Clinical characteristics.

Untreated ataxia with vitamin E deficiency (AVED) generally manifests between ages five and 15 years. The first manifestations include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia. Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. Although age of onset and disease course are more uniform within a given family, disease manifestations and their severity can vary even among sibs.

When lifelong high-dose vitamin E supplementation is initiated in presymptomatic individuals, manifestations of AVED do not develop.

Diagnosis/testing.

The diagnosis of AVED is established in a proband with suggestive findings and biallelic pathogenic variants in TTPA identified by molecular genetic testing.

Management.

Targeted therapy: Lifelong targeted therapy with high-dose oral vitamin E supplementation (that brings plasma vitamin E concentrations into the high-normal range) initiated in presymptomatic individuals (e.g., younger sibs of an index case) prevents the manifestations of AVED. Vitamin E supplementation early in the disease course of a symptomatic individual may to some extent reverse ataxia and mental deterioration.

Supportive care: Supportive care for those with ataxia and related findings is the same multidisciplinary care for individuals with ataxia of other causes.

Surveillance: Monitor plasma vitamin E concentration in treated individuals – particularly children – every six months. For symptomatic individuals, regular evaluations to monitor the individual's response to supportive care and to identify emergence of new manifestations.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of all sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Timely treatment with vitamin E supplementation may completely avert the clinical manifestations of the disease.

Genetic counseling.

AVED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TTPA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the TTPA pathogenic variants have been identified in an affected family member, carrier detection for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

AVED should be suspected a proband with the following clinical and laboratory findings and family history.

Clinical features

• Onset between ages five and 15 years
• Progressive cerebellar findings including the following:
  • Gait ataxia
  • Clumsiness of the hands
  • Loss of proprioception (especially distal joint position and vibration sense)
  • Dysdiadochokinesia
  • Positive Romberg sign
  • Head titubation
• Lower motor neuron involvement. Areflexia
• Upper motor neuron involvement. Positive Babinski sign
• Ophthalmologic involvement. Decreased visual acuity due to macular degeneration, pigmentary retinopathy

Supportive laboratory findings

• Normal lipid and lipoprotein profile
• Very low plasma vitamin E (alpha-tocopherol, or α-tocopherol) concentration
  Note: There is no universal normal range of plasma vitamin E concentration, as it depends on the test method and varies among laboratories.
  In Finckh et al [1995], the normal range lies between 9.0 and 29.8 µmol/L (SD 2). In El Euch-Fayache et al [2014], the normal range is given as 16.3-34.9 µmol/L, while individuals with AVED had vitamin E levels between 0.00 and 3.76 µmol/L (mean 0.95 µmol/L, SD 1.79 µmol/L; n=132). In individuals with AVED, the plasma vitamin E concentration is generally lower than 4.0 µmol/L (<1.7 mg/L) [Cavalier et al 1998, Mariotti et al 2004].
  Because oxidation of α-tocopherol by air may invalidate test results, the following precautions with a blood sample should be taken:
  • Centrifugation of the EDTA blood soon after venipuncture
  • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen
  • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen)
  • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube
  • Shipment of the sample to the test laboratory in dry ice

Electrophysiologic findings

• No electrophysiologic findings (motor nerve conduction velocities, compound muscle action potentials, or nerve sensory action potentials) are specific to or diagnostic of AVED; even the presence of a severe neuropathy does not exclude the diagnosis of AVED. See Clinical Description for more details.
• Somatosensory evoked potentials show increased central conduction time between the segment C1 (N13b) and the sensorimotor cortex (N20) and increased latencies of the N20 (median nerve) and P40 (tibial nerve) waves. The P40 wave may be missing completely [Schuelke et al 1999].

Neuroimaging

• Cerebellar atrophy [Mariotti et al 2004] is present in approximately half of reported individuals.
• Small T₂ high-intensity spots in the periventricular region and the deep white matter [Usuki & Maruyama 2000] are inconsistent findings in some individuals.

Note: No radiologic findings are specific to or diagnostic of AVED.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of AVED is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TTPA identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic TTPA variants of uncertain significance (or of one known TTPA pathogenic variant and one TTPA variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include gene-targeted testing, which requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

The phenotype and disease severity of untreated ataxia with vitamin E deficiency (AVED) vary widely. Although age of onset and disease course tend to be more uniform within a given family, clinical findings and disease severity can vary among sibs [Shorer et al 1996]. Untreated AVED generally manifests in late childhood or the early teenage years, between ages five and 15 years; however, the range may be from age two to 37 years as reported in a series of 132 North African individuals [El Euch-Fayache et al 2014].

When vitamin E treatment is initiated in presymptomatic individuals (e.g., younger sibs of an index case), manifestations of AVED do not develop (see Management, Targeted Therapy).

The following description of the phenotypic features associated with untreated individuals with AVED is based on findings in 132 individuals of North African descent [El Euch-Fayache et al 2014].

Genotype-Phenotype Correlations

To date, only two pathogenic variants have shown clear-cut genotype-phenotype correlations:

• The pathogenic variant p.His101Gln is associated with late-onset disease (age >30 years) with a mild disease course, and increased risk for pigmentary retinopathy. This variant is primarily reported in individuals of Japanese descent [Gotoda et al 1995].
• The pathogenic variant c.744delA is associated with early onset and a more severe disease course, and slightly increased risk for cardiomyopathy. However, disease severity may vary considerably, and even in persons from the same family the onset of manifestations may vary between ages three and 12 years [Cavalier et al 1998, Marzouki et al 2005]. This variant is mainly observed in individuals of Mediterranean or North African descent.

A less clear genotype-phenotype correlation can be seen for other pathogenic variants, particularly when homozygous.

Preliminary genotype-phenotype correlations related to variant and age of onset of disease include:

• Early onset (generally before or around age ten years). p.Arg59Trp, p.Arg134Ter, p.Glu141Lys, p.Arg221Trp, c.486delT, c.513_514insTT, c.530_531delAGinsGTAAGT (See Table 3.)
• Late onset (generally after age 20 years). p.Ala120Thr [Cavalier et al 1998] (See Table 3.)

Pathogenic missense variants that cause substitutions in non- or semi-conserved amino acids (e.g., p.His101Gln, p.Ala120Thr, p.Arg192His, or p.Gly246Arg) are associated with a mild phenotype, whereas substitutions in highly conserved amino acids are associated with early onset and severe symptoms (e.g., p.Arg59Trp, p.Asp64Gly, p.Glu141Lys, p.Leu183Pro, p.Arg221Trp) (see Table 3).

Nomenclature

AVED was first called "Friedreich ataxia phenotype with selective vitamin E deficiency" [Ben Hamida et al 1993]. Subsequent names for AVED include "Friedreich-like ataxia" and "familial isolated vitamin E deficiency."

Prevalence

The TTPA pathogenic founder variant c.744delA has been identified in individuals of Tunisian ancestry.

Several restricted population-based studies have been performed.

Gotoda et al [1995] found one TTPA pathogenic variant (p.His101Gln) in 21 of 801 randomly selected inhabitants of a Japanese island on which one individual had previously been diagnosed with AVED. This would amount to a calculated prevalence of one homozygous individual per 1,500 inhabitants. This pathogenic variant was not detected in 150 unrelated individuals from Tokyo.

Of 29 individuals from Morocco with a Friedreich ataxia-like phenotype, 13 had AVED and the remainder had Friedreich ataxia [Benomar et al 2002].

In a population study in southeast Norway, 1 in 171 individuals with hereditary ataxia had AVED, suggesting a prevalence of 0.6:1,000,000 [Elkamil et al 2015].

Anheim et al [2010] evaluated 102 individuals with suspected autosomal recessive cerebellar ataxia; in 57 individuals (56%) a molecular diagnosis could be established, and of those, one individual had AVED. From their findings, the authors infer a prevalence for AVED in the Alsace region of France of approximately 1:1,800,000.

Zortea et al [2004] performed an epidemiologic study of inherited ataxias in the Italian province of Padua and found a prevalence of 3.5:1,000,000 for AVED.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a hereditary ataxia, the evaluations summarized in Hereditary Ataxia Overview, Table 6, are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Individuals with AVED should avoid:

• Smoking because it considerably lowers TRAP and reduces plasma vitamin E concentrations [Sharpe et al 1996];
• Occupations requiring quick responses or good balance.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of all sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Timely treatment with vitamin E supplementation may completely avert the clinical manifestations of the disease.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Because reduced vitamin E levels are associated with low fertility and embryo resorption in mice [Traber & Manor 2012] and α-tocopherol transfer protein is highly expressed in the human placenta [Müller-Schmehl et al 2004], it is advisable for women with AVED to maintain vitamin E levels in the high-normal range during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Ataxia with vitamin E deficiency (AVED) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a TTPA pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a TTPA pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a TTPA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Clinical findings and disease severity can vary among affected sibs with the same TTPA pathogenic variants (see Clinical Description).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has AVED or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in TTPA (see Family planning).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a TTPA pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the TTPA pathogenic variants in the family.

Note: The moderately lowered plasma vitamin E concentration in heterozygotes is not a sensitive enough measure to distinguish between heterozygous carriers and non-carriers.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing of at-risk family members. Because vitamin E treatment initiated in presymptomatic individuals can prevent the findings of AVED [Amiel et al 1995], predictive testing of all sibs of the proband is appropriate.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with AVED should be considered, particularly if both partners are of the same ethnic background (see Table 3).

Prenatal Testing and Preimplantation Genetic Testing

Once the TTPA pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for AVED are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TTPA encodes the alpha-tocopherol transfer protein (α-TTP). This cytosolic protein is mainly expressed in liver cells [Sato et al 1993] but also in the pyramidal cells of the cerebellum [Hosomi et al 1998, Copp et al 1999] and in the placenta [Kaempf-Rotzoll et al 2003, Müller-Schmehl et al 2004].

Liver α-TTP incorporates α-tocopherol from the chylomicrons into very low-density lipoproteins (VLDLs), which are then secreted into the circulation [Traber et al 1990] – a stereoselective process that favors 2R-α-tocopherols [Weiser et al 1996, Leonard et al 2002]. In the absence of α-TTP, α-tocopherol is rapidly lost into the urine [Schuelke et al 2000a]. Alpha-TTP appears to have two functions that can be tested separately: (1) the stereoselective binding of 2R-α-tocopherols and (2) the transfer of α-tocopherol between membranes [Gotoda et al 1995, Morley et al 2004]. In hepatocytes, α-TTP appears to direct vitamin E trafficking from the endocytic compartment to transport vesicles that deliver the vitamin to the site of secretion at the plasma membrane. In the presence of TTPA pathogenic variants (p.Arg59Trp, p.Arg221Trp, p.Ala120Thr), vitamin E did not travel to the plasma membrane and remained trapped in the lysosomes [Qian et al 2006]. The effect of the pathogenic variant on protein stability appears to be directly related to the clinical phenotype [Qian et al 2006].

Mechanism of disease causation. Loss of function

Revision History

• 16 March 2023 (bp) Comprehensive update posted live
• 13 October 2016 (sw) Comprehensive update posted live
• 2 November 2010 (me) Comprehensive update posted live
• 4 September 2007 (me) Comprehensive update posted live
• 20 May 2005 (me) Review posted live
• 4 October 2004 (ms) Original submission

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