case files neurology
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case files neurology

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\u2756 CASE 5
This 57-year-old man of Portuguese descent noticed that he had difficulty
marching in line as a soldier. From age 20 until the age of 40 he had a slow
progression of symptoms. Since then he experienced a rapidly progressing gait
disturbance, diplopia, dyssynergia, and paraesthesia in the limbs. At age 45 he
was confined to a wheelchair. On examination, he was intellectually normal
but had severe dysarthria and constant drooling. He had bulging eyes, slow
saccades, and impaired voluntary up- and down-gaze but no nystagmus. He
had fasciculations and dyscoordination of the tongue but no facial fascicula-
tions. A general moderate muscle weakness and atrophy were revealed, but
muscle tone was normal. Tendon reflexes were absent, but there were bilateral
Babinski signs. Deep senses were impaired, and coordination was impaired by
severe ataxia, dysmetria, and dysdiadochokinesia. A constant static tremor was
seen in the hands. His mother and paternal grandfather as well as his sister and
her son also had problems with gait, which were progressive and began during
adulthood. MRI of the brain revealed cerebellar folial atrophy.
\u25c6 What is the most likely diagnosis?
\u25c6 What is the next diagnostic step?
\u25c6 What is the next step in therapy?
ANSWERS TO CASE 5: Ataxia, Spinocerebellar
Summary: This is a case of an essentially healthy man who had the insidious
onset and gradual progression of the syndrome heralded by gait difficulties,
which were later characterized as ataxia.
\u25c6 Most likely diagnosis: Autosomal dominant cerebellar degeneration
with additional neurologic features with normal cognition\u2013most likely
spinocerebellar ataxia type 3 (SCA-3).
\u25c6 Next diagnostic step: DNA confirmation of diagnosis.
\u25c6 Next step in management: Supportive care, genetic counseling,
1. Describe the movement disorder of ataxia.
2. List the differential diagnosis of ataxia including genetic and non-
genetic etiologies.
As stated, this essentially healthy man had an insidious onset and gradual pro-
gression of a syndrome heralded by gait difficulties, which were later charac-
terized as ataxia. It later caused dysarthria, abnormal saccades, probable lower
motor neuron findings, neuropathy, and upper motor neuron deficits. This clin-
ical picture suggests a multiple system degeneration with the most prominent
feature being ataxia, and poor coordination on voluntary movements. These are
typically caused by problems either with a motor control as a result of pathology
of the cerebellum or its connections or pathologic proprioception because of
pathology in sensory pathways. Ataxias can either be isolated or seen as part of
the syndrome in conjunction with other neurologic abnormalities or abnormal-
ities in other body systems. This patient has other neurologic abnormalities but
no evidence at least at this time of other body system involvement. In addition,
there is strong familial involvement; specifically, there are four successive gen-
erations affected in his family, and both sexes are affected. Although familial
disorders are not necessarily genetic, this extensive involvement actually sug-
gests an autosomal dominant disorder. This is reinforced by the fact that auto-
somal recessive ataxias tend to have other body systems involved, whereas this
is not the case with adult-onset autosomal dominant disease.
It is worth considering some nongenetic causes of ataxia as they would
suggest other management issues, although most present over a much shorter
time course. Recognizable causes including trauma, toxic and metabolic
factors, neoplasms, and autoimmune mechanisms. Paraneoplastic cerebellar
degenerations (PCD) associated with specific tumor type antineuronal anti-
bodies are a relatively frequent cause of late-onset ataxia and are characterized
by a subacute progressive course and would prompt discovery and treatment
of the underlying neoplasm. More rarely (and controversially), subacute spin-
ocerebellar degeneration is associated with nonparaneoplastic immune dis-
eases such as gluten intolerance. In addition, hormonal abnormalities, such as
thyroid hormone deficiency can cause ataxia.
Ataxia\u2014an unsteady and clumsy motion of the limbs or torso caused by a
failure of the gross coordination of muscle movements.
Trinucleotide repeat expansion disease\u2014caused by stretches of DNA in
a gene that contain the same trinucleotide sequence repeated many
times. These repeats are a subset of unstable microsatellite repeats that
occur throughout all genomic sequences. If the repeat is present in a
gene, an expansion of the repeat results in a defective gene product and
often disease.
Clinical Approach
Harding (1983) proposed a useful clinical classification for late onset autoso-
mal dominant cerebellar ataxias. In addition, sporadic cerebellar syndromes
include idiopathic forms of obscure etiology characterized by progressive
ataxia, autonomic failure, and extrapyramidal features, such as multiple sys-
tem atrophy (MSA). In Harding\u2019s system autosomal dominant cerebellar
ataxia I (ADCA I), cerebellar ataxia is associated with additional features
related to the optic nerve (extra) pyramidal system, cerebral cortex, and periph-
eral nerves. ADCA II is associated with pigmentary macular dystrophy, and
ADCA III is a pure late onset cerebellar syndrome.
Since 1993 autosomal dominant cerebellar ataxias have been increasingly
characterized in terms of their genetic locus and are referred to as spinocere-
bellar ataxia. At this point there are more than 25 such disorders, and the num-
ber is increasing. The most common types are listed in Table 5\u20131. Many of
these can be definitively diagnosed by DNA testing. Clinical characterization
however is helpful in limiting the number of tests required.
There are several gene mutations on different chromosomes that cause spin-
ocerebellar ataxia, and the gene frequency within different populations varies
considerably. In general, the incidence is thought to be approximately 1.5 per
100,000 people, with equal gender distribution. Most of the ADCAs are caused
by a genetic defect that involves an expansion in the DNA sequence, and most
of these are trinucleotide repeat expansions (SCA types 1\u20133, 6\u201310, 12, and 17).
Table 5\u20131
SCA-1 6 6p23 Ataxin-1 CAG repeats Ataxia, dysarthria, Nystagmus, hypermetric
(38\u201383) pyramidal signs, saccades, slow saccades,
peripheral neuropathy, ophthalmoparesis