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Ataxia with isolated vitamin E deficiency and retinitis pigmentosa.

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Ataxia with Isolated Vitamin E Deficiency and
Retinitis Pigmentosa
Takayoshi Shimohata, MD,*t Hidetoshi Date, PhD,?
Hideaki Ishiguro, MD,' Takashi Sizuki, MD,'
Hiroki Takano, MD,t Hajime Tanaka, MD,t
Shoji Tsuji, M D , t and Kohichi Hirota, MD'
We read with great interest the report of Yokota and colleagues' describing Friedreich-like ataxia with retinitis pigmentosa caused by the His'"'G1n mutation of the
a-tocopherol transfer protein (a-TTP) gene, because we also
recently found a novel missense mutation of the a - T T P gene
in a patient with retinitis pigmentosa as well as ataxia.
The proband was a 57-year-old woman who was born of
a consanguineous marriage. On physical examination, she exhibited ataxia, dysarthria, bilateral sensorineural deafness, hyporeflexia, muscular atrophy of extremities, decreased proprioceptive and vibratory sensations, and retinitis pigmentosa.
Brain magnetic resonance imaging revealed marked dilatation
of the cisterna magna, a finding that has also been reported
in a Japanese family with idiopathic vitamin E deficiency.2
Laboratory data revealed an extremely low serum vitamin E
concentration (1.7 pg/ml; normal, 7.5-14.1 pg/ml). Although three of the proband's siblings suffered from similar
symptoms, her 5 1-year-old sister exhibited neither retinal
change nor dilatation of the cisterna magna. The sister's serum vitamin E concentration was higher than that of the
proband (4.2 pg/ml), because by chance, she had been taking 200 mgiday a-tocopherol since she was 20 years old.
High-molecular-weight genomic DNA was extracted from
peripheral blood leukocytes of two affected and two unaffected family members. The a-TTP gene was amplified by
the polymerase chain reaction and subjected to direct nucleotide sequence analysis as described by Ouahchi and coll e a g u e ~ We
. ~ found a single nucleotide alteration in the third
of thc five coding exons of the a-TTP gene. The results revealed that the affected members were homozygous for a
thymine-to-cytidine transition at nucleotide 566 of the
a - T T P cDNA that results in substitution of proline (CCT)
for leucine (CTT) at codon 183. The two unaffected members were heterozygous for the mutation. Because analysis of
the a-TTP gene of 100 unrelated Japanese subjects did not
reveal this mutation, these findings indicate that the
L e ~ ' ~ - ~ mutation
is likely to be the pathogenic mutation.
Our report emphasizes the importance of serum vitamin E
screening in patients with spinocerebellar degeneration resembling Friedreich's ataxia, particularly if the clinical features include retinitis pigmentosa or dilatation of the cisterna
magna, since this neurological disorder can be arrested by
appropriate supplementation with vitamin E.
*Department of Neurology, Akita Red Cross Hospital, Akita,
and 'Department of Neurology, Clinical Neuroscience Branch,
Brain Researcb Institute, Niigata Uniuersig, Niigata, Japan
1. Yokota T, Shiojiri T, Gotoda T, et al. Friedreich-like ataxia with
retinitis pigmentosa caused by the His'"'Gln mutation of the
a-rocopherol transfer protein gene. Ann Neurol 1997;41:826831
2. Aoki K, Washimi Y, Fujimori N , et al. Familial idioparhic vitamin E deficiency associated with cerebellar atrophy. Clin Neurol
3. Ouahchi K, Arira M, Kayden H, et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the a-tocopherol
transfer protein. Nat Genet 1995;9:141-145
Surgical Treatment of Hypothalamic Hamartoma
S. M. Sisodiya,' S. L. Free,? and S. D. Shorvont
Although the demonstration of effective treatment for epilepsy associated with a hypothalamic hamartoma (HH) in
one patient by Kuzniecky and colleagues' is very welcome,
most patients reported on in the literature have failed to become seizure-free whether interventional treatment was directed against HH or neocortical epileptogenic foci.2 Although diencephalic lesions may generate gelastic seizures
(that may secondarily generalize), and apparently focal dysgeneses may be intrinsically epileptogenic, most patients with
HH have multiple seizure types. Munari and associates3
showed that some nongelastic seizures in one patient with
HH may have non-HH, neocortical origin, even if these foci
develop secondarily and are not visible on routine inspection
of volumetric magnetic resonance images (MRI). Apparently
focal cerebral dysgeneses are often associated with locally extensive occult cerebral structural changes*; widespread structural changes detected only by quantitation of MRI may
have biological significance in patients with epilepsy, being
associated with poor outcome after focal surgical r e ~ e c t i o n . ~
We propose that some HH patients may d o well after focal
rescctioii whereas others do not because the latter have additional structural changes not visualized on MRI, as has been
demonstrated in 2 patients by quantitative analysis.6
To determine whether the presence of additional quantitative abnormalities of cerebral structure in patients with HH
is a biological cause of the heterogeneous response to surgery,
a prospective study of quantitation of preoperative MRI data
would be required. This analysis is relatively simple and is
performed on preoperative MRI data, which are prerequisite
for surgery. Although Kuzniecky and colleagues demonstrated elegantly the value of single-photon emission computed tomography, this technique is not available for all patients, whereas MRI data are easily transmitted. Since few
centers are likely to see sufficient patients to undertake a prospective study and to minimize operator variability in performance of quantitative analysis, we offer to perform quantitative analysis on volumetric MRI data acquired by any
center from patients with HH being considered for surgery.
Correlation of MRI quantitation results with surgical outcome would test the hypothesis of biologically important
heterogeneity of cerebral structures associated with HH. This
might in the future assist clinicians, enabling the rational
provision of interventional treatment to patients most likely
to benefit and avoiding exposing patients likely for biological
reasons to do badly to possible morbidity.
Annals of Neurology
Vol 43
No 2
February 1997
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ataxia, vitamins, deficiency, isolated, retinitis, pigmentosa
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