. The symptoms are caused by a genetic mutation
that results in an expansion of abnormal "CAG" trinucleotide repeats in the ATXN3 gene
that results in degeneration of cells in the hindbrain. Some symptoms, such as clumsiness and rigidity, make MJD commonly mistaken for drunkenness and/or Parkinson's disease
.
Machado–Joseph disease is a type of spinocerebellar ataxia
and is the most common cause of autosomal-dominant
ataxia
. MJD causes ophthalmoplegia and mixed sensory and cerebellar
ataxia
.
Unlike many other medical conditions, Machado–Joseph disease isn't named after researchers. It is named after two men ("William Machado" and "Antone Joseph") who were the patriarchs of the families in which the condition was initially described.
The above families come from Portuguese and Azorean descents, which happens to be the ethnicities that MJD is most prevalent in. The highest prevalence of the condition is on the Azorean island of Flores where around 1 in 140 individuals in the population are diagnosed with MJD.
, difficulty with speech and swallowing, weakness in arms and legs, clumsiness, frequent urination and involuntary eye movements. Symptoms can begin in early adolescence and they get worse over time. Eventually, MJD leads to paralysis; however, intellectual functions usually remain the same.
. The Parkinsonian symptoms can be treated with levodopa
therapy. Prism glasses can reduce diplopic symptoms. Physiotherapy or Physical Therapy
can help patients by prescribing mobility aids
to increase the patients' independence, providing gait training
, and prescribing exercises to maintain the mobility of various joints and general health to decrease the likelihood of falls or injuries as a result of falls. Walkers and wheelchairs can greatly help the patient with everyday tasks. Some patients will experience difficulties with speech
and swallowing
, therefore a Speech-Language Pathologist can assist the patients to improve their communicating abilities and their issues with swallowing.
The pons
(a structure located on the brain stem
) is one of the areas affected by MJD. The striatum
(a brain area connected to balance and movement) is also affected by this disease, which could explain both of the main motor problems cause by MJD: the tightening and twisting of the limb and the abrupt, irregular movements.
In affected cells, this protein builds up and assembles intranuclear inclusion bodies.
These insoluble spheres are located in the nucleus of the cell. These spheres conflict with the normal activity of the nucleus and induce the cell to degenerate and die.
The sub-types illustrate a wide variety of symptoms that patients can experience. However, assigning individuals to a specific sub-type of the disease is of limited clinical significance.
Presymptomatic diagnosis of MJD can be made with a genetic test. The direct detection of the generic mutation responsible for MJD has been available since 1995. Genetic testing looks at the number of CAG repeats within the coding region of the MJD/ATXN3 gene on chromosome 14. The test will show positive for MJD if this region contains 61-87 repeats, as opposed to the 12-44 repeats found in healthy individuals. A limitation to this test is that if the number of CAG repeats in an individual being tested falls between the healthy and pathogenic ranges (45-60 repeats), then the test cannot predict whether an individual will have MJD symptoms.
For an ethnographic case study exploring some of the social and ethical consequences of living with Machado–Joseph disease, see João Biehl's Vita: Life in a Zone of Social Abandonment (Berkeley: University of California Press, 2006).
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
neurodegenerative disease that causes progressive cerebellar ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, which results in a lack of muscle control
Motor control
Motor control are information processing related activities carried out by the central nervous system that organize the musculoskeletal system to create coordinated movements and skilled actions...
and coordination
Coordination
Coordination is the act of coordinating, making different people or things work together for a goal or effect to fulfill desired goals in an organization.Coordination is a managerial function in which different activities of the business are properly adjusted and interlinked.Coordination may also...
of the upper
Upper limb
The upper limb or upper extremity is the region in an animal extending from the deltoid region to the hand, including the arm, axilla and shoulder.-Definition:...
and lower extremities. The symptoms are caused by a genetic mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
that results in an expansion of abnormal "CAG" trinucleotide repeats in the ATXN3 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that results in degeneration of cells in the hindbrain. Some symptoms, such as clumsiness and rigidity, make MJD commonly mistaken for drunkenness and/or Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Machado–Joseph disease is a type of spinocerebellar ataxia
Spinocerebellar ataxia
Spinocerebellar ataxia is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a disease in its own right.-Classification:...
and is the most common cause of autosomal-dominant
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
. MJD causes ophthalmoplegia and mixed sensory and cerebellar
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
.
History
The disease was first identified in 1972.Unlike many other medical conditions, Machado–Joseph disease isn't named after researchers. It is named after two men ("William Machado" and "Antone Joseph") who were the patriarchs of the families in which the condition was initially described.
The above families come from Portuguese and Azorean descents, which happens to be the ethnicities that MJD is most prevalent in. The highest prevalence of the condition is on the Azorean island of Flores where around 1 in 140 individuals in the population are diagnosed with MJD.
Symptoms
Symptoms of MJD are memory deficits, spasticitySpasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
, difficulty with speech and swallowing, weakness in arms and legs, clumsiness, frequent urination and involuntary eye movements. Symptoms can begin in early adolescence and they get worse over time. Eventually, MJD leads to paralysis; however, intellectual functions usually remain the same.
Treatment
There is no cure for Machado-Joseph Disease. However, there are treatments available for some symptoms. For example, spasticity can be reduced with antispasmodic drugs, such as baclofenBaclofen
Baclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
. The Parkinsonian symptoms can be treated with levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
therapy. Prism glasses can reduce diplopic symptoms. Physiotherapy or Physical Therapy
Physical therapy
Physical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...
can help patients by prescribing mobility aids
Mobility aids
Mobility aids are devices designed to assist walking or otherwise improve the mobility of people with a mobility impairment.There are various walking aids which can help with impaired ability to walk and wheelchairs or mobility scooters for more severe disability or longer journeys which would...
to increase the patients' independence, providing gait training
Gait training
In its most general form, Gait training is the act of learning how to walk. However, the term is more often used in reference to a person learning how to walk again after injury or with a disability...
, and prescribing exercises to maintain the mobility of various joints and general health to decrease the likelihood of falls or injuries as a result of falls. Walkers and wheelchairs can greatly help the patient with everyday tasks. Some patients will experience difficulties with speech
Aphasia
Aphasia is an impairment of language ability. This class of language disorder ranges from having difficulty remembering words to being completely unable to speak, read, or write....
and swallowing
Aphagia
Aphagia is the inability or refusal to swallow. The word is derived from the Greek root a meaning "not" or "without" and phagia meaning "to eat." It is related to dysphagia, which is difficulty swallowing, and odynophagia, painful swallowing....
, therefore a Speech-Language Pathologist can assist the patients to improve their communicating abilities and their issues with swallowing.
Prognosis
Life expectancy ranges with people who have the disease. A normal life expectancy is expected in patients with a mild form of MJD. Those with severe forms of MJD are expected to live only to their mid-thirties. The cause of death of those who die early is often aspiration pneumonia.Pathophysiology
The disease is caused by a mutation in the ATXN3 gene, which is located on chromosome 14q. The gene contains lengthy irregular repetitions of the code "CAG", producing a mutated protein called ataxin-3. (Normally, the number of copies is between 13 and 41.) MJD is an autosomal dominant disease, meaning that if either parent gives the defective gene to a child, the child will show symptoms of the disease. Therefore, if one parent suffers from this disease and the other parent does not, then if they decide to have children, there will be a 50% chance of their child inheriting the disease.The pons
Pons
The pons is a structure located on the brain stem, named after the Latin word for "bridge" or the 16th-century Italian anatomist and surgeon Costanzo Varolio . It is superior to the medulla oblongata, inferior to the midbrain, and ventral to the cerebellum. In humans and other bipeds this means it...
(a structure located on the brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
) is one of the areas affected by MJD. The striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
(a brain area connected to balance and movement) is also affected by this disease, which could explain both of the main motor problems cause by MJD: the tightening and twisting of the limb and the abrupt, irregular movements.
In affected cells, this protein builds up and assembles intranuclear inclusion bodies.
These insoluble spheres are located in the nucleus of the cell. These spheres conflict with the normal activity of the nucleus and induce the cell to degenerate and die.
Classification
There are five sub-types of MJD that are characterized by the age of onset and range of symptoms.The sub-types illustrate a wide variety of symptoms that patients can experience. However, assigning individuals to a specific sub-type of the disease is of limited clinical significance.
- Type I is distinguished by arrival between the ages of 10 and 30 and represents approximately 13% of individuals. It usually has fast development and severe rigidityHypokinesiaHypokinesia refers to decreased bodily movement. It is associated with basal ganglia diseases , mental health disorders and prolonged inactivity due to illness, amongst other diseases.Hypokinesia describes a spectrum of disorders:...
and dystoniaDystoniaDystonia 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...
.
- Type II is the most common sub-type (approximately 57% of individuals with MJD ) and typically begins between 20 and 50 years of age . It has an intermediate progression and causes symptoms that include spasticity, exaggerated reflex responses and spastic gait, ataxia and upper motor neuron signs.
- Type III MJD has a slow progression. Patients typically have an onset between the ages of 40 and 70 and represent approximately 30% of MJD patients. Symptoms include muscle twitching, tingling, cramps, unpleasant sensations such as numbnessParesthesiaParesthesia , 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"...
, pain in the feet, hands and limbs and muscle atrophyAtrophyAtrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
. Nearly all patients experience a decline in their vision such as blurred vision, double visionDiplopiaDiplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
, inability to control eye movements, and loss of capability to distinguish color. Some patients also experience Parkinsonian symptomsParkinsonismParkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
.
- Type IV is distinguished by Parkinsonian symptomsParkinsonismParkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
that respond particularly well to levodopaLevodopaL-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
treatment.
- Type V is appears to resemble Hereditary Spastic ParaplegiaHereditary spastic paraplegiaHereditary Spastic Paraplegia , also called Familial Spastic Paraplegias or Strumpell-Lorrain disease, is a group of inherited diseases whose main feature is progressive stiffness and contraction in the lower limbs. as a result of damage to dysfunction of the nerves...
; however, more research is needed to conclude the relationship between Type V MJD and hereditary spastic paraplegia.
Diagnosis
MJD can be diagnosed by recognizing the symptoms of the disease and by taking a family history. Physicians ask patients questions about the kind of symptoms relatives with the disease had, the progression and harshness of symptoms, and the ages of onset in family members.Presymptomatic diagnosis of MJD can be made with a genetic test. The direct detection of the generic mutation responsible for MJD has been available since 1995. Genetic testing looks at the number of CAG repeats within the coding region of the MJD/ATXN3 gene on chromosome 14. The test will show positive for MJD if this region contains 61-87 repeats, as opposed to the 12-44 repeats found in healthy individuals. A limitation to this test is that if the number of CAG repeats in an individual being tested falls between the healthy and pathogenic ranges (45-60 repeats), then the test cannot predict whether an individual will have MJD symptoms.
Ethical Consideration
Ethicists have used Machado–Joseph disease as a paradigmatic illness to discuss the rights of a community of patients to control "ownership" of their disease, particularly when it comes to research on genetic testing. Also, as there currently is no clinical intervention to prevent the onset of the disease symptoms, there is discourse over the whether individuals should get tested or not. The benefits of having MJD testing include a reduction in anxiety and uncertainty, and the ability to plan for the future. Some disadvantages include the anticipation of negative results and the individual's difficulties in adapting to this outcome.For an ethnographic case study exploring some of the social and ethical consequences of living with Machado–Joseph disease, see João Biehl's Vita: Life in a Zone of Social Abandonment (Berkeley: University of California Press, 2006).