Machado–Joseph disease (MJD), also known as Machado–Joseph Azorean disease, Machado's disease, Joseph's disease or spinocerebellar ataxia type 3 (SCA3), is a rare
autosomal dominantly inherited neurodegenerative
A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...
disease that causes progressive
cerebellar
The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or e ...
ataxia
Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
,
[Paulson, H. (8 March 2011). Spinocerebellar Ataxia Type 3. In R. A. Pagon, T. D. Bird, C. R. Dolan, & K. Stephens (Eds.), GeneReviews. Seattle, WA: University of Washington. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1196/] which results in a lack of
muscle control and
coordination
Coordination may refer to:
* Coordination (linguistics), a compound grammatical construction
* Coordination complex, consisting of a central atom or ion and a surrounding array of bound molecules or ions
** A chemical reaction to form a coordinati ...
of the
upper and
lower extremities.
The symptoms are caused by a genetic
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
that results in an expansion of abnormal "CAG" trinucleotide repeats in the
ATXN3 gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
that results in an abnormal form of the protein
ataxin which causes degeneration of cells in the
hindbrain
The hindbrain, rhombencephalon (shaped like a rhombus) is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes.
Met ...
.
Some symptoms, such as clumsiness and rigidity, make MJD commonly mistaken for drunkenness or
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
.
Machado–Joseph disease is a type of
spinocerebellar ataxia
Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of ...
and is the most common cause of autosomal-dominant ataxia.
MJD causes
ophthalmoplegia
Ophthalmoparesis refers to weakness (-paresis) or paralysis (-plegia) of one or more extraocular muscles which are responsible for eye movements. It is a physical finding in certain neurologic, ophthalmologic, and endocrine disease.
Internal ...
and mixed sensory and cerebellar ataxia.
Symptoms and signs
Symptoms of MJD are memory deficits,
spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" 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.
Genetics
Flores and São Miguel are centers of the Machado–Joseph disease in the
Azores
The Azores ( , , ; , ), officially the Autonomous Region of the Azores (), is one of the two autonomous regions of Portugal (along with Madeira). It is an archipelago composed of nine volcanic islands in the Macaronesia region of the North Atl ...
.
Machado Joseph's disease has multiple origins as SCA3 comes from haplotype of four different origins and was not from one origin in the Azores.
Japan
Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
,
Brazil
Brazil, officially the Federative Republic of Brazil, is the largest country in South America. It is the world's List of countries and dependencies by area, fifth-largest country by area and the List of countries and dependencies by population ...
and
France
France, officially the French Republic, is a country located primarily in Western Europe. Overseas France, Its overseas regions and territories include French Guiana in South America, Saint Pierre and Miquelon in the Atlantic Ocean#North Atlan ...
all have been founder effects in areas with SCA3.
Spinocerebellar ataxia type 3 (SCA3) on the Azores are believed to have come from
Portugal
Portugal, officially the Portuguese Republic, is a country on the Iberian Peninsula in Southwestern Europe. Featuring Cabo da Roca, the westernmost point in continental Europe, Portugal borders Spain to its north and east, with which it share ...
's northeast where Sephardic
Jew
Jews (, , ), or the Jewish people, are an ethnoreligious group and nation, originating from the Israelites of ancient Israel and Judah. They also traditionally adhere to Judaism. Jewish ethnicity, religion, and community are highly inte ...
s lived.
Belgium
Belgium, officially the Kingdom of Belgium, is a country in Northwestern Europe. Situated in a coastal lowland region known as the Low Countries, it is bordered by the Netherlands to the north, Germany to the east, Luxembourg to the southeas ...
, French-Guiana and
Algeria
Algeria, officially the People's Democratic Republic of Algeria, is a country in the Maghreb region of North Africa. It is bordered to Algeria–Tunisia border, the northeast by Tunisia; to Algeria–Libya border, the east by Libya; to Alger ...
have their own MJD mutation origins. Portuguese have two mutations, while Brazil and France have one mutation, and Germans make up the majority of MJD patients in the United States. Individuals with Azorean MJD have their locus on the 14q24.3–32 chromosome, the same as some Japanese with MJD. It was an Azorean, William Machado, whose offspring in
New England
New England is a region consisting of six states in the Northeastern United States: Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont. It is bordered by the state of New York (state), New York to the west and by the ...
were the first to be diagnosed with MJD. The Azorean Joseph family, living in California, were also diagnosed with MJD. The same origin for MJD is found in the Azores and in America's north-west coast. Not only Portuguese have it since African Americans, Indians, Italians and Japanese also developed MJD.
In
China
China, officially the People's Republic of China (PRC), is a country in East Asia. With population of China, a population exceeding 1.4 billion, it is the list of countries by population (United Nations), second-most populous country after ...
, the mutation causing SCA type 3 has been estimated to have occurred 8,000 to 17,000 years ago.
In Japan, the oldest causative mutation appears to have occurred about 5774 +/- 1116 years ago.
Among aboriginal Australians, the founder mutation appears to have occurred about 7000 years ago. As this mutation is shared with other families based in Asia it seems likely that it was imported into Australia.
MJD affected Azoreans and Japanese had haplotypes in common while Azoreans also had haplotypes of two different origins.
Pathophysiology
The disease is caused by a mutation in the ''
ATXN3'' gene, which is located on
chromosome 14
Chromosome 14 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 14 spans about 107 million base pairs (the building material of DNA) and represents between 3 and 3.5% of the total DNA i ...
(14q32.1). In
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
10 the gene contains lengthy irregular
CAG repeats, producing a mutated protein called
ataxin-3. (Normally, the number of copies is between 13 and 41.)
MJD is an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
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 has this condition and the other parent does not, there will be a 50% chance of their child inheriting the condition.
The
pons
The pons (from Latin , "bridge") is part of the brainstem that in humans and other mammals, lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum.
The pons is also called the pons Varolii ("bridge of ...
in the
brainstem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
is one of the areas affected by MJD. The
striatum
The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...
(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
Inclusion bodies are aggregates of specific types of protein found in neurons, and a number of tissue (biology), tissue cells including red blood cells, bacteria, viruses, and plants. Inclusion bodies of aggregations of multiple proteins are also ...
. These insoluble aggregates are hypothesized to interfere with the normal activity of the nucleus and induce the cell to degenerate and die.
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 genetic mutation responsible for MJD has been available since 1995.
Genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
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.
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 affects approximately 13% of individuals with MJD and has onset of symptoms between the ages of 10 and 30 years old.
It usually progresses quickly, with patients experiencing severe
rigidity and
dystonia
Dystonia is a neurology, neurological Hyperkinesia, hyperkinetic Movement disorders, movement disorder in which sustained or repetitive muscle contractions occur involuntarily, resulting in twisting and repetitive movements or abnormal fixed po ...
.
* Type II is the most common sub-type, affecting approximately 57% of individuals with MJD
and symptoms typically begin between 20 and 50 years of age. It has an intermediate rate of progression and causes symptoms that include ataxia
and spasticity, along with other upper motor neuron signs such as exaggerated deep tendon reflexes (DTRs).
* Type III occurs in approximately 30% of MJD patients and has a relatively slow progression, with symptoms typically arising between the ages of 40 and 70.
Symptoms include muscle twitching and cramps, unpleasant sensations such as
numbness
Hypoesthesia or numbness is a common side effect of various medical conditions that manifests as a reduced sense of touch or sensation, or a partial loss of sensitivity to Sensory receptor, sensory stimuli. In everyday speech this is generally r ...
, tingling, and pain in the feet and hands, and limb muscle
atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...
. Nearly all patients experience a decline in their vision experienced as blurred vision,
double vision
Diplopia is the simultaneous perception of two images of a single object that may be displaced in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often voluntary. However, when occ ...
, inability to control eye movements, and/or loss of capability to distinguish color. Some patients also experience
Parkinsonian symptoms.
* Type IV is distinguished by
Parkinsonian symptoms that respond particularly well to
levodopa
Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...
treatment.
* Type V appears to resemble
Hereditary Spastic Paraplegia
Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive Gait abnormality, gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs. HSP is als ...
; however, more research is needed to conclude the relationship between Type V MJD and hereditary spastic paraplegia.
Treatment
There is no cure for Machado-Joseph Disease. However, treatments are available for some symptoms.
For example, spasticity can be reduced with antispasmodic drugs, such as
baclofen
Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity, such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life, and ...
. The Parkinsonian symptoms can be treated with
levodopa
Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...
therapy. Prism glasses can reduce diplopic symptoms.
Physiotherapy
Physical therapy (PT), also known as physiotherapy, is a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease preventio ...
/
Physical Therapy
Physical therapy (PT), also known as physiotherapy, is a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease preventio ...
and/or
occupational therapy
Occupational therapy (OT), also known as ergotherapy, is a healthcare profession. Ergotherapy is derived from the Greek wiktionary:ergon, ergon which is allied to work, to act and to be active. Occupational therapy is based on the assumption t ...
can help patients by prescribing
mobility aid
A mobility aid is a device designed to assist individuals with impaired movement. These devices help people walk, maintain balance, or get around more easily.
Mobility aids include walking supports like canes, crutches, and walkers for those w ...
s 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
Speech is the use of the human voice as a medium for language. Spoken language combines vowel and consonant sounds to form units of meaning like words, which belong to a language's lexicon. There are many different intentional speech acts, suc ...
and
swallowing
Swallowing, also called deglutition or inglutition in scientific and medical contexts, is a physical process of an animal's digestive tract (e.g. that of a human body) that allows for an ingested substance (typically food) to pass from the mou ...
, therefore a
Speech-Language Pathologist can assist the patients to improve their communicating abilities and their issues with swallowing.
Prognosis
Patients with severe forms of MJD have a life expectancy of approximately 35 years. Those with mild forms have a normal life expectancy. The cause of death of those who die early is often aspiration pneumonia.
The highest prevalence of the condition is on Australia's
Groote Eylandt
Groote Eylandt ( Anindilyakwa: ''Ayangkidarrba''; meaning "island" ) is the largest island in the Gulf of Carpentaria and the fourth largest island in Australia. It was named by the explorer Abel Tasman in 1644 and is Dutch for "large island" ...
where 5% of the population are currently symptomatic or at risk, followed by the Azorean
island of Flores where around 1 in 140 individuals in the population are diagnosed with MJD.
Culture and society
Brazil
Brazil, officially the Federative Republic of Brazil, is the largest country in South America. It is the world's List of countries and dependencies by area, fifth-largest country by area and the List of countries and dependencies by population ...
ian comedian, actor and TV personality
Guilherme Karam was diagnosed with Machado–Joseph disease, having inherited it from his mother, like his brother and sister. He died on 7 July 2016.
In a video on Facebook just days after Karam's death, Brazilian personality, journalist and television presenter,
Arnaldo Duran publicly acknowledged his condition with Machado-Joseph. Brazilian press gave huge attention to both cases.
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 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.
References
External links
*
{{DEFAULTSORT:Machado-Joseph Disease
Disorders of synthesis of DNA, RNA, and proteins
Systemic atrophies primarily affecting the central nervous system
Neurodegenerative disorders
Rare diseases