Pathology Postmortem examination of the Holmes type cases discloses symmetrical atrophy of the cerebellum involving mainly the anterior lobe and vermis, the latter being more affected. Purkinje cells are absent in the lingula, centralis, and pyramis of the superior vermis and reduced in number in the quadrangularis, flocculus, biventral, and pyramidal lobes. The other cerebellar cortical neurons and granule cells and dorsal and medial parts of the inferior olivary nuclei are diminished less so. The white matter is slightly pale in myelin stains. The vermian atrophy and that of adjacent parts of the cerebellum can be visualized with clarity in MRIs (Fig. 38-8).
The vague similarity of the pathologic (and clinical) changes to those of alcoholic cerebellar degeneration is at once apparent and should raise the question of an alcoholic-nutritional cause in sporadic cases (see Chap. 40); in serious alcohol-nutritional disease, there usually is an accompanying polyneuropathy and reduced ankle reflexes.
This type of developmental delay, caused by an unstable extended trinucleotide repeat sequence and breakage of the X-chromosome, is discussed in Chap. 36. Here we refer to an unusual variant of the degenerative process with onset in midor late adulthood, mainly but not exclusively in men, and consisting of gait or limb ataxia and mild tremor. The process affects carriers of a “premutation” who have 50 to 200 CGG repeat sequences in the FMR1 gene, who may manifest tremor and ataxia late in life. The full mutation is better known as a cause of a developmental delay and autistic-like syndrome in boys (Chap. 37). The frequency of the premutation is approximately 1 in 150 to 300 females, and 1 in 400 to 850 males. In contradistinction to the full mutation of over 200 repeats, there is apparently a buildup of messenger ribonucleic acid (mRNA) in the adult form that interferes in some way with cellular function. As a result of anticipation across generations, it was found that fragile X often emerges in a boy whose maternal grandfather had the premutation-tremor syndrome. Aggregating several studies, the frequency of this genetic abnormality among otherwise unassignable adult ataxia cases is less than 10 percent.
The entire clinical spectrum has yet to be defined but our experience has featured mild progressive gait ataxia in the sixth decade that was misattributed to normal- pressure hydrocephalus and an intermittent hand tremor that was probably ataxic in nature. Some reports have included a parkinsonian syndrome and more consistently, a mild frontal dementia, making the distinction from frontotemporal dementia difficult. Many cases have been confused with multiple system atrophy.
T2 hyperintensity in the cerebellar peduncles are characteristic of some cases, but this was not found in our patients, which showed only midline cerebellar atrophy. A family history of developmental delay or autistic spectrum disorder may be a hint to diagnosis and some proportion of individuals with the premutation also have a nonprogressive cognitive deficiency.
A study of the neuropathology by Greco and colleagues showed cerebral and cerebellar spongiform white matter changes and both intranuclear and astrocytic inclusions. Their report demonstrated a correspondence between the quantity of trinucleotide repeats and the number of inclusion bodies.