Ataxia With Vitamin E Deficiency

Clinical characteristics.

Ataxia with vitamin E deficiency (AVED) generally manifests in late childhood or early teens between ages five and 15 years. The first symptoms 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. The phenotype and disease severity vary widely among families with different pathogenic variants; age of onset and disease course are more uniform within a given family, but symptoms and disease severity can vary even among sibs.

Diagnosis/testing.

Presently, no consensus diagnostic criteria for AVED exist; the principal criterion for diagnosis is a Friedreich ataxia-like neurologic phenotype combined with markedly reduced plasma vitamin E (α-tocopherol) concentration and a normal lipoprotein profile in the absence of known causes of malabsorption. Identification of biallelic TTPA pathogenic variants on molecular genetic testing confirms the diagnosis.

Management.

Treatment of manifestations: Lifelong high-dose oral vitamin E supplementation to bring plasma vitamin E concentrations into the high-normal range; treatment early in the disease process may to some extent reverse ataxia and mental deterioration.

Prevention of primary manifestations: Vitamin E therapy in presymptomatic children with biallelic TTPA pathogenic variants prevents development of symptoms.

Surveillance: Monitor plasma vitamin E concentration every six months, particularly in children.

Agents/circumstances to avoid: Smoking; occupations requiring quick responses or good balance.

Evaluation of relatives at risk: Evaluation for vitamin E deficiency, especially in younger sibs of a proband.

Other: Before attempting to drive a car, assessment to determine if the affected individual can drive safely.

Genetic counseling.

AVED is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and carry one pathogenic variant; heterozygotes are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

Ataxia with vitamin E deficiency (AVED) should be suspected in individuals who typically present at the beginning of puberty with the following findings.

Clinical features

• Progressive ataxia
• Clumsiness of the hands
• Loss of proprioception (especially distal joint position and vibration sense)
• Areflexia
• Dysdiadochokinesia
• Positive Romberg sign
• Head titubation
• Decreased visual acuity
• Positive Babinski sign
• Macular atrophy, retinitis pigmentosa

Laboratory findings

• Normal lipid and lipoprotein profile
• Very low plasma vitamin E (α-tocopherol) concentration
  Note: (1) 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 (mean ± 2 SD). 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]. (2) Because oxidation of α-tocopherol by air may invalidate test results, the following precautions 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

• In a large study of 132 individuals with AVED from North Africa, 45 individuals were investigated neurophysiologically (e.g., median and peroneal nerve motor conduction velocity, compound muscle action potential, median and saphenous nerve sensory action potential, and sensory action potential) [El Euch-Fayache et al 2014].
  • 9% had normal findings.
  • 47% had mild neuropathy (at least 1 parameter 70%-100% of lower limit of normal [LLN]).
  • 27% had moderate neuropathy (at least 1 parameter 30%-70% of LLN).
  • 17% had severe neuropathy (at least 1 parameter <30% of LLN or no response).
  • Neuropathy was either purely sensory (34%), purely motor (24%), or combined (42%).
• Somatosensory evoked potentials show increased central conduction time between the segment C1 (N13b) and the sensorimotor cortex (N20), increased latencies of the N20 (median nerve) and P40 (tibial nerve) waves. The P40 wave may be missing completely [Schuelke et al 1999].

Note: No electrophysiologic findings are specific to or diagnostic of AVED; even a severe neuropathy does not exclude AVED.

Neuroimaging

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

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

Histopathology findings [Larnaout et al 1997, Yokota et al 2000, El Euch-Fayache et al 2014, Ulatowski et al 2014]

• Spinal sensory demyelination with neuronal atrophy and axonal spheroids
• Dying back-type degeneration of the posterior columns
• Neuronal lipofuscin accumulation in the third cortical layer of the cerebral cortex, thalamus, lateral geniculate body, spinal horns, and posterior root ganglia
• Fiber type grouping of the peroneus brevis muscle
• Mild loss of Purkinje cells

Establishing the Diagnosis

Presently no consensus diagnostic criteria for ataxia with vitamin E deficiency (AVED) exist.

The diagnosis of AVED is established in a proband with all of the following:

• Friedreich ataxia-like neurologic phenotype
• Markedly reduced plasma vitamin E (α-tocopherol) concentration
• Normal lipoprotein profile
• Exclusion of diseases that cause fat malabsorption

Identification of biallelic TTPA pathogenic variants on molecular genetic testing (see Table 1) establishes the diagnosis if clinical and laboratory features are inconclusive and confirms the diagnosis in individuals with the above features.

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of TTPA is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Targeted analysis for TTPA pathogenic variant c.744delA can be performed first in individuals of Mediterranean or North African ancestry.
• A multigene panel that includes TTPA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of AVED. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The phenotype and disease severity of ataxia with vitamin E deficiency (AVED) vary widely. Although age of onset and disease course tend to be more uniform within a given family, symptoms and disease severity can vary among sibs [Shorer et al 1996].

AVED generally manifests in late childhood or early teens 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]. The first symptoms include progressive ataxia, clumsiness of the hands, and loss of proprioception, especially of vibration and joint position sense. Handwriting deteriorates. In rare individuals, school performance declines secondary to loss of intellectual capacities. Tendon reflexes of the lower extremities are generally absent and the plantar reflexes increase in intensity. Affected individuals have difficulty walking in the dark and often have a positive Romberg sign. A high percentage of affected individuals (e.g., 8/11 individuals in one series) experience decreased visual acuity [Benomar et al 2002].

In many individuals, cerebellar signs such as dysdiadochokinesia and dysarthria with a scanning speech pattern are present. One third of individuals have a characteristic head tremor (head titubation). In some persons, psychotic episodes, intellectual decline, and dystonic episodes have been described. Rarely, AVED may manifest as arm or cervical dystonia [Becker et al 2016].

Most untreated individuals become wheelchair dependent as a result of ataxia and/or leg weakness between ages 11 and 50 years [Harding et al 1985, Ouahchi et al 1995, Hentati et al 1996, Cavalier et al 1998, Gabsi et al 2001, Benomar et al 2002, Mariotti et al 2004].

According to a large study on 132 individuals from North Africa [El Euch-Fayache et al 2014], the signs and symptoms include (in decreasing order of frequency):

• Areflexia (94.7%)
• Gait impairment (93.4%)
• Positive Babinski sign (85.5%)
• Deep sensory disturbances (67.1%)
• Dysarthria (61.8%)
• Head tremor (40.8%)
• Urinary urgency (22.4%)
• Nystagmus (5.3%)
• Urinary incontinence (4.0%)
• Retinitis pigmentosa (2.3%)
• Cardiomyopathy (1.5%)

Genotype-Phenotype Correlations

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

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

A less clear genotype-phenotype correlation can be seen for the following pathogenic variants if they occur in homozygous form. Manifestation of disease:

• Before age ten years. p.Arg59Trp, p.Arg134Ter, p.Glu141Lys, c.486delT, c.513_514insTT, c.530-531AG>GTAAGT (see Table 3)
• After age ten years. p.Arg221Trp, p.Ala120Thr (see Table 3) [Cavalier et al 1998]

Penetrance

AVED shows nearly complete penetrance in individuals who are homozygous or compound heterozygous for a TTPA pathogenic variant.

Nomenclature

AVED was first called "Friedreich ataxia phenotype with selective vitamin E deficiency" [Ben Hamida et al 1993].

Prevalence

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 1500 inhabitants. This pathogenic variant was not detected in 150 unrelated individuals from Tokyo.

In a Moroccan study, AVED was diagnosed in 20% of individuals with a Friedreich ataxia-like phenotype [Benomar, personal communication].

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

Anheim et al [2010] evaluated102 individuals with suspected autosomal recessive cerebellar ataxia; in 57 individuals (56%) a molecular diagnosis could be established. Of these, 36 had Friedreich ataxia (FRDA), seven had ataxia with oculomotor apraxia type 2 (AOA2), four had ataxia-telangiectasia (AT), three had Marinesco-Sjögren syndrome (MSS), three had ataxia with oculomotor apraxia type 1 (AOA1), two had AR spastic ataxia of Charlevoix-Saguenay (ARSACS), one had AR cerebellar ataxia (ARCA2), and one had ataxia with vitamin E deficiency (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.

It also appears to be of interest that TTPA knockout mice are resistant to cerebral malaria and that this resistance can be abrogated by supplementation with vitamin E [Herbas et al 2010a, Herbas et al 2010b]. This may add TTPA pathogenic variants to several inherited alterations that confer protection against malaria [López et al 2010] and could explain the comparatively high prevalence of such pathogenic variants around the Mediterranean Sea.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ataxia with vitamin E deficiency (AVED), the following evaluations are recommended:

• Clinical neurologic examination – particularly reflex status, vibratory and position sense, gait, Babinski sign, tremor, dysarthria
• Ophthalmologic examination for evidence of macular degeneration or retinitis pigmentosa and decreased visual acuity; electroretinogram (ERG)
• Cardiac examination; echocardiography and ECG to assess for cardiomyopathy
• Neurophysiologic examination; nerve conduction velocity (NCV) and somatosensory potentials (especially the central conduction time [Schuelke et al 1999]), which are good objective measures of neurologic improvement after vitamin E supplementation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The treatment of choice for AVED is lifelong high-dose oral vitamin E supplementation. Some symptoms (e.g., ataxia and intellectual deterioration) can be reversed if treatment is initiated early in the disease process [Schuelke et al 1999]. In older individuals, disease progression can be stopped, but deficits in proprioception and gait unsteadiness generally remain [Gabsi et al 2001, Mariotti et al 2004, El Euch-Fayache et al 2014]. With treatment, plasma vitamin E concentrations can become normal.

In presymptomatic individuals, the manifestations of AVED can be prevented if vitamin E supplementation is initiated early [El Euch-Fayache et al 2014].

No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes.

The reported vitamin E dose ranges from 800 mg to 1500 mg (or 40 mg/kg body weight in children) [Burck et al 1981, Harding et al 1985, Amiel et al 1995, Cavalier et al 1998, Schuelke et al 1999, Schuelke et al 2000b, Gabsi et al 2001, Mariotti et al 2004].

One of the following vitamin E preparations is used:

• The chemically manufactured racemic form, all-rac-α-tocopherol acetate
• The naturally occurring form, RRR-α-tocopherol

It is currently unknown whether affected individuals should be treated with all-rac-α-tocopherol acetate or with RRR-α-tocopherol. It is known that alpha-TTP (αTPP) stereoselectively binds and transports 2R-α-tocopherols [Weiser et al 1996, Hosomi et al 1997, Leonard et al 2002]. For some TTPA pathogenic variants, this stereoselective binding capacity is lost and affected individuals cannot discriminate between RRR- and SRR-α-tocopherol [Traber et al 1993, Cavalier et al 1998]. In this instance, affected individuals would also be able to incorporate non-2R-α-tocopherol stereoisomers into their bodies if they were supplemented with all-rac-α-tocopherol. Since potential adverse effects of the synthetic stereoisomers have not been studied in detail, it seems appropriate to treat with RRR-α-tocopherol, despite the higher cost.

Prevention of Primary Manifestations

If vitamin E treatment is initiated in presymptomatic individuals (e.g., younger sibs of an index case), the symptoms of AVED do not develop [Amiel et al 1995, El Euch-Fayache et al 2014].

Surveillance

During vitamin E therapy, the plasma vitamin E concentration should be measured at regular intervals (e.g., every 6 months), especially in children. Ideally the plasma vitamin E concentration should be maintained in the high normal range.

Some protocols call for measuring the total radical-trapping antioxidant parameter of plasma (TRAP). Although α-tocopherol only contributes 5%-10% to TRAP, this parameter appears to be the best surrogate marker for clinical improvement [Schuelke et al 1999]. Discontinuation of vitamin E supplementation, even temporarily, leads to a drop in plasma vitamin E concentration within two to three days and to a prolonged drop in TRAP, even after reinitiating vitamin E supplementation [Kohlschütter et al 1997, Schuelke et al 2000b].

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

Predictive testing should be offered to all sibs of a proband, as timely treatment with vitamin E supplementation may completely avert the clinical manifestations of the disease.

• All relatives at risk, especially younger sibs of a proband, should be evaluated for vitamin E deficiency.
• If plasma vitamin E concentration is low, the person should be tested for presence of the TTPA pathogenic variants found in the proband so that individuals with biallelic pathogenic variants can be treated promptly with vitamin E supplementation.

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

Pregnancy Management

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]; therefore, it is advisable to keep 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.

Other

Because of abnormal position sense in the extremities, individuals with AVED may have difficulty riding a bicycle or driving a car. Before attempting to drive a car, affected individuals need to be tested by a physician to determine whether they can drive safely.