Ataxia

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Ataxia

• Prepared byManar Shawabkeh.M.D
• Supervisor Afaf Areene.M.D

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Outline

• Approach to the child with acute ataxia.
• Acute cerebellar ataxia .
• Friedreich ataxia .
• Ataxia-telangiectasia

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• A previously healthy 22-month-old girl presented
  to the pediatric emergency department with
  complaints of worsening gait and progressive
  jerky movements of the upper and lower
  extremities for the past 10 days.
• The patient developed cough and nasal congestion
  two weeks prior to this admission and was seen by
  her pediatrician.

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• She was diagnosed with bilateral otitis media and
  placed on 10 days of amoxicillin.
• There was no history of fever, vomiting,
  diarrhea or generalized rash.
• Three days later, the upper respiratory infection
  symptoms resolved but the mother noticed feet
  shaking and later shaking of her arms and strange
  movements of the eyes.
• She was seen at another emergency department,
  requiring admission.
• A computed tomography scan of the brain was
  negative.

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• With subsidence of symptoms and tests done on
  admission including complete blood count,
  electrolytes, liver enzymes and spinal tap being
  negative, the patient was discharged from the
  hospital after 96 hours with instructions to
  complete her course of antibiotics.
• The gait worsened during the next 24 hours and
  the parents brought her to the hospital

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• In the ED, the patient was afebrile and had no
  nausea, vomiting, diarrhea or skin rash. She was
  unable to walk, stand without support or stand up
  from a sitting position. Her speech was
  dysarthric. She was extremely irritable and
  consolable only by her parents.
• The parents denied any recent travel history,
  head injury, ingestion of canned food or honey or
  lead exposure risks.

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• Developmental milestones were appropriate for her
  age. She had completed her 10-day course of
  amoxicillin and was not on any chronic
  medications.
• The girls history was up-to-date with her
  immunizations and she had no history of
  vaccination, nor any family history of
  consanguinity, epilepsy, convulsion disorder or
  any joint diseases.

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On examination

• the patient was alert, irritable and crying yet
  consolable by her mother.
• She had persistent high blood pressures.
• she was noted to have rapid, involuntary,
  multivectorial (horizontal and vertical), and
  unpredictable, conjugate fast eye movements
  intermixed with small amplitude movements,
  appearing as tiny deviations from primary
  position.

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• Her pupils were round and equally reactive to
  light. No photophobia was noted. The patient had
  an upper lip hemangioma since birth, no evidence
  of cafe-au-lait macules or ash leaf spots on
  skin.
• Her heart and lung examinations were normal.
• Neurological exam was limited in content of
  patients irritability. She had good muscle tone,
  hyper reflexic ankle jerks and negative Babinski
  reflex.

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• Following admission she had numerous episodes of
  gait unsteadiness and rolling of her eyes each
  lasted for only a few seconds coupled with
  episodes of hypotonicity and hyporeflexia
  followed by complete recovery.
• Dysmetria was clinically evident when she tried
  to reach out for toys and she was unable to sit
  or stand unsupported during these episodes.
  Between the episodes there was complete
  resolution of symptoms with normal physical
  examination and vital signs.

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• Toxicology screen was negative and CBC, basic
  metabolic panel, liver function tests and
  creatinine kinase were all within normal limits
  for age. Urine was negative for amino acids.
• Urine culture for cytomegalovirus was negative
• Lumbar tap performed at admission had normal cell
  count, glucose and protein. Culture for HSV type
  1 and 2 Ig G, CMV IgG, Lyme, and myelin basic
  protein were conducted. Serum was negative result
  for monospot, rapid plasma reagin and varicella
  zoster virus.

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• Immunoglobulins G and M for VZV, HSV 1 and 2 and
  mycoplasma were within normal limits.
• Lyme titer was positive on initial serology but
  with negative on Western blot confirmatory test.
• C-reactive protein, erythrocyte sedimentation
  rate, were within normal limits.

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• CT scan of the brain was negative and magnetic
  resonance imaging of the brain with contrast was
  also negative with no meningeal enhancement.
• Further studies were ordered to rule out
  neuroblastoma including 24 hour urine for
  vanillylmandelic acid, which was negative. MRI of
  the cervical spine and chest, and CT scans of the
  thorax, abdomen and pelvis were normal. Repeat
  lumbar tap was negative as well.

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• The patient remained afebrile and showed no
  meningeal manifestations throughout the
  hospitalization.
• Only supportive care and close monitoring were
  provided during her hospitalization and her
  symptoms improved on the 10th day of admission.

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• The patient was discharged on the 15th day of
  admission to be followed by her pediatrician..
  What do you think is the diagnosis?

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Definition

• Ataxia disturbance in the smooth, accurate
  coordination of movements.
• It is most commonly manifested as an unsteady
  gait.
• Ataxia is usually the result of cerebellar
  dysfunction.
• Acute ataxia is an uncommon presenting complaint
  in children.
• the majority of children have a benign,
  self-limited process .

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• Ataxia maybe acute or chronic.
• Conditions that cause acute ataxia include
• acute infections.
• post-infectious inflammatory conditions.
• Toxins.
• Tumors.
• Trauma
• 80 of children with acute ataxia acute
  cerebellar ataxia, a toxic ingestion, or
  Guillain-Barré syndrome

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• Recurrent ataxia
• migraine syndromes
• Seizures
• inborn errors of metabolism.
• chronic or progressive ataxia
• congenital anomalies
• degenerative diseases
• hereditary ataxias.

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Life-threatening conditions 

•  Life-threatening causes of acute ataxia in
  children are fortunately uncommon.
• For those conditions that create a mass effect,
  signs and symptoms of increased intracranial
  pressure are typically evident.
• Etiologies include tumors, trauma, stroke, and
  infection.

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Tumors 

• Of all childhood brain tumors, 60 arise in the
  brainstem or cerebellum.
• Hx P/E
• Acute decompensation can occur as the result of
  obstructive hydrocephalus, hemorrhage into the
  lesion, or edema.
• opsoclonus-myoclonus.

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Intracranial hemorrhage 

•  Hemorrhage into the cerebellum or posterior
  fossa as the result of trauma or a vascular
  malformation can cause ataxia with dramatic,
  rapid deterioration and life-threatening
  elevation of intracranial pressure

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Stroke 

•  Acute ataxia may develop as the result of
  vertebral or basilar artery disease.
• Conditions that cause cerebrovascular disease
  are rare in children and include sickle cell
  disease, hypercoagulable states, and
  homocystinuria

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Infection 

•  Life-threatening infectious processes that cause
  acute ataxia generally produce other symptoms as
  well.
• Rarely, ataxia may be an early symptom of
  meningitis
• Patients with inflammatory post-infectious
  conditions, such as (ADEM), may also develop
  ataxia.

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Common conditions

•  Acute cerebellar ataxia
• is a self limited syndrome that is frequently
  postinfectious
• typically seen in children between two and five
  years of age.
• The diagnosis can only be made after exclusion of
  other more serious illnesses

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• Guillain-Barré syndrome (GBS)
• result from a post-infectious immune-mediated
  process.
• GBS predominantly affects motor nerves, sensory
  ataxia
• The Miller-Fisher syndrome is a form of GBS
  classically characterized by the triad of ataxia,
  areflexia, and ophthalmoplegia

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• Labyrinthitis
•  Inflammation of the vestibular apparatus
• Symptoms include hearing loss, vomiting, and
  intense vertigo exacerbated by head movements
• Labyrinthitis may be difficult to distinguish
  from acute cerebellar ataxia in a toddler

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• Toxic exposure
• 30 percent of cases of acute childhood ataxia .
• Associated symptoms.
• anticonvulsants ,lead, carbon monoxide,
  inhalants, alcohol, benzodiazepines, and other
  drugs of abuse.
• urine toxicology screens, specific blood tests.

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• Migraine syndromes
•  Acute ataxia is a clinical feature of several
  migraine syndromes.
• Associated symptoms such as headache and
  vomiting, episodic course.

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Other conditions 

• Hypoglycemia
• Seizure disorder
• Conversion disorder
• Inborn errors of metabolism
• Congenital anomalies
• Degenerative/genetic conditions

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EVALUATION

• History
• refusal to walk or with a wide-based, "drunken"
  gait.
• Onset of symptoms
• Associated symptoms
• Otalgia, vertigo, and vomiting
• An older child with inner ear disease may
  complain of dizziness. Most children also have
  nystagmus.
• Recurrent night-time or early-morning headaches
  with or without vomiting
• Personality and behavioral changes.
• Abnormal mental status

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• Access to medications.
• A history of head trauma ,neck trauma
• Patients with a recent infection or vaccination
• Previous similar episodes of acute ataxia.
• Children with family members with ataxia

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Physical examination 

• A systematic, yet flexible, approach to the
  physical examination is necessary to localize the
  source of the child's symptoms.
• careful observation.
• Abnormal vital signs must be recognized
  immediately.
• Bulging of the anterior fontanel

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• An ipsilateral head tilt
• fundoscopic examination
• Nystagmus
• Opsoclonus.
• Otitis media and hearing loss in association with
  vomiting and intense vertigo
• Meningismus with fever and a toxic appearance.
• healing rash or viral exanthem

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Neurologic examination 

• The neurologic examination includes specific
  examination techniques as well as observations
  made while taking the history and throughout the
  general physical examination
• Mental status, Lethargy.
• Cranial nerves .
• Motor examination "paretic" ataxia.
• Sensory examination .
• Cerebellar examination .

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Cerebellar signs

• Gait typically wide-based, unsteady, lurching,
  or staggering.
• speech fluctuations in clarity, rhythm, tone,
  and volume.
• coordination of voluntary movements over- or
  under-shooting (best seen on finger-nose testing)
  and difficulty with rapid alternating movements
  (dysdiadochokinesia)
• Hypotonia and tremor may also occur.
• Patients may have difficulty maintaining truncal
  position (titubation).

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Laboratory

• Toxicologic screen - A urine screen for drugs of
  abuse or blood for specific drug levels (as
  suggested by the history) may be the most useful
  diagnostic test for children with acute ataxia.
• Blood glucose.
• Metabolic evaluation - liver function tests,
  blood pH, CBC, quantitative amino acid
  determinations of blood and urine, serum lactate,
  pyruvate and ammonia levels, and urine organic
  acids.

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• Cerebrospinal fluid (CSF) examination - CSF
  should be obtained whenever there is concern for
  CNS infection, such as meningitis or
  encephalitis.
• Moderate CSF protein elevation can occur in acute
  cerebellar ataxia, ADEM, and multiple
  sclerosis,GBS
• Neuroimaging should be obtained before a lumbar
  puncture is performed when there is concern for
  increased intracranial pressure.

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ALGORITHMIC APPROACH
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Acute cerebellar ataxia
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• has been referred to in the literature as acute
  cerebellitis and cerebellar encephalitis
• typically preceded by an acute febrile illness
  ,Varicella is involved in over one-fourth of
  cases
• following vaccination for varicella, hepatitis B
  and rabies, without evidence of systemic
  infection .

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• The pathogenesis of acute cerebellar ataxia has
  not been fully established, but appears to
  include autoimmune mechanisms
• occurs in children under six years of age

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• characterized by the acute onset of ataxia four
  days to three weeks after the inciting illness
• Gait disturbance is the primary symptom, but the
  cerebellar dysfunction may be limited to fine
  motor control problems or tremor .
• Associated symptoms may include nystagmus ,
  slurred or garbled speech, vomiting, dysarthria,
  or, in older children, headache
• Fever, meningismus, and seizures are absent

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Differential diagnosis

• Toxic
• Infectious
• Structural
• Metabolic
• neurodegenerative

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EVALUATION

• exclusion of other potentially more serious
  illnesses.
• History Physical examination  .
• Laboratory evaluation 
• Imaging

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PROGNOSIS  

• typically resolves without sequelae within two to
  three weeks of presentation.
• If worsening of symptoms or relapse occurs, the
  diagnosis should be reconsidered and other causes
  of ataxia carefully excluded.

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• There are scattered case reports of treatment of
  refractory cases with glucocorticoid or
  intravenous immunoglobulin.
• 10 of children with acute cerebellar ataxia
  have some long-term neurologic sequelae
• Older age at diagnosis and associated
  Epstein-Barr virus infection appear to confer a
  worse prognosis

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Friedreich ataxia
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• autosomal recessive degenerative disorder
• It is the most common hereditary ataxia,
• It primarily affects the central nervous system,
  spinal cord, and peripheral nerves, as well as
  the heart and pancreas.

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• Most cases are caused by loss of function
  mutations in the frataxin gene (FXN gene),
  located on chromosome 9q13
• Frataxin is a mitochondrial protein whose
  precise function is unknown

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• It is expressed at particularly high levels in
  the tissues involved in FA, such as the brain,
  heart, and pancreas and appears to play a role in
  antioxidation
• Compared to healthy controls, patients with FA
  have impairment of enzymatic antioxidants

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• The neuropathologic changes in FA include
  degeneration of the posterior columns and the
  spinocerebellar tracts of the spinal cord and
  loss of the larger sensory cells of the dorsal
  root ganglia

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CLINICAL MANIFESTATIONS 

• The major clinical manifestations of FA are
  neurologic dysfunction, cardiomyopathy, and
  diabetes mellitus.
• Because the disease is progressive, the full
  clinical picture may not be seen until several
  years after presentation.
• The manifestations vary in part with the number
  of GAA expansions.

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Neurologic disease 

• Progressive ataxia often is present by five
  years of age. The mean time to use of a
  wheelchair ranges from 11 to 25 yrs
• Cerebellar dysarthria is a common feature.
• Optic atrophy and swallowing dysfunction.
• Pyramidal tract disease.
• Early loss of position and vibration sense.
• In almost all patients, DTR eventually are lost .

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• Patients with late-onset (after age 25) FA are
  more likely to have retained reflexes, lower limb
  spasticity, and absence of cardiomyopathy than
  patients who have earlier onset FA
• Involvement of the autonomic nervous system.
• Distal muscle atrophy ,results in pes cavus,
  hammer toes, and atrophy of the intrinsic small
  muscles of the hand. Kyphoscoliosis is common.

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DIAGNOSIS

• clinical findings , genetic testing.
• Genetic testing should be performed in all
  patients with autosomal recessive ataxia,
  evidence of a sensory and motor axonal neuropathy
  on electrophysiologic testing, and
  electrocardiographic abnormalities indicative of
  cardiac involvement.
• MRI typically reveals spinal cord and, in some
  cases, cerebellar atrophy

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PROGNOSIS

• severity of disease and rate of progression are
  variable.
• Most patients die between the ages of 30 and 40
  , but those with late onset disease clearly do
  better .
• The major causes of death are complications
  related to the cardiomyopathy or bulbar
  dysfunction.

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Treatment

• No specific therapy corrects the defect in FA.
• The administration of antioxidants such as
  idebenone (a free radical scavenger), or vit.E
  can decrease markers of oxidative injury , but
  whether such a change is clinically important
  remains to be proven.

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Ataxia-telangiectasia
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• Hereditary ataxia has a variety of causes.
• One cause is an autosomal recessive disorder
  associated with defective DNA repair.
• Patients with AT develop progressive cerebellar
  ataxia, abnormal eye movement, oculocutaneous
  telangiectasias, and immune deficiency.

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CLINICAL MANIFESTATIONS 

• Neurologic abnormalities 
• Ataxia is the earliest clinical manifestation of
  AT .
• Most children appear healthy for the first year
  of life, begin walking at a normal age, but are
  slow to develop fluidity of gait.
• They also have difficulty standing still without
  wobbling. narrow base, and young children often
  prefer to walk quickly or run.
• However, they fall less frequently than one might
  expect.
• Gross motor function remains abnormal, but
  relatively stable until school age, and cerebral
  palsy is often misdiagnosed

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• Thereafter, gross and fine motor skills
  deteriorate, leading to reconsideration of the
  diagnosis of cerebral palsy rather than AT.
• At about the same time, children develop
  dysarthria and complex disorders of movement.
• By the second decade of life, most patients must
  rely on wheelchairs for mobility outside the home.

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Eye movements

• Eye movements are often normal in preschoolers,
  but children later develop abnormalities of both
  voluntary and involuntary saccades and have
  difficulty moving their eyes and heads in smooth,
  coordinated pursuit of a moving target .
• delay in initiating eye movement, and the eyes
  move in a series of small jumps rather than in a
  single smooth motion.

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• The most obvious early manifestation is
  oculomotor apraxia.
• Most children with AT never attain normal speech
  due to problems with articulation .

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Oculocutaneous telangiectasias

• bulbar conjunctivae and on exposed areas of the
  skin, typically the pinnae, nose, face, and neck.
  
• In most cases, they first appear when the child
  reaches three to five years of age.
• It is perhaps unfortunate that this disease is
  named ataxia-telangiectasia

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Immune deficiency

• Immune deficiency, affecting both cellular and
  humoral immunity,
• The defect is quite variable but often manifests
  as recurrent sinopulmonary infections.
• Progressive pulmonary disease caused by chronic
  or recurrent infections is a major cause of
  morbidity and mortality in patients with AT

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Malignancy

• Beyond age 10 years, approximately 20 of
  patients will develop malignancy .
• 85 are lymphomas and acute leukemias, but a
  predisposition to other cancers may also exist.

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Laboratory abnormalities 

• The most consistent laboratory abnormality is an
  elevation of serum alpha-fetoprotein level in
  children over the age of eight month.
• humoral and cell-mediated immunity
• there is a striking lack of opportunistic
  infections and the risk for infection has never
  been closely correlated with any single or group
  of laboratory abnormalities.
• Immunoglobulin deficiency
• Lymphopenia with the most prominent reduction in
  T cells

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DIAGNOSIS

• The diagnosis is established by the presence of
  characteristic clinical findings (particularly
  progressive cerebellar ataxia) and identification
  of disabling mutations on both alleles for the
  gene AT mutated (ATM).
• It is supported by serum IgA at least 2 SD below
  normal for age.

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•  In the appropriate clinical setting, the finding
  of a serum AFP at least 2 SD above normal for age
  is diagnostic of the disorder, with a sensitivity
  of 95.
• telangiectasia usually appears after age five
  years and that not all AT patients have elevated
  levels of AFP.
• AT can be difficult to distinguish clinically
  from other chronic ataxic syndromes.

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• If ataxia develops early, it may be misdiagnosed
  as an ataxic variety of cerebral palsy,
  particularly because mental retardation is not a
  feature.
• When the onset is delayed, AT most often is
  mistaken for Friedreich ataxia

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PROGNOSIS AND MANAGEMENT 

• difficult disease to treat and has an especially
  poor prognosis because of its multisystem
  involvement.
• No specific treatment exists for the ataxic
  syndrome or the progressive cerebellar
  neurodegeneration.
• Many patients succumb to progressive pulmonary
  disease caused by repeated infection or to
  cancer.
• the median age at death is approximately 25
  years

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