Familial isolated vitamin E deficiency

Disease definition

• A neurodegenerative disease belonging to the inherited cerebellar ataxias mainly characterized by progressive spino-cerebellar ataxia, loss of proprioception, areflexia, and is associated with a marked deficiency in vitamin E.

Synonym(s):

• AVED
• Ataxia with isolated vitamin E deficiency
• Familial isolated vitamin E deficiency
• Friedreich-like ataxia
• Isolated vitamin E deficiency

Prevalence: 1-9 / 1 000 000

Inheritance: Autosomal recessive

Age of onset: All ages

Epidemiology

The worldwide incidence remains uncertain, though demographic research suggests an approximate rate of 1/300,000. In North African regions, AVED ranks as the second most common inherited cerebellar ataxia. The higher occurrence of AVED in regions affected by Plasmodium may be attributed to vitamin E deficiency potentially offering protection against malaria.

What are the symptoms of Familial isolated vitamin E deficiency?

Very frequent symptoms

• Abnormal pyramidal sign
• Areflexia
• Ataxia
• Babinski sign
• Low levels of vitamin E
• Muscle weakness
• Peripheral neuropathy

Frequent Symptoms

• Abnormality of speech or vocalization
• Cerebellar atrophy
• Clumsiness
• Dysarthria
• Dysdiadochokinesis
• Dysmetria
• Gait disturbance
• Head titubation
• Impaired proprioception
• Nyctalopia
• Nystagmus
• Pes cavus
• Scoliosis
• Sensory neuropathy

Occasional Symptoms

• Abnormality of retinal pigmentation
• Abnormality of visual evoked potentials
• Arrhythmia
• Developmental regression
• Diabetes mellitus
• Dystonia
• Hemiplegia/hemiparesis
• Hypertonia
• Hypertrophic cardiomyopathy 
• Mental deterioration
• Positive Romberg sign
• Skeletal muscle atrophy
• Tremo
• Urinary urgency
• Visual impairment

Very rare symptoms

• Pigmentary retinopathy

Clinical description

• AVED typically manifests between 5 and 20 years of age, showing diverse symptoms and intensity levels. The condition causes progressive spino-cerebellar ataxia, absent reflexes, and diminished proprioception, particularly affecting distal joint positioning and vibration perception, resulting in notable coordination problems and unsteadiness.
• Patients often display distinctive head tremors. Tendon reflexes show significant reduction, with frequent extensor plantar responses. Cerebellar dysfunction commonly presents as impaired movement coordination, rapid alternating movements, and speech difficulties. Vision may deteriorate with retinal pigment degeneration.
• Some cases emerge later (past age 30) with milder progression. Conversely, early-onset cases tend to be more severe, with heightened cardiomyopathy risk. The symptoms generally mirror those of Friedreich’s ataxia.

Etiology

AVED results from mutations in the TTPA gene (8q13), which produces tocopherol transfer protein. This protein connects alpha-tocopherol (vitamin E variant) with very-low-density lipoproteins (VLDLs) in hepatic tissue. Mutated TTPA impairs vitamin E’s ability to bind with VLDLs, preventing its distribution throughout the body. Various mutations exist, with p.His101Gln causing late-onset/mild forms and c.744delA leading to early-onset/severe manifestations.

Diagnostic methods

Diagnosis combines physical assessment, vitamin E blood measurements, and ruling out known malabsorption causes. Tests reveal severely reduced plasma vitamin E, despite normal lipid and lipoprotein levels. Early-stage brain imaging typically shows no significant cerebellar deterioration. Electromyography generally indicates pure sensory nerve cell damage. Genetic testing confirms the diagnosis.

Differential diagnosis

Key conditions to consider include Friedreich ataxia, SANDO syndrome, and abetalipoproteinemia. Other inherited cerebellar ataxias warrant consideration (Refsum disease, ataxia telangiectasia, Charcot-Marie-Tooth disease 1A, and ataxia with oculomotor apraxia types 1 and 2).

Antenatal diagnosis

Prenatal testing is possible through genetic analysis when the family’s specific mutation is known.

Genetic counseling

The condition follows autosomal recessive inheritance, carrying a 25% recurrence probability.

Management and treatment

Treatment requires continuous high-dose vitamin E supplementation taken daily. Early intervention may reverse certain symptoms; in older patients, it can slow disease advancement. The effectiveness of preventive vitamin E therapy in asymptomatic relatives of diagnosed cases remains undetermined.

Prognosis

Despite treatment, outcomes often remain poor, with patients requiring wheelchair assistance between ages 8 and 20.