Ataxia with vitamin E deficiency: Biochemical effects of malcompliance with vitamin E therapy

Schuelke, Markus; Finckh, Barbara; Sistermans, Erik A.; Ausems, Margreet G. E. M.; Hübner, Christoph; Moers, A von

doi:10.1212/wnl.55.10.1584

Cited by 21 publications

(18 citation statements)

References 10 publications

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“…Cardiac involvement was also rare, occurring only in Moroccan and Tunisian patients. Several other symptoms, such as dystonia (Yokota et al, 1987;Cavalier et al, 1998;Schuelke et al, 2000;Angelini et al, 2002), myoclonus (Yokota et al, 1987;Angelini et al, 2002), tongue fasciculations (Martinello et al, 1998;Roubertie et al, 2003) and deafness (Shimohata et al, 1998;Usuki et al, 2000), are considered to be rare findings in patients with AVED and were not observed in our patients. Wheelchair-bound age reported for some of our patients was variable, as reported by Cavalier et al (1998), andMariotti et al (2004) despite vitamin E treatment.…”

Section: Clinical Featuresmentioning

confidence: 64%

Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency

Euch-Fayache

Bouhlal

Amouri

et al. 2013

Brain

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Ataxia with vitamin E deficiency is an autosomal recessive cerebellar ataxia caused by mutations in the a-tocopherol transfer protein coding gene localized on chromosome 8q, leading to lower levels of serum vitamin E. More than 91 patients diagnosed with ataxia with vitamin E deficiency have been reported worldwide. The majority of cases originated in the Mediterranean region, and the 744delA was the most common mutation among the 22 mutants previously described. We examined the clinical and molecular features of a large cohort of 132 Tunisian patients affected with ataxia with vitamin E deficiency. Of these patients, nerve conduction studies were performed on 45, and nerve biopsy was performed on 13. Serum vitamin E was dramatically reduced for 105 of the patients analysed. Molecular analysis revealed that 91.7% of the patients (n = 121) were homozygous for the 744delA mutation. Three other mutations were detected among the remaining patients (8.3%, n = 11) in the homozygous state. Two were previously reported (400C4T and 205-1G4T), and one was novel (553 + 1T4A). Age of onset was 13.2 AE 5.9 years, with extremes of 2 and 37 years. All described patients exhibited persistent progressive cerebellar ataxia with generally absent tendon reflexes. Deep sensory disturbances, pyramidal syndrome and skeletal deformities were frequent. Head tremor was present in 40% of the patients. Absence of neuropathy or mild peripheral neuropathy was noted in more than half of the cohort. This is the largest study of the genetic, clinical and peripheral neuropathic characteristics in patients with ataxia and vitamin E deficiency. The 744delA mutation represents the most common pathological mutation in Tunisia and worldwide, likely because of a Mediterranean founder effect. Our study led us to suggest that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation, even in the absence of a serum vitamin E measurement.

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Section: Clinical Featuresmentioning

confidence: 64%

Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency

Euch-Fayache

Bouhlal

Amouri

et al. 2013

Brain

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“…We found that E− larvae sustain marked locomotor deficits in response to light/dark stimuli (Figure 2). An established symptom of overt VitE deficiency in humans and rodent is spinocerebellar ataxia [28,29], therefore outcomes of our locomotor assay alone were insufficient to indicate specifically cognitive impairments in the E− larvae because lasting motor-related neuropathologies could contribute to the reduced locomotor response observed in the E-group. To deduce specifically whether this outcome was due to cognitive, motor, or perceptual (e.g.…”

Section: Discussionmentioning

confidence: 99%

Vitamin E deficiency during embryogenesis in zebrafish causes lasting metabolic and cognitive impairments despite refeeding adequate diets

McDougall

Choi

Truong

et al. 2017

Free Radical Biology and Medicine

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Vitamin E (α-tocopherol; VitE) is a lipophilic antioxidant required for normal embryonic development in vertebrates, but the long-term effects of embryonic VitE deficiency, and whether they are ameliorated by feeding VitE−adequate diets, remain unknown. We addressed these questions using a zebrafish (Danio rerio) model of developmental VitE deficiency followed by dietary remediation. Adult zebrafish maintained on VitE−deficient (E−) or sufficient (E+) diets were spawned to obtained E− and E+ embryos, respectively, which we evaluated up to 12 days post-fertilization (dpf). The E− group suffered significantly increased morbidity and mortality as well as altered DNA methylation status through 5 dpf when compared to E+ larvae, but upon feeding with a VitE-adequate diet from 5–12 dpf both the E− and E+ groups survived and grew normally; the DNA methylation profile also was similar between groups by 12 dpf. However, 12 dpf E− larvae still had behavioral defects. These observations coincided with sustained VitE deficiency in the E− vs. E+ larvae (p< 0.0001), despite adequate dietary supplementation. We also found in E− vs. E+ larvae continued docosahexaenoic acid (DHA) depletion (p< 0.0001) and significantly increased lipid peroxidation. Further, targeted metabolomics analyses revealed persistent dysregulation of the cellular antioxidant network, the CDP-choline pathway, and glucose metabolism. While anaerobic processes were increased, aerobic metabolism was decreased in the E− vs. E+ larvae, indicating mitochondrial damage. Taken together, these outcomes suggest embryonic VitE deficiency causes lasting behavioral impairments due to persistent lipid peroxidation and metabolic perturbations that are not resolved via later dietary VitE supplementation.

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“…Malabsorption of vitamin E, including in abetalipoproteinaemia, can result in a similar phenotype. Patients may need replacement doses of up to 1500 mg/day 15…”

Section: Introductionmentioning

confidence: 99%

Diagnosis and management of progressive ataxia in adults

Silva¹,

Vallortigara

Greenfield

et al. 2019

Pract Neurol

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Progressive ataxia in adults can be difficult to diagnose, owing to its heterogeneity and the rarity of individual causes. Many patients remain undiagnosed (‘idiopathic’ ataxia). This paper provides suggested diagnostic pathways for the general neurologist, based on Ataxia UK’s guidelines for professionals. MR brain scanning can provide diagnostic clues, as well as identify ‘structural’ causes such as tumours and multiple sclerosis. Advances in molecular genetics, including the wider and cheaper availability of ‘next-generation sequencing’, have enabled clinicians to identify many more cases with a genetic cause. Finally, autoimmunity is probably an under-recognised cause of progressive ataxia: as well as patients with antigliadin antibodies there are smaller numbers with various antibodies, including some associated with cancer. There are a few treatable ataxias, but also symptomatic treatments to help people with the spectrum of complications that might accompany progressive ataxias. Multidisciplinary team involvement and allied health professionals’ input are critical to excellent patient care, including in the palliative phase. We can no longer justify a nihilistic approach to the management of ataxia.

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Ataxia with vitamin E deficiency: Biochemical effects of malcompliance with vitamin E therapy

Cited by 21 publications

References 10 publications

Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency

Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency

Vitamin E deficiency during embryogenesis in zebrafish causes lasting metabolic and cognitive impairments despite refeeding adequate diets

Diagnosis and management of progressive ataxia in adults

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