Hereditary Ataxias (Friedreich’s) – diagnosis, investigations, and treatment

Hereditary Ataxias are a group of degenerative disorders usually heredo familial but may be congenital or acquired. These usually manifest in young age and are characterized by degeneration of cerebellum, olives and ascending and descending tracts of spinal cord. The main features are unsteady gait; in coordination of limbs and intention tremors.

Classically hereditary ataxias have been classified into:

1. Cerebellar cortical degeneration

2. Olivo ponto cerebellar atrophy

3. Spino cerebellar degeneration (Friedreich’s ataxia)

4. Hereditary spastic paraplegia

5. Sanger Brown and Marie varieties

Attempts have been made to classify ataxias on genetic and an identifiable biochemical abnormality. Specific gene mutations have been identified and abnormalities related to lipids, carbohydrates, aminoacids, immune system and mitochondria have been incriminated.

There is increased urinary laurine excretion, reduced pyruvate kinase and lipoamide dehydrogenase in the platelets and cultured fibroblasts with deficiency of malic acid and abnormal lipid deposition.

Aetiology

It is unknown and as per Harding classification these may be broadly classified into:

1. Early onset ataxia (before age 20 years)

(Autosomal recessive)

(a) Friedreich’s ataxia (FA)

(b) Ramsay Hunt syndrome

(c) Friedreich’s atoxia with retained reflexes (FARR)

2. Late onset ataxias (after 20 years of age) (Autosomal dominant)

(a) Spino cerebellar ataxias (SCA, 1, 2, 3, 4,5,6,7)

(b) Autosomal dominant cerebellar ataxias (ADCA IT, III)

(c) Periodic ataxias (EA, 1, EA2)

The gene responsible has been mapped to long arm of chromosome 9q 13 and is labeled X25. It contains trinucleotide repeat sequence of 3 bases GAA arranged in tandem (GAA, GAA, GAA).

The gene product is called frataxin and the disease is caused by loss of expression of frataxin protein. Its reduced levels are found in those suffering from the disease.

Pathology

It is mainly in the cerebellum and spinal cord which are usually smaller than the normal and main thrust may fall into either of them depending on the form of ataxia.

In the spinal forms of ataxias there is degeneration and demyelination of posterior columns, spino cerebellar tracts, pyramidal tracts and ganglion cells of clarkes column which is more severe in lumbar region.

In cerebellar forms of ataxias changes are most marked in anterior columns and cerebellar cortex. There is not only degeneration of myelin but destruction of axones with reactionary gliosis. In the cerebral cortex there is loss of Betz cells in precentral gyri as well as degeneration of deetate nuclei of cerebellum.

Friedreich’s ataxia

It is an autosmal recessive disorder which generally manifests between 5 and 15 years. It is characterized by degeneration of long ascending and descending tracts of spinal cord (pyramidal tracts, dorsal spinocerebellar tracts.

Diagnostic criteria for Hereditary ataxias (Harding 1981)

Essential criteria for diagnosis

A. Within 5 years of onset

(a) Progressive ataxia of limbs and gait

(b) Onset before 25 years of age

(c) Absent knee and ankle jerks

(d) Extensor plantar response

(e) Motor nerve conduction velocity> 40 m / sec in upper limbs and small or absent sensory action potential.

B. After 5 years of onset

(a) Dysarthria

(b) Additional criteria not essential for diagnosis present in> 66% cases

(e) Scoliosis

(d) Pyramidal weakness in lower limbs

(e) Absent reflexes in upper limbs

(f) Loss of joint position and vibration sense distally in lower limbs

(g) Abnormal ECG

Features present in > 50% cases

1. Nystagmus

2. Optic atrophy

3, Deafness

4. Distal weakness and wasting

5. Pes cavus

6. Diabetes

and posterior columns) along with degeneration of peripheral axons and myelin sheaths in the form of chronic peripheral neuropathy. Ventral spino cerebellar tracts usually escape. The heart may show diffuse changes in the form of fibrosis. Cerebellum is invariably affected.

Clinical features

Cases usually present with progressive ataxia, marked in the lower limbs. Patient is unsteady on standing and begins to stagger while walking. In severe form he is unable to walk without support. Unsteadiness of limbs is not intensified by closing of eyes.

Features of cerebellar involvement (nystagmus, dysarthria, scanning / slurred! monotonous speech, tremors) appear soon. Skeletal deformities like kyphoscoliosis and Pes cavus develop.

Since there is pyramidal degeneration, there is weakness in lower limbs. Tone may be either decreased or slightly increased depending on relative severity of loss of afferent impulses from muscles. Ankle jerks are lost before the knee jerks which may be exaggerated.

Sensory changes are inconstant. Impairment of vibration and position sense in lower limbs may be prominent due to post column loss. Loss of all types of sensations (Pain, touch, temperature) indicates peripheral nerve involvement.

Spincters are usually unaffected though in late stages their involvement may occur. Cardiac involvement in the form of interstitial myocardial fibrosis, arrhythmias and congestive failure may occur in few cases. Occasionally optic atrophy and opthalmoplegia may be present.

Investigations

1. Nerve conduction studies – Sensory action potentials are small or absent and motor conduction velocity in upper limbs is > 40 m/sec.

2. CT scan and MRI (brain and spinal cord) show atrophy of cerebellum and cord.

3. ECO – Abnormal T waves in left ventricular leads. Cardiac arrhythmias.

4. Echocardiography – Hypertrophic cardiomyopathy.

Prognosis

It is a slowly progressive disorder and occasionally it may become arrested. Survival usually ranges between 15-20 years after the appearance of symptoms. Death is usually due to either respiratory failure or cardiac failure.

Treatment

There is no known treatment for the disease. Drug like idebenone (free radical scavenger), physostigmine and 5-hydroxytryptamine have been tried but without much success.

Variants of Friedreichs Ataxia

1. Friederichs ataxia with retained reflexes (FARR), The clinical picture here is like classical case of friederichs Ataxia. The only difference is that here the reflexes are retained.

2. Roussy Levy syndrome: It is characterized by ataxia, Pes cavus. absent reflexes and wasting of lower leg muscles.

3. Sanger Brown ataxia: Age of onset is between

16 to 35 years. There is degeneration of posterior columns and dorsal spino cerebellar tracts with little or no pyramidal degeneration. Cerebellum does not show much changes. Clinically there is optic atrophy, ptosis, diplopia, opthalmoplegia, exaggerated deep tendon reflexes and absent pes cavus and nystagmus.

4. Manes cerebellar ataxia: Onset of disease occurs in adolescence and runs in families. Pathologically there is degenration of ascending cerebellar tracts and anterolateral columns while pyramidal tracts and posterior columns are little affected. Cerebellum shows little atrophy. Clinically there is cerebellar ataxia with optic atrophy.

5. Hereditary spastic paraplegia: Here the predominant lesion is degneration of pyramidal tracts especially in the upper dorsal region. There is associated degeneration of spino cerebellar tracts and posterior columns. It is inherited as autosomal dominant and first manifests in young age with stiff and clumsy gait. Lower limbs are weak and spastic with exaggerated tendon reflexes. Plantars are extensor. Pes cavus is usually present. Later on upper limbs are affected and finally mucles innervated from brain stem leading to dysarthria and dysphagia, There is no loss of superficial or deep sensations. Primary optic atrophy may be present in few. Disease runs a slow course and patient may progress to complete disability. Death usually occurs from intercurrent infections.

Late onset ataxias (after age 20 years)

These are usually autosomal dominant form of cerebellar ataxias and have been differentiated on clinical and genetic basis.

Main ataxias in this group are:

1. Olivo ponto cerebellar atrophy

2. Cerebellar cortical degeneration

Olivoponto cerebellar atrophy (OPCA)

It is autosomal dominant form of cerebellar ataxia which may run in families. Genetic linkage has been shown to chromosome 6. Pathologically there is atrophy of ganglion cells of olives, grey matter of pons and degeneration of middle cerebellar peduncles. Lesions of cerebellum, basal ganglia and substantia nigra account for most of the clinical picture.

The onset of the disease is between 20-40 years and some patients may present themselves in late middle age. Symptoms are those of a slowly progressive cerebellar degeneration with ataxia, limb incoordination intention tremors, dysarthria.

Slurred speech and muscular hypotonia. Chorea, athetosis, dystonia and parkinsonian features may be prsent in some. Mild mental retardation develops in late stages.

Optic atrophy and opthalmoplegia is seen in some cases. Nystagmus is usually absent. Reflexes are preserved though in late stage ankle jerks may be lost.

Cerebellar cortical degeneration

It is inherited as autosomal dominant trait and usually occurs in early middle life between the ages of 35-40 years.

Pathalogically there is degeneration of cerebellum with atrophy and gliosis of olivocerebellar fibres in the medulla and restiform body. Other parts of the nervous system like Pons, medulla and spinal cord are not effected.

Clinically patient presents with unsteadiness of gait. Features of cerebellar involvement like ataxia, intention tremors, explosive speech and nystagmus develop.

Dementia is mild and is a late feature. Vision and optic nerves are normal. There are no sensory disturbances.

It is a slowly progressive disorder and continues for many years with varying degree of disability. Diagnosis can he confirmed by CT scan which shall show atrophy of cerebellar cortex.

There are other forms of cerebellar degeneration ie one associated with paraneoplastic disorders. Delayed cerebellar degeneration also occurs in late age. CSF study is helpful in such cases.

While CSF is normal in cerebellar degenerations, it shall show raised protein content and cell count in cases of paraneoplastic cerebellar degeneration. Treatment in all cases of cerebellar degeneration is not satisfactory.

No drug is of any benefit. Symptomatic treatment is instituted. Patient shall require training in walking and ability to look after his nutrition. Falls should be avoided so that the patient does not injure himself.