2 12 08 20Machado Joseph 20Disease 20Pagliei

							Machado-Joseph
   Disease
   Jennifer Pagliei
  February 12, 2008
                  Introduction
   Machado-Joseph disease is a movement
    disorder.
   It is also known as spinocerebellar ataxia (SCA)
    type 3.
   It was first discovered in the 1970s.
   It is a rare hereditary ataxia, which is a general
    term for lack of muscle control.
   MJD is inherited as autosomal dominant.
   It is the most common autosomal dominant
    spinocerebellar ataxia.
                   Origin
 The name Machado-Joseph disease comes
  from two families of Portuguese/Azorean
  descent who were among the first families
  described with the unique symptoms of the
  disease.
 The name Machado comes from William
  Machado, a native of an island in the
  Portuguese Azores.
 The name Joseph comes from Antone Joseph, a
  Portuguese sailor with the defective gene who
  migrated to California in 1845.
              Prevalence
 The prevalence of the disease is highest
  among people of Portuguese/Azorean
  descent.
 The prevalence of MJD is around 1 in
  4,000 among immigrants of Portuguese
  ancestry in the US.
 The highest prevalence in the world,
  around 1 in 140, occurs on the small
  Azorean island of Flores.
                 Prevalence
 Recently, researchers have identified MJD
 in several family groups not of obvious
 Portuguese descent, including:
     An African-American family from North
      Carolina
     An Italian-American family
     Several Japanese families
             Genetic Inheritance
   MJD belongs to a class of genetic disorders called triplet
    repeat diseases.
   The MJD/SCA3 gene is located on the long arm of
    chromosome 14q32.
   The gene produces a mutated protein called ataxin-3.
   The mutant gene has an increased number of “CAG”
    repeats, which can range from 40 to more than 200.
   The result in an unstable, expanded, disease-casing
    allele.
   This is in contrast to the 6 to 34 repeats in the wild-type
    allele.
             Genetic Inheritance
   The wild-type protein is located predominantly in the
    cytoplasm of cells.
   In contrast, the mutant ataxin-3 protein is localized within
    the nucleus of neuronal cells.
   The mutant protein accumulates in affected cells and
    forms intra-nuclear inclusion bodies, which are insoluble
    spheres located in the nucleus of the cell.
   The spheres interfere with the normal operation of the
    nucleus and cause the cell to degenerate and die.
   The cell degeneration and death occurs in the hindbrain,
    which includes the cerebellum, brainstem, and upper
    spinal cord, thus leading to deficits in movement.
               Genetic Inheritance
   A trait of MJD and other triplet repeat diseases is
    anticipation, in which the children of affected parents:
       Develop symptoms of the disease much earlier in life
       Have a faster progression of the disease
       Experience more severe symptoms
   This is due to the tendency of the triplet repeat mutation
    to expand with the passing of genetic material from
    parent to offspring.
   Thus, a longer expansion is associated with an earlier
    age of onset and a more severe form of the disease.
   Nevertheless, it is not possible to predict the exact
    course of the disease for an individual based solely on
    the repeat length.
               Symptoms
 Symptoms     can begin any time between
  early adolescence and about 70 years of
  age.
 The severity of symptoms is related to the
  age of onset.
 Earlier onset is associated with a more
  severe form of the disease.
 It is a progressive disease, therefore
  symptoms get worse with time.
                        Symptoms
   MJD is characterized by many symptoms, among these
    are:
       Clumsiness
       Arm and leg weakness
       Spasticity - continuous, uncontrollable muscle contractions.
       A staggering, lurching gait, which can be mistaken for
        drunkenness
       Frequent urination
       Face or tongue twitching
       Saccades – quick, simultaneous movements of both eyes in the
        same direction
       Lid retraction that gives the impression of a persistent stare
       Peripheral neuropathy
       Diffuse joint pain
       Low back pain
                          Symptoms
   Other common symptoms include:
       Dystonia - sustained muscle contractions that cause:
         •   Twisting of the body and limbs
         •   Repetitive movements
         •   Abnormal postures
         •   Rigidity
   Some patients also experience Parkinson’s like
    symptoms, including:
       Slow movement
       Trunk and limb rigidity or stiffness
       Hand tremor
       Impaired balance and coordination
                      Symptoms
   Signs of brainstem dysfuncion:
       Dysarthria due to spastic weakness in the throat
        muscles.
       Difficulty swallowing
       Poor cough
       Tongue fasciculations
   Signs of upper and lower motor neuron
    neuropathy:
       Tone ranging from hypotonia to rigidity
       Reflexes ranging from absent to exaggerated
       An extensor plantar reflex
                  Symptoms
 Vision   problems:
     Bulging eyes
     Double vision (diplopia)
     Blurred vision
     Loss of ability to distinguish color and/or
      contrast
     Involuntary eye movements
     Supranuclear opthalmoplegia – the inability to
      voluntarily move the eyes in all directions
                  Symptoms
 Cognitive   impairments:
     Verbal and visual memory deficits
     Impaired verbal fluency
     Visuospatial and constructional dysfunction
 Autonomic     dysfunction:
     Cold intolerance
     Nocturia
     Orthostatic dizziness
             Types of MJD
 MJD   has been subclassified into 3 types,
  which are distinguished by the age of
  onset and range of symptoms.
 However, many patients have clinical
  features of the disease that classify them
  into more than one type.
 Thus, the classification system is not
  always clinically useful, and is becoming
  less frequently used.
               Types of MJD
 Type   I:
     Typical age of onset between 10 and 30
      years.
     Progresses rapidly.
     Characterized by severe dystonia and rigidity.
                Types of MJD
 Type    II:
     Begins between 20 and 50 years of age.
     Has an intermediate rate of progression.
     Common symptoms include:
       • Spasticity
       • Spastic gait.
       • Exaggerated reflex responses.
                          Types of MJD
   Type III:
       Onset between 40 and 70 years of age.
       Has a relatively slow rate of progression.
       Is often characterized by:
         •   Muscle twitching
         •   Muscle atrophy in the arms and legs
         •   Uncoordinated gait that may cause stumbling or falling
         •   Slurred speech
         •   Unpleasant sensations:
                  Numbness
                  Tingling
                  Cramps
                  Pain in the hands, feet, and limbs
                     Diagnosis
 The diagnosis of MJD is made by recognizing
  and identifying the typical symptoms of the
  disease.
 It is also based upon a detailed family history of
  the patient, including:
       Family members who currently show symptoms of the
        disease.
       Deceased family members who showed symptoms of
        the disease.
       The specific symptoms the relatives have or had.
       The age of onset of symptoms in family members.
       The progression and severity of their symptoms.
             Genetic Testing
 In patients with a positive FH, genetic testing is
  the most efficient and definitive way to make the
  diagnosis.
 Legal and ethical considerations, such as loss of
  health insurance and employment
  discrimination, may discourage some individuals
  with symptoms from getting tested.
 For the same reasons, many physicians
  recommend against genetic testing for
  individuals with a family history of the disease
  but who do not show any symptoms.
                      Diagnosis
 If genetic testing is not revealing and/or a
  question exists about a co-existing disease
  process, additional studies are warranted.
 Neuroimaging with MRI or CT scan often reveals
  cerebellar atrophy.
 It is also important to rule out other causes of
  ataxia, including:
       Space occupying lesions
       Demyelination
       Vascular events
                          Treatment
   MJD, like all other spinocerebellar ataxias, is incurable.
   Treatments do exist, however, for some symptoms of the
    disease.
   Levodopa therapy can be helpful for patients with
    parkinsonian features.
   Antispasmodic drugs, such as baclofen, can help reduce
    spasticity.
   Botulinum toxin:
       Can be used to treat severe spasticity as well as some
        symptoms of dystonia.
       Should be used as a last resort due to the possibility of side
        effects, such as dysphagia.
                      Treatment
   Speech therapy can aide in the treatment of dysarthria
    and dysphagia.
   Prism glasses can reduce blurry vision or double vision.
   Eye surgery can be beneficial, but only in the short-term,
    due to the progressive degeneration of eye muscles.
   Physiotherapy can help patients cope with disability
    associated with gait problems.
   Physical aids, such as walkers and wheelchairs, can be
    used to assist patients with everyday activities.
   Medication can be used to treat other problems, such as
    sleep disturbances, cramps, and urinary dysfunction.
                Prognosis
 Early  onset and large CAG length predict
  shorter overall survival times.
 Life expectancy ranges from the mid-
  thirties for those with severe disease to a
  normal life expectancy for those with mild
  forms of the disease.
 For those who die early from the disease,
  a frequent cause of death is aspiration
  pneumonia.
                             Research
   The National Institute of Neurological Disorders and Stroke (NINDS)
    conducts and supports research on all diseases of the nervous
    system, including MJD.
   Their goals are to learn how to better treat, cure, and prevent these
    diseases.
   Ongoing research includes efforts to better understand the genetic,
    molecular, and cellular mechanisms that underlie triplet repeat
    diseases, including their characteristics of inheritance and
    transmission.
   Other research areas include:
        The development of novel therapies to treat the symptoms of MJD.
        Efforts to identify new diagnostic markers of the disease and to improve
         current diagnostic procedures.
        Population studies to identify affected families.
                       References
   Franca MC, et al. Chronic Pain in Machado-Joseph Disease. A
    Frequent and Disabling Symptom. Arch Neurol. Vol 64 (No. 12), Dec
    2007.
   Horimoto, Y, et al. Brainstem in Machado-Joseph disease: atrophy
    or small size? European Journal of Neurology 2008, 15: 102-105.
   Kieling C, Prestes PR, Saraiva-Pereira ML, Jardim LB. Survival
    estimates for patients with Machado-Joseph disease (SCA 3). Clin
    Genet 2007: 72: 543-545.
   Machado Joseph Disease
    http://www.mazornet.com/genetics/machado.htm
   National Institute of Neurological Disorders and Stroke. Machado-
    Joseph Disease Fact Sheet.
   Opal P; Zoghbi HY. The spinocerebellar ataxias. UpToDate. 2007.