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CASE REPORT
Ataxia with vitamin E deficiency in the Philippines :A case report of two siblings
Ma. Daisy Tabuena1, Ryoma Morigaki2,3, Ryosuke Miyamoto4, Hideo Mure3,5, Nobuaki Yamamoto2,4, Kazuhisa Miyake3,Taku Matsuda3, Yuishin Izumi4, Yasushi Takagi2,3, Rollin P. Tabuena6, and Toshitaka Kawarai4
Outpatient Neurology Clinic, Asclepius Drugstore, Med Lab and Allied Services Corp., Iloilo City, Philippines, 2Department of Advanced
Brain Research, Institute of Biomedical Sciences, Graduate School of Medicine, Tokushima University, Tokushima, Japan, 3Department ofNeurosurgery, Institute of Biomedical Sciences, Graduate School of Medicine, Tokushima University, Tokushima, Japan, 4Department of Neurology, Institute of Biomedical Sciences, Graduate School of Medicine, Tokushima University, Tokushima, Japan, 5Neuromodulation Center,Kurashiki Heisei Hospital, Okayama, Japan, 6Outpatient Pulmonary Clinic, Asclepius Drugstore, Med Lab and Allied Services Corp., IloiloCity, Philippines
1Abstract : Here we report two siblings with ataxia and peripheral neuropathy. One patient showed head tremors. Genetic analysis revealed a mutation in the hepatic α-tocopherol transfer protein (α-TTP) gene (TTPA)on chromosome 8q13. They were diagnosed with ataxia with vitamin E deficiency which is firstly reported in
the Philippines. As the symptoms of ataxia with vitamin E deficiency can be alleviated with lifelong vitamin E
administration, differential diagnosis from similar syndromes is important. In addition, ataxia with vitamin
E deficiency causes movement disorders. Therefore, a common hereditary disease in the Philippines, X-linked
dystonia-parkinsonism, could be another differential diagnosis. The Philippines is an archipelago comprising
7,107 islands, and the prevalence of rare hereditary diseases among the populations of small islands is still
unclear. For neurologists, establishing a system of genetic diagnosis and counseling in rural areas remains
challenging. These unresolved problems should be addressed in the near future. J. Med. Invest. 68 : 400-403,
August, 2021
Keywords : ataxia with vitamin E deficiency, movement disorders, genetic medicine, alpha-tocopherol transfer protein

INTRODUCTION
Ataxia with vitamin E deficiency (AVED) is a rare autosomal
recessive inherited disease characterized by ataxia and peripheral neuropathy with a massive decrease in plasma vitamin Elevels (1). Epidemiological studies have shown that the prevalence of this condition is 0.6 and 3.5 per 1,000,000 people insoutheast Norway and Italy, respectively (2, 3). The causative
mutations have been identified in the hepatic α-tocopherol transfer protein (α-TTP) gene (TTPA) on chromosome 8q13 (4).
Vitamin E is a fat-soluble antioxidant and includes 10 homologs, namely, four tocopherols, four tocotrienol isoforms, and two
tocomonenols (5, 6). In the liver, α-tocopherol has the highestbiological activity among these isoforms, and dietary vitamin
E requirements in humans are limited only to α-tocopherol because other forms of vitamin E are poorly recognized by hepatic
α-TTP (7, 8). After intestinal absorption and transportation withchylomicrons, α-tocopherol is transferred to parenchymal cellsof the liver where most of the fat-soluble vitamins are stored.
α-TTP has a high binding affinity for α-tocopherol and facilitates
its incorporation into very-low-density lipoproteins (VLDL) andhigh-density lipoprotein (HDL) for secretion from the liver into
the circulation system (9-11). All tocopherols and tocotrienols act
as free radical scavengers in the membranes and lipoproteins,quenching fatty acid peroxyl radicals.
Only α-tocopherol has been tested for its potent antioxidative
Received for publication March 4, 2021 ; accepted August 29, 2021.
Address correspondence and reprint requests to Ryoma Morigaki,
MD, PhD., Department of Advanced Brain Research, Instituteof Biomedical Sciences, Graduate School of Medicine, Tokushima
University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan andFax : +81-88-632-9464.

properties, which show beneficial effects against AVED (6). Patients with AVED are unable to maintain normal plasma levelsof α-tocopherol due to impaired incorporation into VLDL andHDL, which may cause excessive oxidative stress on the body, including neural tissues, over time (11). Clinically, AVED generally manifests as progressive ataxia, clumsiness of the hands, andloss of proprioception as the first symptom between the ages 5and 15 years (12). Interestingly, patients with AVED experience
movement disorders such as head tremors in one-third of individuals and, in rare instances, myoclonus or dystonia (12-15). Here,
we report two siblings with AVED, which are the first case fromthe island of Panay, the Philippines, where a hereditary neurodegenerative disorder, X-linked dystonia-parkinsonism, also
known as DYT/PARK-TAF1 or “Lubag” disease, is endemic (16,17). The differential diagnosis of movement disorders is especially important and challenging for neurologists in this island.

CASE DESCRIPTION
We report two siblings with AVED, a 24-year-old male anda 30-year-old female. The symptoms began at approximately
16 years of age for the male patient and 19 years of age for thefemale patient, and they initially sought medical help 5 years ago
due to difficulty in walking, frequent falls, and slurring of speech
at a local neurology clinic on Panay Island, the Philippines. They
had no family history of ataxia or movement disorders (Fig. 1A).
Physical examination revealed cerebellar dysarthria, gait andlimb ataxia, mild weakness of the distal extremities, areflexia,
positive Romberg sign, and extensor plantar response in both patients. The female patient also experienced neck and head tremors. The mental status of the patients was normal. Head titubation
with Friedreich-like symptoms and early-onset cerebellar ataxia in

The Journal of Medical Investigation Vol. 68 2021

The Journal of Medical Investigation Vol. 68 August 2021
combination with peripheral neuropathy suggested AVED. Laboratory tests showed normal lipid and lipoprotein profiles, andundetectable plasma α-tocopherol concentrations (< 0.2 mg / L).
The analysis of TTPA at Tokushima University (ethical committee approval number : R2-10) revealed a homozygous missense
mutation, c.358G > A, in TTPA, leading to amino acid substitutions p.A120T. We performed genetic testing of other family
members (Fig. 1B). The siblings received genetic counseling on
the island of Panay and started receiving lifelong high-dose oralvitamin E supplementation (800 IU daily). Their symptoms improved after a 2-year follow-up. Currently, the severity of ataxia
in the male patient is very mild. He can perform the activities ofdaily life without assistance as well as heavy exercise. Presently,the female patient has residual very mild dysarthria ; her headtremors have decreased in intensity by 50%. The assessment
and rating of ataxia scores before and after vitamin E treatment
were 18 and 7 for the male, and 16 and 10 for the female patients,
respectively.

401DISCUSSION
Depending on the pathogenic variants of TTPA, there are differences in the AVED phenotype. If the amino acid substitutions
caused by variants of TTPA occur in non- or semi-conserved
amino acids, they cause a mild phenotype, whereas substitutions in highly conserved amino acids, cause severe symptoms(12). Different mutations have been reported in North Africa(c.744delA), Italy (c.744delA and c.513insTT), North Europe(c.513insTT), the Netherlands (c.175C > T and c.437delT), andJapan (c.552G > A) (18-20). The prevalence of the missense
mutation in the patients, c.358G > A (p.A120T), is relatively low
and caused mild symptoms. This mutation has been reported in
Norwegian and Belgian patients with AVED (3, 18) (Table 1).
All patients associated with this mutation manifested cerebellar ataxia, loss of proprioceptive and vibratory sensation, andhyporeflexia. Our patients had mild weakness possibly due toskeletal myopathies (1). Head titubation was observed only in
two female patients suffering for a relatively longer period. Further studies are necessary to reveal the prevalence of AVED in

Figure 1. Pedigree chart and sequence of the patients and other family members.

A : Pedigree of the sibling patients with a homozygous missense mutation in TTPA. Solid symbols, affectedindividuals ; circles, females ; squares, males.
B : Fluorescent chromatograms of TTPA exon 2 and 3 sequences of the family members. The homozygous
nucleotide variant c.358G > A (p.Ala418Thr) is indicated by the red arrows. Nucleotide and amino acidnumbers are based on the longest isoform (NM_000370).

M. D. Tabuena, et al. Ataxia with vitamin E deficiency

402

Table 1. Clinical characteristics of ataxia with vitamin E deficiency due to p.A120T mutation

Cavalier et al.
1998 (18)

Koht et al. 2009 (23),Elkamil et al. 2015 (3)Sex

Age atonset(y.o.)

Age atdiagnosis(y.o.)

Neurological symptoms

V.E. level atdiagnosis(mg / L)

Dosage ofV.E.
(mg / day)

SARA
scores
b/a

N.A.

21

N.A.

Cerebellar ataxia,
vibration-sense disturbance,
partially decreased
deep tendon reflexes

1N.A.

N.A.

45

Truncal and extremities ataxia,
loss of proprioceptive sense,
severe sensory neuropathy,
titubation of the head,dysarthria, pes cavus,
extensor plantar response,
decreased deep tendon reflexes

Undetectable

1,000

30 / 30

Undetectable(< 0.2)

800

18 / 7

Undetectable(< 0.2)800

16 / 10F

5Present case 1M

16

24

Cerebellar ataxia, dysarthria,
mild weakness of the distal
extremities, positive Romberg
sign, extensor plantar
response, areflexia

Present Case 2F

1930

Same as above except
titubation of the headF : female, M : male, N.A. : not available, V.E. : vitamin E, SARA : Scale for assessment and rating of ataxia, b / a : before / after thetreatments

the Philippines and its pathogenic variants.
According to previous reports, administering a daily highdosage of vitamin E resulted in the cessation of progressionof the neurological symptoms, and amelioration of establishedneurological abnormalities (18, 20, 21). Furthermore, vitamin
E treatment prevented disease progression over 30 years (22). It
is advocated that earlier administration of vitamin E after theonset might be important for improvements in neurological deficits (23). In a previous study, patients with the same mutationas our cases did not show any symptomatic improvement whenvitamin E administration was started 40 years after disease
onset (23).
Differential diagnosis is important because some symptomsof AVED can be alleviated if the treatment is initiated early
during the pathogenesis of the disease (12). Friedreich ataxia isa primary differential diagnosis. However, other diseases thatcause vitamin E deficiency, such as abetalipoproteinemia, hypobetalipoproteinemia, and malnutrition due to reduced vitamin E
uptake, could be other candidate diagnoses. Rare diseases, such
as Refsum disease, Charcot-Marie-Tooth neuropathy type 1A,
ataxia with oculomotor apraxia type 1 and 2, ataxia-telangiectasia, Marinesco-Sjögren syndrome, and chylomicron retention
disease, should be considered if serum vitamin E levels arenormal (12). In the Philippines, another important aspect should
be considered. AVED patients can manifest movement disorders,such as tremors and/or dystonia (12). X-linked dystonia-parkinsonism, which is also endemic to this area, can manifest as tremors and/or dystonia depending on the clinical stage (17). Fromthe perspective of movement disorders, AVED is an importantdifferential diagnosis for X-linked dystonia-parkinsonism in thisarea.
To the best of our knowledge, the present study reports thefirst cases of AVED in the Philippines. Interestingly, TTPA
knockout mice are resistant to cerebral malaria, which could
explain the comparatively high prevalence of TTPA pathogenic
variants in areas around the Mediterranean Sea (12, 24). In thePhilippines, 6,604 cases of malaria were reported in 2016 (25).
Given that TTPA mutations help protect against malaria, AVED

might be more prevalent and underestimated in the Philippines.
The country comprises numerous small islands (26). The islandof Panay is the sixth-largest island of the Philippines. The lackof genetic diversity in these islands might induce a relatively
high risk of genetic diseases, as represented by the prevalenceof X-linked dystonia-parkinsonism on the island of Panay (27).
The Philippines still has difficulties in conducting genetic
research and counseling due to limited resources, geographicalissues, and cultural barriers (26). Genetic testing is an imperative step in the process of securing a diagnosis for patients.
Thus, it is important to establish a system for diagnosing rare
hereditary diseases, even in rural areas with support from thepublic and government. Increase in genetic screening of thesuspected population groups by geneticists is not only beneficial
for patients but will facilitate regular updating of clinical information, including epidemiological data ; development in genetic
counseling system ; and establishment of the education systemfor patients, family members, health professionals, and society
in general, leading to comprehensive benefit in national publichealth (26, 28).

CONFLICT OF INTEREST-DISCLOSURE
Ma. Daisy Tabuena ; none declared, Ryoma Morigaki ; none
declared, Ryosuke Miyamoto ; none declared, Hideo Mure ; none
declared, Nobuaki Yamamoto ; none declared, Kazuhisa
Miyake ; none declared, Taku Matsuda ; none declared, Yuishin
Izumi ; none declared, Yasushi Takagi ; none declared, Rollin P.
Tabuena ; none declared, Toshitaka Kawarai ; none declared.

ACKNOWLEDGMENT
This work is supported by the Kanae Foundation for the promotion of medical science, JSPS KAKENHI Grant Numbers
20K17932, 20K07904, and 16KK0182. Department of Advanced
Brain Research is supported by Beautylife corporation.

The Journal of Medical Investigation Vol. 68 August 2021
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