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)