Background

Ataxia with vitamin E deficiency (AVED) was first described in 1981 by Burck et al. [1] as a progressive cerebellar ataxia in a 12-year-old boy with low vitamin E levels and without any alternative diagnosis. A few more reports presented similar cases resembling Friedreich ataxia (FA), all with low vitamin E levels but with variable severity of symptoms. In 1993, two consanguineous Tunisian families were reported with the same characteristics but there was no linkage to the locus on chromosome 9q as expected in FA [2]; instead, the genetic locus was mapped to proximal chromosome 8q [3]. Two years later, the alpha-tocopherol transfer protein (TTPA) gene was identified and the condition was termed AVED [4]. The identification of the gene led to therapeutic opportunities by supplementation of vitamin E in these patients.

Vitamin E

Vitamin E is a fat-soluble antioxidant which prevents lipid oxidation in membranes. There are various forms of tocopherols and tocotrienols. Alpha-tocopherol is probably the most important. It is absorbed in the small intestine and transported to the liver where it is incorporated into very low-density lipid proteins and then enters the circulation. Vitamin E is reported to have an anti-inflammatory effect and modulates DNA repair. Several studies have examined the effect of supplemental therapy using tocopherols and tocotrienols in aging populations. Immune-enhancing effects were attributed to the inhibition of cyclooxygenase (COX) activity, neutralizing reactive oxygen species-mediated damage, modulating T-cell function, and influencing the activities of several enzymes involved in signaling pathways related to immune response and inflammation. Numerous clinical trials reported a beneficial effect of vitamin E supplementation on cardiovascular disease, diabetes, cancer, and neurodegenerative diseases [5]. Adequate alpha-tocopherol is essential for normal cell function, especially in the central nervous system. Vitamin E deficiency presents primarily as a neurological disorder with spinocerebellar ataxia as a result of cerebellar Purkinje cell loss [6].

Etiology

AVED is caused by bi-allelic mutations in the TTPA gene on chromosome 8q13. TTPA codes for the protein TTPA, which mediates the integration of vitamin E from chylomicrons to the very low-density lipoprotein (VLDL) in the liver and enables its systemic circulation. Patients with AVED have normal absorption of vitamin E from the gut and uptake into chylomicrons but the incorporation of alpha-tocopherol to the VLDL by the cytosolic protein TTPA is impaired. This leads to the rapid elimination and deficient recycling of vitamin E.

Genetics

The causative gene, TTPA, is localized to chromosome 8q [7]. The majority of cases originate from populations in North Africa with high rates of consanguinity [8–11]. A common haplotype in the North African families suggested an increased frequency in the region with a possible founder effect [12]. The majority of cases are reported from Tunisia and Morocco but some rare cases were also reported from other geographic regions.

Over 20 mutations have been identified covering all five exons of the gene. The 744delA mutation is the most common [10, 11, 13–16] and was first described in 1995 in North African and southern Italian patients [4]. Two other mutations, 530AG>GTAAGT and 513insTG, were found in a northern German family and in a US family with Danish and English ancestry [4]. In Japanese patients, three further mutations were detected: 486delT, R192H [17], and H101Q [18].

In North African patients the 744delA is the most common mutation while in the European countries the 513insTT seems to be the most frequent disease-causing mutation [10, 15, 16, 19].

A genotype–phenotype correlation has been described. Truncating gene mutations seem to lead to an earlier onset and more severe form, while missense mutations might cause a more benign form. Semiconservative missense mutations H101Q, A120T, and R192H may cause a milder type, and non-conservative mutations R59W, E141K, and R221W have been described with a severe, early-onset disease. The homozygous truncating mutations 530AG>GTAAGT, 744delA, 486delT, and R134X are reported to lead to a more severe phenotype [15, 19]. Table 24.1 presents the known mutations in the TTPA gene.

Prevalence

The prevalence of AVED varies between geographic regions and ethnic groups. Only a few population-based studies have been performed. AVED is a rare movement disorder in most countries with an estimated prevalence of 0.5–3.5 in 1,000,000 in Europe. In Mediterranean and North African countries, and particularly in those with high rates of consanguinity, the prevalence may be much higher [10, 11].

A Moroccan study reported similar frequency of FA and AVED. In Rabat, 29 patients with symptoms resembling FA were admitted to the local department of neurology between 1987 and 1997; 16 had FA and 13 AVED [13].

An Algerian study examined 166 patients with cerebellar ataxia, segregating in an autosomal-recessive pattern. Nineteen patients had a genetically confirmed diagnosis of AVED, the second most common autosomal-recessive cerebellar ataxia after FA. Twelve of the 19 patients belonged to families with clear consanguinity [20].

A Japanese study found one homozygous and 21 heterozygous carriers for a mutation in TTPA in a population of 821 inhabitants of an isolated island outside of the main island of Japan but none of these mutations were found in 150 probands from Tokyo [18].

An epidemiological study from Italy reported a prevalence of 3.5 in 1,000,000 for AVED in the province of Padua [21]. A French study reported 102 cases with autosomal-recessive progressive cerebellar ataxia with only one subject identified as AVED. The overall prevalence of AVED in the Alsace region was 1 in 1,800,000 (0.6 per million) [22], similar to a Norwegian study which estimated an AVED prevalence of 0.6 in 1,000,000 [23].

Clinical Symptoms

Most AVED cases manifest in childhood or early adolescence, usually before the age of 20 years. A few Japanese cases had a later onset, which seemed more common in male patients. The clinical presentation is similar to FA although symptoms are heterogeneous and there is heterogeneity within the same family and among carriers of the same mutation [10, 11, 15, 16, 20]. The main symptoms are progressive spinocerebellar ataxia accompanied by neuropathy, head titubation and vision impairment. In a few cases, other neurological symptoms like torticollis might be the initial sign. A careful individual evaluation is needed in all cases.

The most common initial signs are gait impairment, clumsiness, and cerebellar ataxia affecting both lower and upper extremities. Ataxia persists throughout the disease course. Dysarthria, head tremor, and neuropathy are common. Sensory deficits combined with weak or absent tendon reflexes in the lower extremities with inverted plantar reflexes are found in most of the cases. Spasticity is rare [16]. Skeletal deformities may be present and may manifest as kyphoscoliosis, pes cavus, or hammertoes [10, 16, 20]. Distal lower limb amyotrophy may be seen [10, 24].

Dystonia has been reported [9, 15, 25–29]. Becker et al. reported two siblings manifesting with cervical and bilateral arm dystonia as the initial symptoms, and one of them progressed to develop generalized dystonia [30]. Another case with severe generalized dystonia was found to be unresponsive to vitamin E supplementation, requiring treatment with botulinum toxin injections [31].

Ophthalmological manifestations consist of reduced visual acuity and retinitis pigmentosa [10, 11, 13, 16]. Retinitis pigmentosa seems to be more common in Japanese patients [18, 32–36]. Other eye symptoms are rare but oculomotor apraxia and exotropia have both been reported [10]. A recent case report described macular degeneration [37]. Deafness is uncommon, only reported in three cases [34, 35, 38].

Urinary urgency and incontinence is rare [10, 35]. A male patient was examined and normal seminal parameters and normal fertility was found [39].

Arrhythmia and cardiomyopathy are rare features; however, cardiac abnormalities have been reported in up to 31% of Moroccan patients [11, 15]. This is an important feature that might help to distinguish AVED from FA. Diabetes mellitus is rare [11].

Growth retardation was observed in all 16 Moroccan patients [11]. Cognitive decline and learning difficulties requiring special education services is not often seen and behavioral changes are rare [30, 40]. Seizures have been reported in four cases [20, 41].

Diagnostic Studies

The diagnosis is based on clinical features in association with low serum vitamin E levels. Genetic testing confirms the diagnosis and excludes other conditions.

Related posts:

Chapter 1 – Treatable Metabolic Movement Disorders: The Top 10 Chapter 10 – A Phenomenology-Based Approach to Inborn Errors of Metabolism with Spasticity Chapter 7 – A Phenomenology-Based Approach to Inborn Errors of Metabolism with Ataxia Chapter 16 – Syndromes of Neurodegeneration with Brain Iron Accumulation Chapter 4 – Imaging in Metabolic Movement Disorders Chapter 27 – Purine Metabolism Defects: The Movement Disorder of Lesch–Nyhan Disease

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