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Retinitis pigmentosa and macular degeneration in a patient with ataxia with isolated vitamin E deficiency with a novel c.717 del C mutation in the TTPA gene
Journal of the Neurological Sciences 345 (2014) 228–230
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Retinitis pigmentosa and macular degeneration in a patient with ataxia with isolated vitamin E deficiency with a novel c.717 del C mutation in the TTPA gene Kazuo Iwasa a,⁎,1, Keisuke Shima a,1, Kiyonobu Komai b, Yoichiro Nishida c, Takanori Yokota c, Masahito Yamada a a b c
Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Japan Department of Neurology, National Hospital Organization Iou National Hospital, Japan Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan
a r t i c l e
i n f o
Article history: Received 2 February 2014 Received in revised form 29 May 2014 Accepted 1 July 2014 Available online 9 July 2014 Keywords: Alpha-tocopherol transfer protein Macular degeneration Vitamin E deficiency Ataxia Retinitis pigmentosa TTPA gene mutation
a b s t r a c t Ataxia with isolated vitamin E deficiency (AVED) is a neurodegenerative disease caused by a mutation in the α-tocopherol transfer protein gene (TTPA). The clinical features of the disease resemble Friedreich's ataxia. However, AVED is associated with low plasma vitamin E levels, which results in compromised antioxidant function. Dysregulation of this lipid-soluble antioxidant vitamin plays a major role in the neurodegeneration observed in AVED. Some AVED patients experience decreased visual acuity. Retinitis pigmentosa is thought to be the main cause of this visual impairment. Although antioxidant levels are important for the prevention of macular degeneration, there have been no reports of macular degeneration in AVED. Here, we describe a patient with AVED with progressive macular degeneration, who carried a novel truncating mutation—c.717 del C (p.D239EfsX25)—in exon 5 of the TTPA gene. These findings suggest that this newly identified mutation results in severely low serum vitamin E levels, which may be associated with the development of retinitis pigmentosa and macular degeneration. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Ataxia with isolated vitamin E deficiency (AVED) is an autosomal recessive neurodegenerative disease. Clinical features include cerebellar ataxia, dysarthria, lower limb areflexia, as well as the loss of proprioception, sense of vibration, and bilateral extensor plantar reflexes [1]. AVED is caused by mutations in the α-tocopherol transfer protein gene (TTPA) located on chromosome 8q13 (GeneBank number NM_000370) [2]. The α-tocopherol transfer protein (α-TTP) is a liver protein that transfers vitamin E (α-tocopherol) to a very-low-density lipoprotein (VLDL). VLDLs circulate throughout the body and regulate plasma vitamin E levels [3]. AVED patients have very low serum vitamin E levels because a mutation in α-TTP inhibits its ability to bind VLDL.
⁎ Corresponding author at: Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan. Tel.: +81 76 265 2292; fax: +81 76 234 4253. E-mail addresses: [email protected] (K. Iwasa), [email protected] (K. Shima), [email protected] (K. Komai), [email protected] (Y. Nishida), [email protected] (T. Yokota), [email protected] (M. Yamada). 1 These authors contributed equally.
http://dx.doi.org/10.1016/j.jns.2014.07.001 0022-510X/© 2014 Elsevier B.V. All rights reserved.
The loss of antioxidative function that results from vitamin E deficiency may be the underlying cause of the neurodegeneration observed in AVED [4]. Some AVED patients present with retinitis pigmentosa, presumably due to a loss of the protective antioxidant effects of vitamin E [5,6]. However, while low levels of micronutrients and antioxidants, including vitamin E, can cause macular degeneration [7,8], this condition has not yet been reported in AVED. Here, we report a novel TTPA gene mutation (c.717 del C) in a patient of AVED with both retinitis pigmentosa and macular degeneration. 2. Case report A 48-year-old woman was presented with a 36-year history of progressive gait disturbance and dysarthria and a 21-year history of visual disturbance. She first presented at the age of 18 with slow, slurred speech and clumsy hands. At the age of 27, she was admitted to our hospital for the first time. A neurological examination confirmed the presence of visual disturbances including a loss of peripheral vision and nystagmus, slurred speech, absence of deep tendon reflexes, bilateral Babinski sign, trunk ataxia, loss of proprioception, and bilateral pes cavus. She was diagnosed with Friedreich's ataxia with macular degeneration (Fig. 1). Although her maternal grandmother and father were cousins, there was no family history of ataxia or visual disorders,
K. Iwasa et al. / Journal of the Neurological Sciences 345 (2014) 228–230
229
Fig. 1. Ophthalmoscopic examination of patient's fundi: Micrographs in the left and right panels were taken at 33 (A and C) and 48 years of age (B and D), respectively. Fluorescein angiograms of the ocular fundi are shown in the bottom panels (C and D). At 33 years of age, the patient had some retinal pigmentation (arrows), and minor changes were observed in the macular images taken during ophthalmoscopy (A). Fundus fluorescein angiography revealed the presence of a neovascular lesion in the right eye (C). An ophthalmoscopic examination at age 48 showed severe and progressive neovascular macular degeneration with retinal pigmentation (B and D).
including macular degeneration. Prior to her second hospital admission at the age of 48, her serum vitamin E level was measured at 0.12 mg/dl (normal values, 0.75–1.41 mg/dl), and her neurological symptoms and visual disturbances had progressed. A blood analysis identified slightly elevated liver enzyme and total cholesterol (234 mg/dl) levels. Her triglyceride (104 mg/dl) and high-density lipoprotein (HDL) cholesterol (59 mg/dl) levels were normal. The percentage of lipoprotein was normal. Brain magnetic resonance imaging (MRI) showed minimal atrophy of the mesencephalon and cerebellum, and a small right periventricular infarct lesion was also detected. There was no abnormality on electrocardiography (ECG). Nerve conduction studies indicated that the median and ulnar motor nerve conduction velocities and distal latencies were normal. Although the median and ulnar sensory nerves showed normal conduction velocities, the sensory latencies in these nerves were delayed (5.95 and 3.75 ms, respectively), and the sensory nerve action potentials were decreased (3.2 and 1.15 μV, respectively).
Sural nerve action potentials were not detected. Electromyogram did not detect active denervations or chronic re-innervations. An ophthalmologic examination identified the presence of macular degeneration and retinal pigmentation, and optic nerve atrophy was also detected (Fig. 1). Visual acuity and peripheral vision were assessed with hand motions in the bilateral visual field. After written consent was obtained from the patient, all exons of the TTPA gene were analyzed by direct nucleotide sequencing. These analyses revealed a homozygous single nucleotide deletion of C at position 717 on exon 5 of the TTPA gene (Fig. 2). After diagnosis, 800 mg/day of vitamin E was administered. 3. Discussion AVED is clinically characterized by progressive cerebellar ataxia, dysarthria, loss of proprioception and sense of vibration, and the
Fig. 2. DNA sequence of exon 5 of the TTPA gene (A) and electrophoresis of target DNA (B). While the normal sequence from position 715 is GACATTCTTC, we detected a homozygous point deletion of C at nucleotide position 717 in the TTPA gene: GAATTCTTC. This deletion produced a frameshift mutation in the TTPA gene (c.717 delC, p.D239EfsX25) (A). The restriction enzyme EcoRI can cut at an additional site in the mutant allele (GAATTC cut into G and AATTC) in comparison to the normal allele. In the normal exon 5 allele of the TTPA gene, EcoRI digested this 269-bp sequence into two products that are 148 and 121 bp (lane EcoRI (+) in the NA lane), whereas in this patient's allele (Pt lanes), the EcoRI digestion of this 268-bp sequence produced three products of 148, 91, and 29 bp because of the additional EcoRI digestion site (B). NA: normal allele, Pt: patient's allele.
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K. Iwasa et al. / Journal of the Neurological Sciences 345 (2014) 228–230
absence of tendon and extensor plantar reflexes [1]. Vitamin E is an antioxidant that is incorporated into VLDL and prevents lipid oxidation. Vitamin E deficiency results in compromised scavenging functions and plays a major role in the neurodegeneration observed in AVED [4]. AVED is caused by mutations in the TTPA gene. The resulting vitamin E deficiency is more severe in cases involving a truncating mutation or a non-conservative missense mutation in comparison to a semiconservative missense mutation [4]. The heterogeneity of the disease may therefore correlate with the different mutations, affecting the clinical manifestation of the disease and also the response to treatment [9]. The novel homozygous single nucleotide deletion (c.717 del C) identified in the present case resembles the clinical features of c.744 del A, which is a severe type of AVED. Both of these single nucleotide deletions produce frameshift mutations that introduce a premature stop codon at the same site. However, our patient presented with progressive macular degeneration, a unique clinical feature of AVED. Therefore, the homozygous c.717 del C mutation, which results in the replacement of the last 40 amino acids by an aberrant 25-amino acid peptide, might alter α-TTP function in a unique way [10]. The macula is sensitive to oxidative damage. Cumulative oxidative damage may therefore have an important role in age-related macular degeneration [7], and lower vitamin E serum levels may be associated with increased risk for macular degeneration [8]. Indeed, an association between the accumulation of lipofuscin pigments (oxidized lipoprotein) and age-related macular degeneration has been reported [11]. Elevated levels of lipofuscin pigments may arise as a consequence of antioxidant deficiency. In the present case study, vitamin E deficiency resulted in retinal degeneration [6], and excess lipofuscin accumulation in the retina may have caused macular degeneration in our patient [12]. Although we could not find any family history of visual problems, we should exclude other genetic causes of macular degeneration, such as mutations in APOE, HMCN1, CFHR3, CFHR1, and PLEKHA1 [13,14]. Here, we report a case of AVED with both retinitis pigmentosa and macular degeneration in which we identified a novel mutation c.717 del C (p.D239EfsX25) in the TTPA gene. Severe and long-term vitamin E deficiency due to the novel mutation may have led to the development of both macular degeneration and progressive ataxia in our patient. Some AVED patients may present with an acceleration of age-related macular degeneration, showing symptoms in their early senior years. Administration of vitamin E may delay the progression of the clinical features of AVED, including retinal and macular degeneration.
Conflict of interest statement The authors declare that they have no conflicts of interest.
Acknowledgments Funding was not required for this work.
References [1] Mariotti C, Gellera C, Rimoldi M, Mineri R, Uziel G, Zorzi G, et al. Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci 2004;25(3):130–7. [2] Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 1995;9(2):141–5. [3] Zingg JM. Vitamin E: an overview of major research directions. Mol Aspects Med 2007;28(5–6):400–22. [4] Di Donato I, Bianchi S, Federico A. Ataxia with vitamin E deficiency: update of molecular diagnosis. Neurol Sci 2010;31(4):511–5. [5] Yokota T, Shiojiri T, Gotoda T, Arai H. Retinitis pigmentosa and ataxia caused by a mutation in the gene for the alpha-tocopherol-transfer protein. N Engl J Med 1996;335(23):1770–1. [6] Tanito M, Yoshida Y, Kaidzu S, Chen ZH, Cynshi O, Jishage K, et al. Acceleration of age-related changes in the retina in alpha-tocopherol transfer protein null mice fed a vitamin E-deficient diet. Invest Ophthalmol Vis Sci 2007;48(1):396–404. [7] Porter L, Reynolds N, Ellis JD. Total parenteral nutrition, vitamin E, and reversible macular dysfunction morphologically mimicking age related macular degeneration. Br J Ophthalmol 2005;89(11):1531–2. [8] Schleicher M, Weikel K, Garber C, Taylor A. Diminishing risk for age-related macular degeneration with nutrition: a current view. Nutrients 2013;5(7):2405–56. [9] Aparicio JM, Belanger-Quintana A, Suarez L, Mayo D, Benitez J, Diaz M, et al. Ataxia with isolated vitamin E deficiency: case report and review of the literature. J Pediatr Gastroenterol Nutr 2001;33(2):206–10. [10] Bromley D, Anderson PC, Daggett V. Structural consequences of mutations to the alpha-tocopherol transfer protein associated with the neurodegenerative disease ataxia with vitamin E deficiency. Biochemistry 2013;52(24):4264–73. [11] Torrini M, Marchese C, Vanzetti M, Marini V, Origone P, Garre C, et al. Mutation analysis of oxisterol-binding-protein gene in patients with age-related macular degeneration. Genet Test 2007;11(4):421–6. [12] Yokota T, Uchihara T, Kumagai J, Shiojiri T, Pang JJ, Arita M, et al. Postmortem study of ataxia with retinitis pigmentosa by mutation of the alpha-tocopherol transfer protein gene. J Neurol Neurosurg Psychiatry 2000;68(4):521–5. [13] Fisher SA, Rivera A, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, et al. Case-control genetic association study of fibulin-6 (FBLN6 or HMCN1) variants in age-related macular degeneration (AMD). Hum Mutat 2007;28(4):406–13. [14] Puche N, Blanco-Garavito R, Richard F, Leveziel N, Zerbib J, Tilleul J, et al. Genetic and environmental factors associated with reticular pseudodrusen in age-related macular degeneration. Retina 2013;33(5):998–1004.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Retinitis pigmentosa and macular degeneration in a patient with ataxia with isolated vitamin E deficiency with a novel c.717 del C mutation in the TTPA gene Kazuo Iwasa a,⁎,1, Keisuke Shima a,1, Kiyonobu Komai b, Yoichiro Nishida c, Takanori Yokota c, Masahito Yamada a a b c
Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Japan Department of Neurology, National Hospital Organization Iou National Hospital, Japan Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan
a r t i c l e
i n f o
Article history: Received 2 February 2014 Received in revised form 29 May 2014 Accepted 1 July 2014 Available online 9 July 2014 Keywords: Alpha-tocopherol transfer protein Macular degeneration Vitamin E deficiency Ataxia Retinitis pigmentosa TTPA gene mutation
a b s t r a c t Ataxia with isolated vitamin E deficiency (AVED) is a neurodegenerative disease caused by a mutation in the α-tocopherol transfer protein gene (TTPA). The clinical features of the disease resemble Friedreich's ataxia. However, AVED is associated with low plasma vitamin E levels, which results in compromised antioxidant function. Dysregulation of this lipid-soluble antioxidant vitamin plays a major role in the neurodegeneration observed in AVED. Some AVED patients experience decreased visual acuity. Retinitis pigmentosa is thought to be the main cause of this visual impairment. Although antioxidant levels are important for the prevention of macular degeneration, there have been no reports of macular degeneration in AVED. Here, we describe a patient with AVED with progressive macular degeneration, who carried a novel truncating mutation—c.717 del C (p.D239EfsX25)—in exon 5 of the TTPA gene. These findings suggest that this newly identified mutation results in severely low serum vitamin E levels, which may be associated with the development of retinitis pigmentosa and macular degeneration. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Ataxia with isolated vitamin E deficiency (AVED) is an autosomal recessive neurodegenerative disease. Clinical features include cerebellar ataxia, dysarthria, lower limb areflexia, as well as the loss of proprioception, sense of vibration, and bilateral extensor plantar reflexes [1]. AVED is caused by mutations in the α-tocopherol transfer protein gene (TTPA) located on chromosome 8q13 (GeneBank number NM_000370) [2]. The α-tocopherol transfer protein (α-TTP) is a liver protein that transfers vitamin E (α-tocopherol) to a very-low-density lipoprotein (VLDL). VLDLs circulate throughout the body and regulate plasma vitamin E levels [3]. AVED patients have very low serum vitamin E levels because a mutation in α-TTP inhibits its ability to bind VLDL.
⁎ Corresponding author at: Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan. Tel.: +81 76 265 2292; fax: +81 76 234 4253. E-mail addresses: [email protected] (K. Iwasa), [email protected] (K. Shima), [email protected] (K. Komai), [email protected] (Y. Nishida), [email protected] (T. Yokota), [email protected] (M. Yamada). 1 These authors contributed equally.
http://dx.doi.org/10.1016/j.jns.2014.07.001 0022-510X/© 2014 Elsevier B.V. All rights reserved.
The loss of antioxidative function that results from vitamin E deficiency may be the underlying cause of the neurodegeneration observed in AVED [4]. Some AVED patients present with retinitis pigmentosa, presumably due to a loss of the protective antioxidant effects of vitamin E [5,6]. However, while low levels of micronutrients and antioxidants, including vitamin E, can cause macular degeneration [7,8], this condition has not yet been reported in AVED. Here, we report a novel TTPA gene mutation (c.717 del C) in a patient of AVED with both retinitis pigmentosa and macular degeneration. 2. Case report A 48-year-old woman was presented with a 36-year history of progressive gait disturbance and dysarthria and a 21-year history of visual disturbance. She first presented at the age of 18 with slow, slurred speech and clumsy hands. At the age of 27, she was admitted to our hospital for the first time. A neurological examination confirmed the presence of visual disturbances including a loss of peripheral vision and nystagmus, slurred speech, absence of deep tendon reflexes, bilateral Babinski sign, trunk ataxia, loss of proprioception, and bilateral pes cavus. She was diagnosed with Friedreich's ataxia with macular degeneration (Fig. 1). Although her maternal grandmother and father were cousins, there was no family history of ataxia or visual disorders,
K. Iwasa et al. / Journal of the Neurological Sciences 345 (2014) 228–230
229
Fig. 1. Ophthalmoscopic examination of patient's fundi: Micrographs in the left and right panels were taken at 33 (A and C) and 48 years of age (B and D), respectively. Fluorescein angiograms of the ocular fundi are shown in the bottom panels (C and D). At 33 years of age, the patient had some retinal pigmentation (arrows), and minor changes were observed in the macular images taken during ophthalmoscopy (A). Fundus fluorescein angiography revealed the presence of a neovascular lesion in the right eye (C). An ophthalmoscopic examination at age 48 showed severe and progressive neovascular macular degeneration with retinal pigmentation (B and D).
including macular degeneration. Prior to her second hospital admission at the age of 48, her serum vitamin E level was measured at 0.12 mg/dl (normal values, 0.75–1.41 mg/dl), and her neurological symptoms and visual disturbances had progressed. A blood analysis identified slightly elevated liver enzyme and total cholesterol (234 mg/dl) levels. Her triglyceride (104 mg/dl) and high-density lipoprotein (HDL) cholesterol (59 mg/dl) levels were normal. The percentage of lipoprotein was normal. Brain magnetic resonance imaging (MRI) showed minimal atrophy of the mesencephalon and cerebellum, and a small right periventricular infarct lesion was also detected. There was no abnormality on electrocardiography (ECG). Nerve conduction studies indicated that the median and ulnar motor nerve conduction velocities and distal latencies were normal. Although the median and ulnar sensory nerves showed normal conduction velocities, the sensory latencies in these nerves were delayed (5.95 and 3.75 ms, respectively), and the sensory nerve action potentials were decreased (3.2 and 1.15 μV, respectively).
Sural nerve action potentials were not detected. Electromyogram did not detect active denervations or chronic re-innervations. An ophthalmologic examination identified the presence of macular degeneration and retinal pigmentation, and optic nerve atrophy was also detected (Fig. 1). Visual acuity and peripheral vision were assessed with hand motions in the bilateral visual field. After written consent was obtained from the patient, all exons of the TTPA gene were analyzed by direct nucleotide sequencing. These analyses revealed a homozygous single nucleotide deletion of C at position 717 on exon 5 of the TTPA gene (Fig. 2). After diagnosis, 800 mg/day of vitamin E was administered. 3. Discussion AVED is clinically characterized by progressive cerebellar ataxia, dysarthria, loss of proprioception and sense of vibration, and the
Fig. 2. DNA sequence of exon 5 of the TTPA gene (A) and electrophoresis of target DNA (B). While the normal sequence from position 715 is GACATTCTTC, we detected a homozygous point deletion of C at nucleotide position 717 in the TTPA gene: GAATTCTTC. This deletion produced a frameshift mutation in the TTPA gene (c.717 delC, p.D239EfsX25) (A). The restriction enzyme EcoRI can cut at an additional site in the mutant allele (GAATTC cut into G and AATTC) in comparison to the normal allele. In the normal exon 5 allele of the TTPA gene, EcoRI digested this 269-bp sequence into two products that are 148 and 121 bp (lane EcoRI (+) in the NA lane), whereas in this patient's allele (Pt lanes), the EcoRI digestion of this 268-bp sequence produced three products of 148, 91, and 29 bp because of the additional EcoRI digestion site (B). NA: normal allele, Pt: patient's allele.
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K. Iwasa et al. / Journal of the Neurological Sciences 345 (2014) 228–230
absence of tendon and extensor plantar reflexes [1]. Vitamin E is an antioxidant that is incorporated into VLDL and prevents lipid oxidation. Vitamin E deficiency results in compromised scavenging functions and plays a major role in the neurodegeneration observed in AVED [4]. AVED is caused by mutations in the TTPA gene. The resulting vitamin E deficiency is more severe in cases involving a truncating mutation or a non-conservative missense mutation in comparison to a semiconservative missense mutation [4]. The heterogeneity of the disease may therefore correlate with the different mutations, affecting the clinical manifestation of the disease and also the response to treatment [9]. The novel homozygous single nucleotide deletion (c.717 del C) identified in the present case resembles the clinical features of c.744 del A, which is a severe type of AVED. Both of these single nucleotide deletions produce frameshift mutations that introduce a premature stop codon at the same site. However, our patient presented with progressive macular degeneration, a unique clinical feature of AVED. Therefore, the homozygous c.717 del C mutation, which results in the replacement of the last 40 amino acids by an aberrant 25-amino acid peptide, might alter α-TTP function in a unique way [10]. The macula is sensitive to oxidative damage. Cumulative oxidative damage may therefore have an important role in age-related macular degeneration [7], and lower vitamin E serum levels may be associated with increased risk for macular degeneration [8]. Indeed, an association between the accumulation of lipofuscin pigments (oxidized lipoprotein) and age-related macular degeneration has been reported [11]. Elevated levels of lipofuscin pigments may arise as a consequence of antioxidant deficiency. In the present case study, vitamin E deficiency resulted in retinal degeneration [6], and excess lipofuscin accumulation in the retina may have caused macular degeneration in our patient [12]. Although we could not find any family history of visual problems, we should exclude other genetic causes of macular degeneration, such as mutations in APOE, HMCN1, CFHR3, CFHR1, and PLEKHA1 [13,14]. Here, we report a case of AVED with both retinitis pigmentosa and macular degeneration in which we identified a novel mutation c.717 del C (p.D239EfsX25) in the TTPA gene. Severe and long-term vitamin E deficiency due to the novel mutation may have led to the development of both macular degeneration and progressive ataxia in our patient. Some AVED patients may present with an acceleration of age-related macular degeneration, showing symptoms in their early senior years. Administration of vitamin E may delay the progression of the clinical features of AVED, including retinal and macular degeneration.
Conflict of interest statement The authors declare that they have no conflicts of interest.
Acknowledgments Funding was not required for this work.
References [1] Mariotti C, Gellera C, Rimoldi M, Mineri R, Uziel G, Zorzi G, et al. Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci 2004;25(3):130–7. [2] Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 1995;9(2):141–5. [3] Zingg JM. Vitamin E: an overview of major research directions. Mol Aspects Med 2007;28(5–6):400–22. [4] Di Donato I, Bianchi S, Federico A. Ataxia with vitamin E deficiency: update of molecular diagnosis. Neurol Sci 2010;31(4):511–5. [5] Yokota T, Shiojiri T, Gotoda T, Arai H. Retinitis pigmentosa and ataxia caused by a mutation in the gene for the alpha-tocopherol-transfer protein. N Engl J Med 1996;335(23):1770–1. [6] Tanito M, Yoshida Y, Kaidzu S, Chen ZH, Cynshi O, Jishage K, et al. Acceleration of age-related changes in the retina in alpha-tocopherol transfer protein null mice fed a vitamin E-deficient diet. Invest Ophthalmol Vis Sci 2007;48(1):396–404. [7] Porter L, Reynolds N, Ellis JD. Total parenteral nutrition, vitamin E, and reversible macular dysfunction morphologically mimicking age related macular degeneration. Br J Ophthalmol 2005;89(11):1531–2. [8] Schleicher M, Weikel K, Garber C, Taylor A. Diminishing risk for age-related macular degeneration with nutrition: a current view. Nutrients 2013;5(7):2405–56. [9] Aparicio JM, Belanger-Quintana A, Suarez L, Mayo D, Benitez J, Diaz M, et al. Ataxia with isolated vitamin E deficiency: case report and review of the literature. J Pediatr Gastroenterol Nutr 2001;33(2):206–10. [10] Bromley D, Anderson PC, Daggett V. Structural consequences of mutations to the alpha-tocopherol transfer protein associated with the neurodegenerative disease ataxia with vitamin E deficiency. Biochemistry 2013;52(24):4264–73. [11] Torrini M, Marchese C, Vanzetti M, Marini V, Origone P, Garre C, et al. Mutation analysis of oxisterol-binding-protein gene in patients with age-related macular degeneration. Genet Test 2007;11(4):421–6. [12] Yokota T, Uchihara T, Kumagai J, Shiojiri T, Pang JJ, Arita M, et al. Postmortem study of ataxia with retinitis pigmentosa by mutation of the alpha-tocopherol transfer protein gene. J Neurol Neurosurg Psychiatry 2000;68(4):521–5. [13] Fisher SA, Rivera A, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, et al. Case-control genetic association study of fibulin-6 (FBLN6 or HMCN1) variants in age-related macular degeneration (AMD). Hum Mutat 2007;28(4):406–13. [14] Puche N, Blanco-Garavito R, Richard F, Leveziel N, Zerbib J, Tilleul J, et al. Genetic and environmental factors associated with reticular pseudodrusen in age-related macular degeneration. Retina 2013;33(5):998–1004.