Vitamin E deficiency ataxia associated with adenoma

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Journal of the Neurological Sciences 162 (1999) 97–101

Vitamin E deficiency ataxia associated with adenoma a, a a a a Ali Benomar *, Mohammed Yahyaoui , Naima Marzouki , Nezha Birouk , Naima Bouslam , Halima Belaidi a , Afaf Amarti b , Reda Ouazzani a , Taieb Chkili a


a ˆ ´ ´ , CHU Ibn Sina, Rabat-instituts, BP: 6220, Morocco des Specialites Service de Neurologie ( T. Chkili), Hopital ˆ ), Hopital ˆ ´ ´ , CHU Ibn Sina, Rabat-Instituts, BP: 6220, Morocco des Specialites Laboratoire d’ anatomopathologie ( Pr. Saıdi

Received 12 March 1998; received in revised form 28 July 1998; accepted 25 September 1998

Abstract Vitamin E is one of the most important lipid-soluble antioxidant nutrient. Severe vitamin E deficiency (VED) can have a profound effect on the central nervous system. VED causes ataxia and peripheral neuropathy that resembles Friedreich’s ataxia. We report here a patient presenting this syndrome, but also a prolactin and FSH adenoma. Both the neurological syndromes and the adenoma regressed after treatment with alpha-tocopherol. Although, the presence of the prolactinoma in this patient may not be related to his vitamin E deficiency, alpha-tocopherol treatment seems to be beneficial and might usefully be tested in patients with hypophyseal secreting other forms of adenoma.  1999 Elsevier Science B.V. All rights reserved. Keywords: Ataxia; Vitamin E deficiency; Immunohistochemistry; Hyperprolactinemia; FSH secreting adenoma; 744 del A mutation

1. Introduction A neurological syndrome resembling Friedreich ataxia associated with vitamin E deficiency has recently been described [1–3,6,7]. The disorder is characterized by diffuse areflexia, gait and limb ataxia, sensory impairment, muscle weakness and amyotrophy. Malabsorption of lipids is observed in most, but not all, cases. A gene for the form without malabsorption has been mapped to the proximal region of chromosome 8q in two kindred Tunisian families [3]. We report here a patient with vitamin E associated ataxia who also had a prolactin and FSH secreting adenoma in the anterior pituitary gland. Both the ataxia syndrome and the adenoma regressed following treatment with alpha-tocopherol.

2. Methods

2.1. Direct detection of 744 Del A mutation Part of exon c of alpha-tocopherol transfert protein gene was amplified with the following primers: D,59GACATTCTTCCTCTGGAATATG39 R,59-GATAATCTTCAGACTTCATTATAAA39. Each PCR reaction was directly digested with 4 U of MboII. Digestion products were run on a 10% polyacrylamide gel, stained with Ethidium Bromide and visualised by UV. The family was also analysed with 8q microsatellite markers: D8S1227 and D8S512 [11].

2.2. Immunohistochemical study *Corresponding author. Tel.: 1212 7 775281; fax: 1212 7 779348.

Advances in the characterization of pituitary tumors

0022-510X / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00284-6


A. Benomar et al. / Journal of the Neurological Sciences 162 (1999) 97 – 101

have been dependent on the development of techniques for defining the cell types as well as the hormone products of these tumors. The development of the radioimmunoassay for prolactin (PRL), for example, has led to the recognition that adenomas produced PRL [8]. Fragments of tumor were taken from the patient, fixed in 10% formalin and embedded in paraffin for immunocytochemical staining. The tumor was stained for the following pituitary peptides: PRL, human growth hormone (GH), the beta subunits of FSH, LH, and TSH, and the common alpha subunit of the glycoprotein hormones. The immunocytochemical staining was carried out on 5mm paraffin-embedded sections of tumor, using the avidin-biotin-peroxidase complex (ABC) technique.

3. Case report A 20 year old man with no significant medical history became aware of unsteadiness at the age of 16. Motor abnormalities were observed, mainly impairing walking and the coordination of the legs and arms. The ataxia progressed and he soon lost the ability to run. Dysarthria was developed after 1 year of disease evolution. There was no family history of cystic fibrosis, or malabsorption. The parents had no neurological symptoms, but were consanguineous. The patient was first admitted to the neurology departˆ ´ ´ in Rabat in 1991, at the ment of ‘Hopital des Specialites’ age of 19. Neurologic examination revealed hypotonic limbs with severe gait and stance ataxia, lower limb areflexia, decreased vibration sense, bilateral babinski sign, minor dorsal cyphoscoliosis, important pes cavus and normal intellectual function. The fundoscopy was normal. There were no clinical signs of malabsorption. Peroneal and ulnar motor conduction velocities were normal (Fig. 1). Paraclinical investigations showed a decreased of blood vitamin E level of 1.16 mmol / l (normal levels: 10–37 mmol / l) whereas vitamin A level (1.8 mmol / l) was in the normal range (1.5–2.6 mmol / l). Other routine blood tests were performed: calcium, phosphorus, magnesium, cholesterol, triglyceride, ApoA and ApoB levels were normal. Lipid and protein electrophoretic profiles and cerebrospinal fluid were also normal. The absence of lipid malabsorption was confirmed by the Van der Kramer D-xylose methods. Cranial CT scan (Fig. 2A and 2C) revealed the presence of a hypophyseal adenoma with lateral and suprasellar extension. There were no clinical signs of intracranial hypertension or clinical hormonal dysfunction, but serum prolactin level was increased to 511 mU / ml (normal: 70–470 mU / ml), indicating probably, a prolactinoma without any changes in other hormones (FSH, LH, TSH, T3 and T4). The immunohistochemical study is a unique test confirming the tumor type.

Fig. 1. Pedigree’s family with ApoA, ApoB, prolactin and vitamin E concentrations.

The vitamin E deficiency ataxia was treated with atocopherol without bromocriptine treatment. The dosage was progressively increased from 5 to 8 mg / kg / day. After 1 year of treatment, the gait improved so that the patient could walk unaided, and dysmetria regressed. The volume of the adenoma decreased concomitantly (Fig. 2B,2D), and serum prolactin levels feel to 416 mU / ml. A minimal amputation of the visual field was observed on the right. Initially, the patient refused surgery. But, then he accepted surgical intervention. The tumor cells were insignificantly marked by b-TSH, b-GH, b-LH and alpha gonadotropins hormones subunits, but, revealed a remarkable positive labelling with prolactin and FSH in the majority of the tumor cells. Seventy five percent of tumor cells had positive staining for prolactin (Fig. 3D) and 50 percent for b-FSH (Fig. 3C). Therefore, there is a mixed follicle-stimulating hormone (b-FSH) and prolactin adenoma type. We observed a patient’s sister (Fig. 1, IV7) who presented the same symptoms. Ataxia began before cerebellar tumor since 3 years old. In her examination, we observed a criteria of Friedreich ataxia (cerebellar ataxia, decreased of vibration sense, babinski sign and areflexia without any abnormalities in the fondoscopy examination at home). Two abnormalities were found in this patient: • A decrease of the level of vitamin E in the blood (0.5 mg / l; normal: 7.8–122 mg / l) without any changes in the other vitamins. • A higher prolactin level (2240 mU / ml) that was more likely due to a prolactin secreting tumor without any changes in the other hormones: FSH, LH and free testosterone. At the end, ApoA and ApoB were normal.

A. Benomar et al. / Journal of the Neurological Sciences 162 (1999) 97 – 101


Fig. 2. Frontal (A) and axial (C) sections of a non-contrast computed tomographic scan showing an adenoma of hypophysis with lateral and suprasellar extention before treatment. (B) and (D): Regression of tumor volume after one year of alpha-tocopherol treatment.

Fig. 3. (A): (G3200) HES coloration: Features of established adenohypophyseal cell types; (B): All tumors cell had a chromatophobe cytoplasm; (C) (G3400) Beta-FSH immunolabelling: Most of the tumoral cells were Beta-FSH immunopositive (D): (G3400) Prolactin immunolabelling: Tumoral cells are also strongly reactive for prolactm immunolabelling.


A. Benomar et al. / Journal of the Neurological Sciences 162 (1999) 97 – 101

Fig. 4. Genetic study: (a) The AVED family, with the parents, four healthy children and two affected children, were analysed with 8q microsatellites markers (D8S1227 and D8S512) [11]: The two affected children carried on the same haplotype. (b) MboII digestion was analysed in the mother (1) and affected patient (2). Digestion products were run on a 10% polyacrylamide gel with one normal individual (3) who didn’t have the 744 del A mutation and was used as a control for restriction digestion. Mutated (93pb) and normal fragments (54pb and 40pb) are indicated.

This patient refused completely any treatment and also CT scan exam. Both the patient and her sister were homozygous for the 744 adenine deletion of the alpha-tocopherol transfert protein (a-TTP) gene (Fig. 4) which is a vitamin E deficiency responsible gene. That’s why vitamin E levels are lower than in normal groups. They had, in addition, the hypophyseal adenoma. In contrast, we found normal levels of vitamin E and prolactin in parents. But, they were heterozygous for «744 del A» mutation (Fig. 4). We suggest that vitamin E deficiency segregates simultaneously with hyperprolactinemia in this family. Effects of vitamin E on the prolactin secretion of the pituitary gonadal axis will be discussed.

4. Discussion The neurological syndrome in the apparently sporadic case of vitamin E deficiency ataxia described here is similar to previously reported cases [2,6,7]. The presence of the adenoma with prolactin and FSH secretion in this patient may have been fortuitous, since it was not reported in similar cases, and the regression of the tumor during a-tocopherol treatment may have been spontaneous. In uremic patients on hemodialysis, oral vitamin E (300 mg / day) significantly increased serum vitamin E and reduced prolactin levels, without affecting FSH, LH or free testosterone concentrations [10]. Vitamin E lowers the recurrence rate of adenoma and can be proposed as chemopreventive agent [9]. These results show that vitamin E treatment reduces prolactin level in vitamin E deficient patients. This might be due to inhibition of central prolactin secretion. The

treatment of pituitary adenomas with dopamine agonists allows reduction of hormone hypersecretion and tumor size in the majority of the patients with prolactinomas [4]. We supposed that vitamin E may have the effects on Dopamine which also inhibits ant-hypophyseal prolactin secretion. It is possible, that vitamin E is the antioxidant involved in Dopa decarboxylation reaction to produce Dopamine. This reaction must be activated by an unknown antioxidant. Probably, this antioxidant might be a vitamin E which has the same effect as Dopamine agonists on hyperprolactinemia. On the basis of alpha-tocopherol results, previous studies were designed to measure the effects of vitamin E deficiency on the cortisol concentration in the blood constituents. The vitamin E had increased blood cortisol concentration. Although, plasma cortisol concentration indicated that cortisol level decreased in our patient to 59 ng / ml / 8h (VN560–230 ng / ml / 8h). The regulator effect of cortisol on enzymes of dopamine production has been already described. Probably, this correlation between vitamin E level and cortisol concentration explains another effect of vitamin E on Dopamine and in second time on prolactin secreting adenoma. The original research carried out in the 1920s found that a vitamin E deficiency in rats produced problems in their reproductive capacity [5]. Our histologic analysis confirmed this idea by revealing an increase of folliclestimulating hormone (FSH). Therefore, vitamin E stimulated secretion of hypophyseal and peripheral sex hormones and might usefully be tested in other adenoma patients. It would be of interest to systematically investigate the hypophyseal axis in such patients for subclinical alterations that might escape routine detection.

A. Benomar et al. / Journal of the Neurological Sciences 162 (1999) 97 – 101

5. Conclusion The exact mechanism(s) of the chemopreventive effect of antioxidant vitamins in humans are still unknown. The possible antitumoral effect of vitamin E has been less investigated. The results of the present study provide evidence that vitamin E, taken daily, are similar to Dopamine agonists effective in reducing the recurrence rate of prolactinoma indicating that probably, vitamin E can have an effect on Dopamine which also regulated prolactin secretion.



[5] [6]

Acknowledgements The authors are grateful to Pr Najat Boukhrissi for performing the radiological investigations and Drs Merle Ruberg, Bertrand Fontaine, Fatiha Lahjouji and Kabbaj Asmae for critical reading of the manuscript.





References [11] [1] Burck U, Goebel HH, Kuhlendahl HD, Meier C, Goebel KM. Neuropathy and vitamin E deficiency in man. Neuropediatrics 1981;12:267–78. [2] Ben hamida M, Belal S, Sirugo G, et al. Friedreich’s ataxia


phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families. Neurology 1993;43:2179–83. Ben hamida C, Doerflinger N, Belal S, et al. Localisation of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nature Genet 1993;5:195–200. D’angelo VA, Fiumara E, Scillitani A, et al. In vivo visualization of pituitary dopaminergic receptors by Iodine-123 methoxybeuzamide (IBZM) correlates with sensitivity to dopamine agonists in macroprolactinomas. J Neurosurg Sci 1995;39(2):112. Gray MA. Vitamin E: hype or hope. Orthopaed Nurs 1996;15(4):55– 7. Kayden HJ. The neurologic syndrome of vitamin E deficiency: A significant cause of ataxia. Neurology 1993;43:2167–9. Laplante P, Vanasse M, Michaud J, Geoffroy G, Brochu P. A progressive neurological syndrome associated with an isolated vitamin E deficiency. Can J Neurol Sci 1984;11:561–4. Peter Mcl, Black DWA, Klibanski B, et al. Hormone production in clinically nonfunctioning pituitary adenomas. J Neurosurg 1987;66:244–250. Roncucci L, Didonato P, Carati L, et al. Antioxidant vitamins or lactulose for the prevention of the recurrence of colorectal adenomas. Dis Colon Rectum 1993;36:227–34. Yeksan M, Polat M, Turk S, et al. Effect of vitamin E therapy on sexual functions of uremic patients in hemodialysis. Int J Artificial Org 1995;15(11):648–52. Doerflinger N, Linder C, Ouahchi K, et al. Ataxia with vitamin E deficiency: refinement of genetic localisation and analysis of linkage disequilibrium by using new markers in 14 families. Am J Hum Genet 1995;56:1116–24.

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