The hereditary ataxias are a heterogeneous group of
diseases. Most attempts at classification have been
based on pathologic findings and are not always useful
for the clinicians. Many of these disorders are multisystem
degeneration in which the underlying biochemical or
other defect is usually unknown. The pathophysiology
is correspondingly poorly understood. Hereditary ataxia
can be divided into the hereditary congenital ataxia,
the ataxia linked with metabolic disorder, and early
onset ataxia of unknown etiology (1) (Table 1). Primary
care physicians should be aware of the differential
diagnosis of hereditary ataxia when faced with ataxia
of unknown etiology.
Table 1. Classification of Hereditary Ataxia
Congenital Cerebellar Ataxia
II. Ataxia associated with metabolic disorders
...b. Progressive unremitting
...c. Ataxia disorders
associated with defective DNA repairs
III. Progressive ataxia disorders of unknown
...a. Early - onset
cerebellar ataxia (onset usually before age 20)
...b. Late - onset
cerebellar ataxia (onset usually after age 20)
The degenerative cerebellar and spinocerebellar
disorders are a complex group of diseases, most of which
are genetically determined. Tremendous confusion exists
in classifying degenerative disorders causing ataxia,
and there is no universally accepted system, these disorders
can be divided into two main groups, depending on whether
onset of symptoms is before or after the age of 20 years.
Most of the early onset are autosomal recessive, and
the later onset ones autosomal dominant (2). Most of
these disorders are multisystem degenerations in which
the underlying biochemical or other defect is usually
unknown; the pathophysiology is correspondingly poorly
understood. The differential diagnosis of ataxia is
important since some of them are treatable if detected
early. The discussion will concentrate on congenital
cerebellar ataxia, ataxia associated with metabolic
disorders and progressive ataxia of unknown etiology.
I. Congenital Cerebellar
Non-progressive rare type of ataxia: Cerebellar dysfunction
usually starts in infancy with abnormal motor development,
and hypotonic. Other symptoms includes nystagmus, intention
tremor, feeding problems, marked truncal ataxia, delay
in ability to sit, and stand, and variable degree of
mental retardation and spasticity (2). Classification
of the congenital cerebellar syndromes are shown in
Table 2. The inheritance pattern of the majority of
these syndromes are of autosomal recessive, with a 25%
recurrence risk to subsequent siblings.
Table 2: Congenital Cerebellar Ataxias
ataxia with mental retardation and spasticity
Congenital ataxia + /- mental retardation
... (includes granule
Congenital ataxia with mental retardation, episodic
abnormal eye movements
... (Joubert's syndrome)
Congenital ataxia with partial aniridia and mental
X-linked recessive ataxia with mental retardation
II. Ataxia Associated with
Ataxia secondary to metabolic
disorder may lead to either persistent progressive ataxia
or to intermittent ataxia. The underlying pathophysiology
is usually accumulation of neurotoxic substances such
as ammonia. (Table 3).
Table 3: Ataxia Associated with Metabolic Disorders
* Ataxia may not be prominent
Disorders of pyruvate and lactate metabolism
Progressive Unremitting Ataxic Syndromes
* (metachromatic, late-onset globoid cell,
Ataxia Disorders Associated with Defective
...Ataxia - telangiectasia
A. Intermittent Ataxia
The hyperammonemias are usually caused by deficiencies
of urea cycle enzymes and are of autosomal recessive
inheritance, with the exception of ornithine - Transcarbamylase
deficiency, which is X-linked. The clinical manifestations
include intermittent ataxia, dysarthria, vomiting, headache
ptosis, involuntary movements, confusion seiuzures and
mental retardation. These episodes are usually precipitated
by intercurrent illness and high protein load (3).
Ornithine Transcarbamylase deficiency
is the most common urea cycle enzyme deficiency; it
is X-linked. Antenatal diagnosis is available for this
deficiency and for some of the other hyperammonemias.
Protein restriction is the treatment of choice in addition
to intravenous fluid administration during acute episodes
of neurologic dysfunction. Aminoacidurias usually have
similar manifestations as that of the hyperammonemias.
Inheritance is autosomal recessive and treatment consists
of restricting the intake of branched chain amino acids
through special diets (4). Pyruvate dehydrogenase disorders
are heterogeneous and rare. When the level of enzyme
activity is between 35 and 50% of normal a syndrome
of intermittent ataxia and choreathetosis occur during
febrile illness and mild cerebellar dysfunction between
episodes (5). Severe lactic acidosis occurs when the
activity of this enzyme is below 15% of normal (5).
A ketogenic diet may slow progression of the disease.
B. Progressive Unremitting
A number of hereditary metabolic
ataxia lead to progressive unremitting syndrome (Table
3). Most of them are autosomal recessive disorders.
Abnormal function of apolipoprotein B, the carrier of
lipid from the intestinal cells to plasma, lead to Abetalipoproteinemia.
The most prominent features of this disease include
ataxia, areflexia, loss of vibration and position sense,
and pigmentary retinopathy. Symptoms of fat malabsorption
are often mild and may be overlooked. Serum cholesterol
level is low and serum vitamin E concentrations are
low or undetectable from birth and this deficiency may
be the cause of neurologic disorders. Onset of symptoms
is usually in the second decade of life. Large doses
of vitamin E results in improvement or stabilization
of symptoms or may prevent the development of neurological
symptoms. Retinopathy may be related to deficiency of
both vitamins A & E (6).
Isolated cases of vitamin E
deficiency with no evidence of hypolipidemia or generalized
fat absorption can occur (6). This is caused by a specific
defect of vitamin E absorption which is inherited as
an autosomal recessive trait. Adequate vitamin E therapy
usually halts the progression of neurologic symptoms.
Other disorders associated with ataxia include adrenoleukomyeloneuropathy,
the sphingomyelin lipidoses (combined with supranuclear
gaze palsy and dementia), metachromatic leukodystrophy,
galactosylceramide lipidoses (Krabbe's disease), and
the hexominidase deficiencies (7). A rare autosomal
recessive disorder in cholestanolosis is caused by defective
bile salt metabolism. This disease is characterized
by ataxia, dementia, spasticity, peripheral neuropathy,
cataract, and xanthomas in the second decade of life.
Neurological function usually improves with treatment
with chenodeoxycholic acid (8). Mitochondrial myopathies
consist of various phenotypes with late onset ataxic
disorders associated with such features as deafness,
dementia, ataxia, peripheral neuropathy and myoclonus
(9). Ataxia is an important albeit pathognomic finding
in the poorly glycosylated glycoprotein syndrome.
C. Ataxia Disorders Associated
With DNA Repair
Ataxia - telangiectasia is the
most common ataxic disorder associated with defective
DNA repair. It is a multisystem, autosomal recessive
disorder. It usually starts with recurrent sinopulmonary
infections. Telangiectasis appear on the skin between
3 & 6 years. Ataxia is truncal and is progressive.
Other symptoms include dysarthria, tremor, ophthalmologic
and insulin resistance. Immunologic abnormalities include
reduced level of secretary IgA serum IgE and abnormalities
in cellular immunity. The cause of death is usually
recurrent infections or malignant tumors. Helpful diagnostic
clues are elevation of serum and fetoproteins (10).
A heterogenous disorder consisting
of at least six genetically distinct autosomal recessive
diseases is Xeroderma Pigmentosum. It is caused by reduced
capacity to perform excision repair of DNA damaged by
ultraviolet light and of some carcinoembryonic antigen.
The disorders manifest mainly with skin photosensitivity,
skin diseases malignancies and in three forms of the
disease neurologic dysfunction occurs (11). In about
half of the patients with neurologic disease, ataxia
and hyporeflexia occur with mental retardation, deafness,
involuntary movements and spasticity being more common.
III. Progressive Ataxia Disorders
of Unknown Etiology
These can be divided into two
main groups, depending on whether onset of symptoms
is before or after the age of 20 years. Most of the
early onset disorders are autosomal recessive, and the
later onset ones autosomal dominant (2).
A. Early Onset Cerebellar
Friedreich's ataxia is the most common of the early
onset ataxia. It is one of the best defined and most
common forms of hereditary ataxias of unknown etiology(1,2).
In some large case series it comprises about 50% of
the hereditary ataxia (2,12). It is transmitted in an
autosomal recessive manner, and usually appearing in
childhood or in adolescence but rarely in old age (13).
The disease usually progresses slowly without remission,
affecting both the central and peripheral nervous system
(13-14). The most frequent first symptom is ataxia of
The epidemiology of Friedreich's
ataxia is perplexing. The clinical features and diagnostic
criteria were defined by the Quebec Cooperative Study
of Friedreich's Ataxia (QCSFA) (15) and by Harding (1,2
) (Table 4). Both authors regarded recessive inheritance,
progressive ataxia of limbs and gait and lower limb
areflexia as obligatory criteria. The onset, according
to the QCSFA and Harding (2, 15), should never occur
after the age of 20 years, and always before 25, according
to Harding (2). A recent case was reported in the literature
where symptoms started at a later stage (16). Dysarthria,
decreased lower limb deep sensation and weakness, obligatory
signs for the QCSFA, are not considered essential for
an early diagnosis by Harding (2). The diagnosis is
made essentially on clinical grounds, CT scan of the
brain may show mild cerebellar atrophy.
Table 4: Friedreich's Ataxia : Diagnostic Criteria
* Present in nearly all cases
within 5-10 years of onset.
Criteria for Diagnosis: Present in More than 95%
Autosomal recessive inheritance
Age at onset of symptoms before 25 years
Progressive limb and gate ataxia
Absent knee and ankle jerks
Extensor plantar responses
Motor nerve conduction velocity > 40m/s in upper
Small or undetectable sensory action potentials
Criteria, Not Essential for Diagnosis: Present
than 65% of Cases
Pyramidal weakness of lower limbs
Absent reflexes in upper limbs*
Distal loss of joint position and vibration sense
in lower limbs*
Present in 50% of cases or less
Distal weakness and wasting
The prevalence is known only
for some populations (12, 17-20). The range is from
0.6 to 1.4/100,000 population. The incidence has been
estimated to be approximately 1-
2/100,000 (17, 21).
Friedreich's ataxia is characterized
by degeneration of the spinocerebellar pathways, the
dorsolateral columns, and the dentate nuclei (1). There
are few changes in the cerebellar cortex itself (1).
The cerebrospinal fluid is usually normal and the CT
scan of the brain is either normal or shows mild cerebellar
atrophy. The primary clinical signs include ataxia,
most marked in the lower limbs and often accompanied
by dysarthria; nystagmus is usually present in 70% along
with skeletal-muscle weakness (22). Optic atrophy and
retinal pigmentation is usually present. Pes cavus and
scoliosis almost always develop (23). Death is usually
sudden and may be secondary to cardiac arrythmias (22).
Cardiac involvement is frequent occurring in some 50%
to 90% of cases (24); most commonly concentric hypertrophic
cardiomyopathy is found (24,25).
Multiple studies have shown
that the small coronary arteries are abnormal in patients
who have cardiac disease and Friedreich's ataxia (26,27).
The functional significance of this has been challenged
by Hewer (26). Biller et al. (27) reported a prevalence
of 1.5% of cerebral infarction in 131 patients. It occurred
in half of the patients who developed atrial fibrillation
or atrial flutter with underlying symptomatic cardiomyopathy
(27). Speech disorder is common in FA (28).
Electrophysiological and pathological
studies suggest that axon degeneration and secondary
demyelination occur in peripheral sensory nerves (29).
of FA patients usually includes determination of motor
and sensory conduction velocities (MCV, SCV) and multimodal
evoked potentials (30). The degeneration of peripheral
sensory and somatosensory pathway is usually measured
by using nerve conduction studies and somatosensory
evoked potential (SEPs) and brain-stem auditory evoked
potentials (BAEPs) and the blink reflex (30).
Biochemical alterations observed
in this disease include a reduced insulin receptor activity
which leads to an insulin resistance state and a reduced
glucose tolerance in about 40% of patients (31). Several
lipid abnormalities have been noted as well, including
a striking reduction in linoleic acid (32), low cholesterol
levels with a total cholesterol reduction in serum and
in the LDL and HDL fractions are described (32).
The results of therapeutic trials
in Friedreich's ataxia with a number of drugs, including
choline chloride, lecithine, physostigmine, y-vinyl
aminobutyric acid, 5-hydroxytrptophan, benserazide,and
thyrotropin releasing hormone, have been inconsistent
or unconfirmed in terms of producing functional neurologic
Amantadine hydrochloride (AH)
is known to stimulate dopamine release (33). The use
of AH in FA and OPCA was recently tested (34). Both
studies revealed an improvement in reaction time (RT)
and movement time (MT).
So there is no treatment known
to influence the slowly deteriorating disease course.
In order to minimize disability and prolong ambulation,
strengthening and stretching exercises and functional
retraining including aerobic endurance exercise are
- Onset Cerebellar ataxia with Retained Tendon Reflexes
The other early onset ataxia
are listed in Table (5) . They are usually rare, with
exception of early onset cerebellar ataxia with retained
reflexes, which occurs at a
frequency about one quarter of that of FA, and is often
confused with it, but is genetically distinct. The main
clinical difference is that the tendon reflexes are
normal or brisk in the disorder(36). It is important
to distinguish between these two disorders, since the
prognosis is better in the former, with patients losing
the ability to walk on average 13 years later than in
FA. In addition, severe skeletal deformity, heart disease,
and diabetes do not occur (37).
Table 5: Early-Onset Ataxic Disorders of Unknown Etiology
Early-onset cerebellar ataxia with
Ramsay Hunt syndrome, progressive
... myoclonic ataxia)
...optic atrophy +
or - mental retardation
...cataract and mental
retardation (Marinesco-Sjogren syndrome)
Ataxia with Hypogonadism
The association of progressive
ataxia with hypogonadotrophic hypogonadism is rare (2).
Neurological symptoms usually develop in the third decade
and hypogonadism is obvious at puberty. Neurological
syndromes include dysarthria, nystagmus, progressive
limb and gait ataxia, mental retardation, dementia deafness,
choreoathetosis, retinopathy and sensory loss.
Ataxia with myoclonus
The association of cerebellar
ataxia and myoclonus, is often referred to as the Ramsay
Hunt syndrome. This is a very heterogenous entity. Some
of the identifiable causes include Baltic myoclonus,
mitochondreal encephalomyopathy, and sialidosis (37).
The rest of cases can be labelled as progressive myoclonic
ataxia (37). Symptoms include the development of stimulus
- sensitive myoclonus or generalized seizures at the
end of the first decade of life. Ataxia and dysarthia
develop a few years later with pyramidal signs in the
limb. The myoclonic part of this syndrome may respond
to clonazepan or valproate sodium with marked improvement
in motor function.
B. Late Onset Cerebellar
These disorders have proved
the most difficult and controversial in terms of
classification (Table 6). The pathological findings
are heterogenous reflecting huge
clinical variations in the dominant ataxia (2).
Table 6: Late-Onset Ataxic Disorders Of Unknown Etiology
dominant cerebellar ataxia (ADCA) with
dementia, optic atrophy, extrapyramidal features
... and amyotrophy
may include Machado- Joseph disease) (ADCA
... type I)
ADCA with pigmentary retinopathy +/- Ophthalmoplegia
features (ADCA type II)
Pure ADCA of later onset (after age 50) (ADCA type
Autosomal Dominant Cerebellar
Ataxia Type I (ADCA Type I).
The age of onset of symptoms
in this syndrome ranges from 15 to 65 years but is most
commonly in the third or fourth decade of life. Ataxia
of gait is the most frequent presenting symptom; it
usually involves the limbs and is invariably associated
with dysarthria. Early onset usually predicts more progressive
disability (38). Associated symptoms may include ophthalmoplegia,
nystagmus, lid retraction and optic atrophy. Bulbar
symptoms are common during the later stages of disorder
and predispose the patient to respiratory infection.
Other common symptoms include dementia, extrapyramidal
signs, wasting and fasiculation of the face and Tongue.
Autosomal dominant cerebellar ataxia Type II (ADCA
This is clinically and genetically
different from ADCA type I. It is characterized in all
families having retinopathy. The age at onset is earlier
than that of ADCA type I, most commonly occurring between
15 and 35 (2,39).
Autosomal Dominant Cerebellar
Ataxia Type III
This is relatively pure cerebellar
syndrome in which dementia, ocular or extrapyramidal
features do not occur and onset of symptoms are usually
after the age of 50 years(3). Nystagmus and pyramidal
signs in the limbs are quite common.
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