Machado-Joseph Disease

Machado-Joseph Machado-Joseph DiseaseDisease

Jennifer PaglieiJennifer Pagliei

February 12, 2008February 12, 2008

IntroductionIntroduction

Machado-Joseph disease is a movement Machado-Joseph disease is a movement disorder.disorder.

It is also known as spinocerebellar ataxia (SCA) It is also known as spinocerebellar ataxia (SCA) type 3.type 3.

It was first discovered in the 1970s.It was first discovered in the 1970s. It is a rare hereditary ataxia, which is a general It is a rare hereditary ataxia, which is a general

term for lack of muscle control.term for lack of muscle control. MJD is inherited as autosomal dominant.MJD is inherited as autosomal dominant. It is the most common autosomal dominant It is the most common autosomal dominant

spinocerebellar ataxia.spinocerebellar ataxia.

OriginOrigin

The name Machado-Joseph disease comes The name Machado-Joseph disease comes from two families of Portuguese/Azorean from two families of Portuguese/Azorean descent who were among the first families descent who were among the first families described with the unique symptoms of the described with the unique symptoms of the disease.disease.

The name Machado comes from William The name Machado comes from William Machado, a native of an island in the Machado, a native of an island in the Portuguese Azores.Portuguese Azores.

The name Joseph comes from Antone Joseph, a The name Joseph comes from Antone Joseph, a Portuguese sailor with the defective gene who Portuguese sailor with the defective gene who migrated to California in 1845.migrated to California in 1845.

PrevalencePrevalence

The prevalence of the disease is highest The prevalence of the disease is highest among people of Portuguese/Azorean among people of Portuguese/Azorean descent.descent.

The prevalence of MJD is around 1 in The prevalence of MJD is around 1 in 4,000 among immigrants of Portuguese 4,000 among immigrants of Portuguese ancestry in the US.ancestry in the US.

The highest prevalence in the world, The highest prevalence in the world, around 1 in 140, occurs on the small around 1 in 140, occurs on the small Azorean island of Flores.Azorean island of Flores.

PrevalencePrevalence

Recently, researchers have identified MJD Recently, researchers have identified MJD in several family groups not of obvious in several family groups not of obvious Portuguese descent, including:Portuguese descent, including: An African-American family from North An African-American family from North

CarolinaCarolina An Italian-American familyAn Italian-American family Several Japanese familiesSeveral Japanese families

Genetic InheritanceGenetic Inheritance

MJD belongs to a class of genetic disorders called triplet MJD belongs to a class of genetic disorders called triplet repeat diseases.repeat diseases.

The MJD/SCA3 gene is located on the long arm of The MJD/SCA3 gene is located on the long arm of chromosome 14q32.chromosome 14q32.

The gene produces a mutated protein called ataxin-3.The gene produces a mutated protein called ataxin-3. The mutant gene has an increased number of “CAG” The mutant gene has an increased number of “CAG”

repeats, which can range from 40 to more than 200.repeats, which can range from 40 to more than 200. The result in an unstable, expanded, disease-casing The result in an unstable, expanded, disease-casing

allele.allele. This is in contrast to the 6 to 34 repeats in the wild-type This is in contrast to the 6 to 34 repeats in the wild-type

allele.allele.

Genetic InheritanceGenetic Inheritance

The wild-type protein is located predominantly in the The wild-type protein is located predominantly in the cytoplasm of cells.cytoplasm of cells.

In contrast, the mutant ataxin-3 protein is localized within In contrast, the mutant ataxin-3 protein is localized within the nucleus of neuronal cells.the nucleus of neuronal cells.

The mutant protein accumulates in affected cells and The mutant protein accumulates in affected cells and forms intra-nuclear inclusion bodies, which are insoluble forms intra-nuclear inclusion bodies, which are insoluble spheres located in the nucleus of the cell.spheres located in the nucleus of the cell.

The spheres interfere with the normal operation of the The spheres interfere with the normal operation of the nucleus and cause the cell to degenerate and die.nucleus and cause the cell to degenerate and die.

The cell degeneration and death occurs in the hindbrain, The cell degeneration and death occurs in the hindbrain, which includes the cerebellum, brainstem, and upper which includes the cerebellum, brainstem, and upper spinal cord, thus leading to deficits in movement. spinal cord, thus leading to deficits in movement.

Genetic InheritanceGenetic Inheritance A trait of MJD and other triplet repeat diseases is A trait of MJD and other triplet repeat diseases is

anticipation, in which the children of affected parents:anticipation, in which the children of affected parents: Develop symptoms of the disease much earlier in lifeDevelop symptoms of the disease much earlier in life Have a faster progression of the diseaseHave a faster progression of the disease Experience more severe symptomsExperience more severe symptoms

This is due to the tendency of the triplet repeat mutation This is due to the tendency of the triplet repeat mutation to expand with the passing of genetic material from to expand with the passing of genetic material from parent to offspring.parent to offspring.

Thus, a longer expansion is associated with an earlier Thus, a longer expansion is associated with an earlier age of onset and a more severe form of the disease.age of onset and a more severe form of the disease.

Nevertheless, it is not possible to predict the exact Nevertheless, it is not possible to predict the exact course of the disease for an individual based solely on course of the disease for an individual based solely on the repeat length.the repeat length.

SymptomsSymptoms

Symptoms can begin any time between Symptoms can begin any time between early adolescence and about 70 years of early adolescence and about 70 years of age.age.

The severity of symptoms is related to the The severity of symptoms is related to the age of onset.age of onset.

Earlier onset is associated with a more Earlier onset is associated with a more severe form of the disease.severe form of the disease.

It is a progressive disease, therefore It is a progressive disease, therefore symptoms get worse with time.symptoms get worse with time.

SymptomsSymptoms MJD is characterized by many symptoms, among these MJD is characterized by many symptoms, among these

are:are: ClumsinessClumsiness Arm and leg weaknessArm and leg weakness Spasticity - continuous, uncontrollable muscle contractions.Spasticity - continuous, uncontrollable muscle contractions. A staggering, lurching gait, which can be mistaken for A staggering, lurching gait, which can be mistaken for

drunkennessdrunkenness Frequent urinationFrequent urination Face or tongue twitchingFace or tongue twitching Saccades – quick, simultaneous movements of both eyes in the Saccades – quick, simultaneous movements of both eyes in the

same directionsame direction Lid retraction that gives the impression of a persistent stareLid retraction that gives the impression of a persistent stare Peripheral neuropathy Peripheral neuropathy Diffuse joint painDiffuse joint pain Low back painLow back pain

SymptomsSymptoms Other common symptoms include:Other common symptoms include:

Dystonia - sustained muscle contractions that cause: Dystonia - sustained muscle contractions that cause: • Twisting of the body and limbsTwisting of the body and limbs• Repetitive movements Repetitive movements • Abnormal posturesAbnormal postures• RigidityRigidity

Some patients also experience Parkinson’s like Some patients also experience Parkinson’s like symptoms, including:symptoms, including: Slow movementSlow movement Trunk and limb rigidity or stiffnessTrunk and limb rigidity or stiffness Hand tremorHand tremor Impaired balance and coordinationImpaired balance and coordination

SymptomsSymptoms

Signs of brainstem dysfuncion:Signs of brainstem dysfuncion: Dysarthria due to spastic weakness in the throat Dysarthria due to spastic weakness in the throat

muscles.muscles. Difficulty swallowingDifficulty swallowing Poor coughPoor cough Tongue fasciculationsTongue fasciculations

Signs of upper and lower motor neuron Signs of upper and lower motor neuron neuropathy:neuropathy: Tone ranging from hypotonia to rigidityTone ranging from hypotonia to rigidity Reflexes ranging from absent to exaggeratedReflexes ranging from absent to exaggerated An extensor plantar reflexAn extensor plantar reflex

SymptomsSymptoms

Vision problems:Vision problems: Bulging eyesBulging eyes Double vision (diplopia)Double vision (diplopia) Blurred visionBlurred vision Loss of ability to distinguish color and/or Loss of ability to distinguish color and/or

contrastcontrast Involuntary eye movementsInvoluntary eye movements Supranuclear opthalmoplegia – the inability to Supranuclear opthalmoplegia – the inability to

voluntarily move the eyes in all directionsvoluntarily move the eyes in all directions

SymptomsSymptoms

Cognitive impairments: Cognitive impairments: Verbal and visual memory deficitsVerbal and visual memory deficits Impaired verbal fluencyImpaired verbal fluency Visuospatial and constructional dysfunctionVisuospatial and constructional dysfunction

Autonomic dysfunction: Autonomic dysfunction: Cold intoleranceCold intolerance NocturiaNocturia Orthostatic dizzinessOrthostatic dizziness

Types of MJDTypes of MJD

MJD has been subclassified into 3 types, MJD has been subclassified into 3 types, which are distinguished by the age of which are distinguished by the age of onset and range of symptoms.onset and range of symptoms.

However, many patients have clinical However, many patients have clinical features of the disease that classify them features of the disease that classify them into more than one type.into more than one type.

Thus, the classification system is not Thus, the classification system is not always clinically useful, and is becoming always clinically useful, and is becoming less frequently used.less frequently used.


Type I:Type I: Typical age of onset between 10 and 30 Typical age of onset between 10 and 30

years.years. Progresses rapidly. Progresses rapidly. Characterized by severe dystonia and rigidity.Characterized by severe dystonia and rigidity.


Type II:Type II: Begins between 20 and 50 years of age.Begins between 20 and 50 years of age. Has an intermediate rate of progression.Has an intermediate rate of progression. Common symptoms include:Common symptoms include:

• Spasticity Spasticity • Spastic gait.Spastic gait.• Exaggerated reflex responses.Exaggerated reflex responses.

Types of MJDTypes of MJD Type III:Type III:

Onset between 40 and 70 years of age.Onset between 40 and 70 years of age. Has a relatively slow rate of progression.Has a relatively slow rate of progression. Is often characterized by:Is often characterized by:

• Muscle twitchingMuscle twitching• Muscle atrophy in the arms and legsMuscle atrophy in the arms and legs• Uncoordinated gait that may cause stumbling or fallingUncoordinated gait that may cause stumbling or falling• Slurred speechSlurred speech• Unpleasant sensations:Unpleasant sensations:

Numbness Numbness Tingling Tingling CrampsCramps Pain in the hands, feet, and limbsPain in the hands, feet, and limbs

DiagnosisDiagnosis The diagnosis of MJD is made by recognizing The diagnosis of MJD is made by recognizing

and identifying the typical symptoms of the and identifying the typical symptoms of the disease.disease.

It is also based upon a detailed family history of It is also based upon a detailed family history of the patient, including:the patient, including: Family members who currently show symptoms of the Family members who currently show symptoms of the

disease.disease. Deceased family members who showed symptoms of Deceased family members who showed symptoms of

the disease.the disease. The specific symptoms the relatives have or had.The specific symptoms the relatives have or had. The age of onset of symptoms in family members.The age of onset of symptoms in family members. The progression and severity of their symptoms.The progression and severity of their symptoms.

Genetic TestingGenetic Testing

In patients with a positive FH, genetic testing is In patients with a positive FH, genetic testing is the most efficient and definitive way to make the the most efficient and definitive way to make the diagnosis.diagnosis.

Legal and ethical considerations, such as loss of Legal and ethical considerations, such as loss of health insurance and employment health insurance and employment discrimination, may discourage some individuals discrimination, may discourage some individuals with symptoms from getting tested.with symptoms from getting tested.

For the same reasons, many physicians For the same reasons, many physicians recommend against genetic testing for recommend against genetic testing for individuals with a family history of the disease individuals with a family history of the disease but who do not show any symptoms.but who do not show any symptoms.

DiagnosisDiagnosis

If genetic testing is not revealing and/or a If genetic testing is not revealing and/or a question exists about a co-existing disease question exists about a co-existing disease process, additional studies are warranted.process, additional studies are warranted.

Neuroimaging with MRI or CT scan often reveals Neuroimaging with MRI or CT scan often reveals cerebellar atrophy. cerebellar atrophy.

It is also important to rule out other causes of It is also important to rule out other causes of ataxia, including:ataxia, including: Space occupying lesionsSpace occupying lesions Demyelination Demyelination Vascular eventsVascular events

TreatmentTreatment

MJD, like all other spinocerebellar ataxias, is incurable.MJD, like all other spinocerebellar ataxias, is incurable. Treatments do exist, however, for some symptoms of the Treatments do exist, however, for some symptoms of the

disease.disease. Levodopa therapy can be helpful for patients with Levodopa therapy can be helpful for patients with

parkinsonian features.parkinsonian features. Antispasmodic drugs, such as baclofen, can help reduce Antispasmodic drugs, such as baclofen, can help reduce

spasticity.spasticity. Botulinum toxin:Botulinum toxin:

Can be used to treat severe spasticity as well as some Can be used to treat severe spasticity as well as some symptoms of dystonia.symptoms of dystonia.

Should be used as a last resort due to the possibility of side Should be used as a last resort due to the possibility of side effects, such as dysphagia.effects, such as dysphagia.

TreatmentTreatment

Speech therapy can aide in the treatment of dysarthria Speech therapy can aide in the treatment of dysarthria and dysphagia.and dysphagia.

Prism glasses can reduce blurry vision or double vision.Prism glasses can reduce blurry vision or double vision. Eye surgery can be beneficial, but only in the short-term, Eye surgery can be beneficial, but only in the short-term,

due to the progressive degeneration of eye muscles.due to the progressive degeneration of eye muscles. Physiotherapy can help patients cope with disability Physiotherapy can help patients cope with disability

associated with gait problems.associated with gait problems. Physical aids, such as walkers and wheelchairs, can be Physical aids, such as walkers and wheelchairs, can be

used to assist patients with everyday activities.used to assist patients with everyday activities. Medication can be used to treat other problems, such as Medication can be used to treat other problems, such as

sleep disturbances, cramps, and urinary dysfunction.sleep disturbances, cramps, and urinary dysfunction.

PrognosisPrognosis

Early onset and large CAG length predict Early onset and large CAG length predict shorter overall survival times.shorter overall survival times.

Life expectancy ranges from the mid-Life expectancy ranges from the mid-thirties for those with severe disease to a thirties for those with severe disease to a normal life expectancy for those with mild normal life expectancy for those with mild forms of the disease.forms of the disease.

For those who die early from the disease, For those who die early from the disease, a frequent cause of death is aspiration a frequent cause of death is aspiration pneumonia.pneumonia.

ResearchResearch The National Institute of Neurological Disorders and Stroke (NINDS) The National Institute of Neurological Disorders and Stroke (NINDS)

conducts and supports research on all diseases of the nervous conducts and supports research on all diseases of the nervous system, including MJD.system, including MJD.

Their goals are to learn how to better treat, cure, and prevent these Their goals are to learn how to better treat, cure, and prevent these diseases.diseases.

Ongoing research includes efforts to better understand the genetic, Ongoing research includes efforts to better understand the genetic, molecular, and cellular mechanisms that underlie triplet repeat molecular, and cellular mechanisms that underlie triplet repeat diseases, including their characteristics of inheritance and diseases, including their characteristics of inheritance and transmission.transmission.

Other research areas include:Other research areas include: The development of novel therapies to treat the symptoms of MJD. The development of novel therapies to treat the symptoms of MJD. Efforts to identify new diagnostic markers of the disease and to improve Efforts to identify new diagnostic markers of the disease and to improve

current diagnostic procedures.current diagnostic procedures. Population studies to identify affected families.Population studies to identify affected families.

ReferencesReferences Franca MC, et al. Chronic Pain in Machado-Joseph Disease. A Franca MC, et al. Chronic Pain in Machado-Joseph Disease. A

Frequent and Disabling Symptom. Arch Neurol. Vol 64 (No. 12), Frequent and Disabling Symptom. Arch Neurol. Vol 64 (No. 12), Dec 2007.Dec 2007.

Horimoto, Y, et al. Brainstem in Machado-Joseph disease: atrophy Horimoto, Y, et al. Brainstem in Machado-Joseph disease: atrophy or small size? European Journal of Neurology 2008, 15: 102-105.or small size? European Journal of Neurology 2008, 15: 102-105.

Kieling C, Prestes PR, Saraiva-Pereira ML, Jardim LB. Survival Kieling C, Prestes PR, Saraiva-Pereira ML, Jardim LB. Survival estimates for patients with Machado-Joseph disease (SCA 3). Clin estimates for patients with Machado-Joseph disease (SCA 3). Clin Genet 2007: 72: 543-545.Genet 2007: 72: 543-545.

Machado Joseph Disease Machado Joseph Disease http://www.mazornet.com/genetics/machado.htmhttp://www.mazornet.com/genetics/machado.htm

National Institute of Neurological Disorders and Stroke. Machado-National Institute of Neurological Disorders and Stroke. Machado-Joseph Disease Fact Sheet.Joseph Disease Fact Sheet.

Opal P; Zoghbi HY. The spinocerebellar ataxias. UpToDate. 2007.Opal P; Zoghbi HY. The spinocerebellar ataxias. UpToDate. 2007.

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