N. Friedreich Ataxia
By Mohammad Zubair
Ataxia = A (lack of) taxia (coordination)
What is ataxia?
What is Friedreich's ataxia ?
an autosomal recessive inherited disease that causes progressive damage to the nervous system, resulting in symptoms ranging from gait disturbance to speech problems; it can also lead to heart disease and diabetes.
First described by
German physician Nikolaus
Friedreich in the 1860s
Incidence 1:50,000
Onset before age 20 – 25 y
Genetics
FXN gene contains amplified intronic GAA
repeats.
The FXN gene encodes the protein frataxin
Normal alleles 6-34 repeats
Expanded alleles 67-1700
Location: chromosome 9q13
GAA repeat expansion
Frataxin decreased
mitochondrial iron overload
Mitochondrial dysfunction
oxidative phosphorylatio
n and ATP (impaired function)
protein biosynthesis,
signalling, transcription,
Altered DNA replication/repa
ir,
Frataxin is an iron-binding protein responsible for forming iron–sulphur clusters
The primary site of pathology is spinal cord
and peripheral nerves
Degeneration of nerve tissue in the spinal cord,
in particular sensory neurons essential (through
connections with the cerebellum) for directing
muscle movement of the arms and legs.
The spinal cord becomes thinner and nerve
cells lose some of their myelin sheath
Pathology
Early onset of symptoms at the ages of 5 to 15 year
Late Onset may occur in the 20s or 30s. Symptoms include any combination, of the following:
Muscle weakness in the arms and legs(stumbling gait and frequent falling)
Loss of coordination Vision impairment Hearing impairment Slurred speech Curvature of the spine (scoliosis) High plantar arches (pes cavusdeformity of the foot)
Signs and symptoms
Diabetes (about 20% of people with Friedreich's ataxia develop carbohydrate intolerance and 10% develop diabetes mellitus)
Heart disorders (e.g., atrial fibrillation, and resultant tachycardia , hypertrophic cardiomyopathy
• Signs and symptoms cont….
Diagnosis
Clinical
Features
Physical
Examination
Instrumental Invetigations
Genetic Tests
I. Clinical Features ( abnormal walking, pes cavus, scoliosis,non-neurological findings)
II. Physical Examination • Cerebellar: Nystagmus, fast saccadic eye movements, truncal ataxia, dysarthria
• Lower motor neuron lesion: absent deep tendon reflexes.
• Pyramidal: extensor plantar responses, and distal weakness are commonly found.
• Dorsal column: Loss of vibratory and proprioceptive sensation occurs.
• Cardiac involvement occurs in 91% of patients
Diagnosis
III. Instrumental Investigations : 1. Nerve conduction studies show motor
velocities >40 ms-1 in arms and absent sensory action potentials.
2. ECG - there may be ventricular hypertrophy and T-wave inversion.
3. Echocardiography - may show ventricular hypertrophy, septal hypertrophy and hypertrophic cardiomyopathy.
4. MRI scan of the brain and spinal cord - shows characteristic atrophic changes, particularly of the cervical spinal cord
IV. Genetic analysis ( for confirmation of diagnosis, prenatal diagnosis. Carrier testing for relatives of affected patients and their partners is also possible.
• Diagnosis cont…
1. Vitamin E deficiency
2. Metabolic and immune diseases
3. Paraneoplastic disorders
4. Posterior fossa tumors
5. Multiple sclerosis
6. Leukodystrophies
Differential diagnosis
Friedreich's ataxia is a disease with multisystem involvement
So a multidisciplinary approach is needed This should include a NeurologistGeneticist and Genetic counsellorPhysiotherapistsSpeech and Language therapistsOther Specialities ( Cardiology, Orthopaedics and Diabetes Specialists)
Management
Management
Specific drug treatment
Supportive treatment
1. Idebenone short chain quinine analogue Act as potent antioxidant and electron carrier Benefit neurological function2. deferiprone (an iron chelator)3. erythropoietin, pioglitazone4. peroxisome proliferator-activated receptors
Physiotherapy and mobility aids(wheel chair.)Speech and language therapy.Treatment of cardiac failure and/or arrhythmiasOrthopaedic surgery (scoliosis, pes cavus)Diabetes (if present require insulin)Antidepressants for depression (SSRIs)
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