“Surprisingly, the mother informed me that Emily had clumsiness since childhood. In addition, Emily had never walked like ordinary people, and she seemed to have frequent leg shaking, especially climbing the stairs. Next, I demonstrated a clinical examination with the students and found that Emily had poor muscle coordination and balance (ataxia), numbness of both legs, and loss of joint and vibration senses.”
Ataxia with vitamin E deficiency (AVED) is a rare genetic disorder that is characterized by progressive ataxia combined with other neurodegenerative symptoms such as loss of proprioception since childhood, as in the case of Emily from My Odyssey #13.
Timely diagnosis of AVED is crucial because early treatment initiation increases the chance of preventing the worsening of the symptoms. Nevertheless, AVED is often misdiagnosed as Friedreich’s ataxia (FRDA) because of their similar clinical features. Herein, we explore how a misdiagnosis of AVED can be prevented and investigate the types of available treatment. 1
Symptoms of AVED generally begin to appear during late childhood or early teens between the ages of 5 and 15 years. 2
Typical symptoms of AVED include progressive ataxia, head titubation (tremor), clumsiness of the hands, loss of proprioception (especially at the distal joint position and vibration sense), dysdiadochokinesia, dystonia, reduced visual acuity, macular atrophy, and retinitis pigmentosa. 1,4
Symptoms generally progressively worsen over time. If left untreated, ataxia and leg weakness may worsen, resulting in wheelchair dependency. 2,5
AVED can be diagnosed by determining the concentration of vitamin E in the body via laboratory testing and checking for clinical symptoms. However, an accurate diagnosis is difficult as normal range of plasma vitamin E concentration varies with among labs and detection methods. Moreover, ataxia can also be a symptom of other genetic disorders. Therefore, genetic testing is recommended as a rapid and accurate diagnostic method. 2
As previously mentioned, FRDA is a rare genetic disorder that can be easily misdiagnosed as AVED because of the similarity of the two diseases. Both FRDA and AVED are rare genetic disorders that present similar neurodegenerative symptoms, including ataxia. 3
FRDA and AVED are difficult to differentiate based on symptoms alone. However, both are caused by mutations in different genes; this makes accurate diagnosis possible through genetic testing. AVED is caused by a mutation in TTPA located at 8q12.3 of chromosome 8 2,4, whereas FRDA is caused by a mutation in FXN at 9q21.11 of chromosome 9. 3
The genetic mutations responsible for AVED occur in the exon and can be diagnosed via whole-exome sequencing and whole genome sequencing (WGS), whereas the genetic mutation responsible for FRDA is often located at a GAA repeat expansion site on intron-1 and thus, can only be diagnosed through WGS.
Hence, for any patients with early-onset ataxia, WGS would be an appropriate choice for an accurate diagnosis as misdiagnosis can often delay the appropriate initial treatment period for patients with AVED.
More information on the potential mutations and characteristics of genes including TTPA and FXN is available on 3billion’s gene browser.
AVED is caused by a mutation in TTPA. Loss-of-function mutation in TTPA activates the α-tocopherol protein that is involved in vitamin E absorption and delivery, leading to lower vitamin E concentration in blood.
Vitamin E plays a role in protecting the cells from the free radicals generated by metabolic processes and from exposure to toxic substances. Therefore, when the concentration of vitamin E in our body decreases, cells become exposed to free radicals damages, leading to movement disorders and other neurological problems.4
Two pathogenic TTPA variants have been reported to have a clear genotype-phenotype association. 2
|c.303T>G||Late-onset after the age of 30 years, mild symptoms and retinitis pigmentosa|
|c.744delA||Early-onset, severe symptoms and cardiomyopathy|
AVED is an autosomal recessive disorder that is caused by homozygous or compound heterozygous pathogenic loss-of-function mutation in TTPA. Therefore, both copies of the TTPA gene must carry this pathogenic variant to have any effect. Parents of patients are considered obligate carriers with no symptoms. The risk of two carrier parents with the defective gene having a child with the disease is 25%.2
- Vitamin E Supplementation
The symptoms of AVED are caused by a deficiency of vitamin E. Vitamin E is an important molecule that protects nerve cells from free radicals. Initiating vitamin E supplementation promptly in the early phase of the disease can help prevent nerve cell damage and stop the progression of the symptoms. Furthermore, an improvement from certain symptoms can be expected2. Moreover, continuous vitamin E supplementation for presymptomatic individuals can ensure that the symptoms are prevented for as long as the vitamin E supplementation continues5.
- Checking Family History
AVED is a genetic disorder; therefore, the family members of patients with AVED should be screened for the presence or absence of the genetic mutation through genetic testing. Because most of the symptoms appear after early infancy, any siblings of the patient should be screened for early diagnosis and treatment initiation2.
- Elkamil, A., Johansen, K. K., & Aasly, J. (2015). Ataxia with vitamin E deficiency in Norway. Journal of Movement Disorders, 8(1), 33.
- Schuelke, M. (2016). Ataxia with vitamin E deficiency. GeneReviews
- Bidichandani, S. I., & Delatycki, M. B. (2017). Friedreich ataxia. GeneReviews.
- Ataxia with vitamin E deficiency: Medlineplus genetics. MedlinePlus. Accessed July 18, 2022.
- Sencen L. Ataxia with vitamin E deficiency. NORD (National Organization for Rare Disorders). Accessed July 18, 2022.
- P49638 · TTPA_HUMAN. Uniprot. Accessed July 18, 2022.
- Q16595 · FRDA_HUMAN. Uniprot. Accessed July 18, 2022.