Ataxia with vitamin E deficiency (AVED) is a rare, autosomal recessive neurodegenerative disorder, with approximately 225 reported cases in over 100 families. Mutations in the gene encoding the α-tocopherol transfer protein (TTPA/αTTP) result in normal intestinal absorption of vitamin E but defective transportation out of the liver, resulting in systemic vitamin E deficiency.1 The disease typically presents in childhood with progressive ataxia, areflexia, and loss of proprioceptive and vibratory sense, resembling Friedreich’s ataxia.2,3 Early diagnosis is imperative, as treatment can halt or even reverse disease progression.3,4
Dystonia occurs rarely in AVED and has been described as a presenting feature only once previously, in a child who presented with a syndrome that resembled myoclonic dystonia.5 We present the clinical and genetic features and initial treatment response of two siblings with AVED who presented atypically with dystonia.
Two siblings (male, 14.5 years, and female, 11 years) presented for evaluation of head tremor. Perinatal history and development had been normal for both siblings until age 11 years, when they each developed involuntary shaky movements of the head that worsened during times of stress. Each had also experienced new mild school difficulties requiring special education services at age 11 or 12 years. The male also had symptoms of depression.
The female was examined 6 months after symptom onset (Video 1 seg.1: 00:21). She had cervical dystonia and an irregular, horizontal, jerky head tremor of variable amplitude consistent with dystonic tremor. She also had bilateral postural arm dystonia, most pronounced in the left arm during writing. Her gait was narrow-based and steady.
The male was examined 2–3 years after symptom onset (Video 2, Segment 1). He had intermittent head tremor and generalized dystonia involving the neck, trunk, and limbs. Dystonic contractions of abdominal muscles were present at rest, and shoulder and limb dystonia worsened with action, particularly walking. Dystonia did not respond to any sensory tricks. There was mild bilateral weakness of ankle dorsiflexion. His gait was normal-based and steady, but tandem gait was mildly impaired, attributed at the time to his dystonia and distal weakness.
Both siblings had diminished upper extremity and patellar tendon reflexes but normal ankle jerks and downgoing plantar responses. Neurologic examinations and ophthalmologic examinations were otherwise normal, specifically without evidence of limb dysmetria, nystagmus, dysarthria, or impaired vibration or proprioception. The initial clinical impression was of a progressive neurological disorder characterized by dystonia, mild cognitive dysfunction, and weakness of neuromuscular origin.
Initial investigations, including serum copper, ceruloplasmin, alpha-fetoprotein, serum and cerebrospinal fluid lactate concentrations, and brain magnetic resonance imaging were all normal (Figure 1). Nerve conduction studies as well as muscle, nerve and skin biopsies were performed in the brother. The nerve conduction study, skin biopsy, and nerve biopsy were normal; his muscle biopsy revealed rare myofibrillar derangement and mild, non-specific cytoarchitectural abnormalities consistent with mild myopathic changes. Treatment with trihexyphenidyl was initiated in both siblings. The dose in the sister was 6 mg per day, and for the brother, 15 mg per day. The head tremor improved in the sister; the brother reported subjective improvement in walking, but examination findings did not clearly improve.
One year after presentation, the brother developed dysarthria, dysdiadochokinesia, limb dysmetria, and gait ataxia (Video 2, Segment 2). The plasma alpha-tocopherol (vitamin E) level was found to be low in both siblings (<0.5 mg/L; reference range 5.5–18.0 mg/L). Compound heterozygous frameshift mutations in the TTPA gene (c.161_164del, p.R54fs and c.487delT, p.W163fs) were detected in both siblings, confirming the diagnosis of AVED.
The siblings were started on high-dose vitamin E supplementation. Ten months later, on 2,400 IU/day, plasma vitamin E levels were in the normal range for both (brother, 7.4–10.4 μg/mL; sister, 7.0–7.8 μg/mL). Follow up examination demonstrated improved dysarthria and dysdiadochokinesia in the brother (Video 2, Segment 3). His dystonia and ataxic gait did not improve. The sister had developed mild gait ataxia on examination (Video 1 seg 2: 00:46), although she did not notice any impairment of balance, gait, or coordination in daily life. Her new gait ataxia was explained, in retrospect, by a delay in the proper initiation of her treatment because of intermittent medication non-compliance.
Our patients had an atypical presentation of AVED, with initial cervical dystonia and mild cognitive dysfunction in the absence of ataxia. Dystonia has been described in only 10 previous patients with AVED (Table 1). In only one previous case was dystonia the presenting symptom, in an 8-year-old patient with head jerks and cervical dystonia that resembled myoclonus–dystonia.5 Our cases reinforce that dystonia may precede the onset of ataxia, and highlight cervical distribution as a characteristic feature of dystonia in AVED.
|Study||Age at Onset (years)||Initial Symptoms||Age at Dystonia Onset (years)||Dystonia Distribution||Vitamin E Treatment (target dose/day; total duration)||Clinical Course|
|Krendel et al.17||7||Gait difficulty, clumsiness, dysarthria||19||GDNeckUE LE||3,600 IU; 5 mo||Stable|
|Stumpf et al.18||4||Unsteady gait,||30||Face||800 mg; 6 mo||Stable|
|Amiel et al.15||7||Ataxia||16||FaceUE||1,000 mg; 5 yr||Improved: social contact, speech|
|Jackson et al.19||7||Head and hand tremor||22||GDFace NeckTrunkLE||1,200 IU; 3 yr||Stable|
|Yokota et al.20||30||ND||ND||ND||ND||Stable|
|Cavalier et al.21||3||ND||ND||ND||ND||ND|
|Schuelke et al.22||9||Clumsiness||13||ND||40 mg/kg; 18 mo||Improved: psychiatric, cognitive, ataxia, dysarthria, sensation, Deep tendon reflex's|
|Angelini et al.5||8||Cervical myoclonus- dystonia||At onset||NeckTrunk||2,400 mg; 1.75 yr||Improved: ataxia, dystonia, myoclonus|
|Roubertie et al.16||8.6||Gait instability, clumsiness, slurred/scanning speech||11.75||GDNeckTrunkUE LE||2,000 mg; 5 yr||Improved: ataxiaOnset: progressive dystonia|
|Mariotti et al.3||8||ND||ND||ND||2,400 mg; 5 yr||Improved: ataxia, dystonia|
|Our case: female||11||Dystonic head tremor||At onset||NeckUE||2,400 IU; 10 mo||Onset: ataxia|
|Our case: male||11||Dystonic head tremor||At onset||GDNeckTrunkUE LE||2,400 IU; 10 mo||Improved: dysarthria, dysdiadochokinesia|
In the 12 reported cases of dystonia in patients with AVED (our two included), the development of ataxia preceded dystonia in the majority of patients. The average age at onset of symptoms was 9.5 years, and the average at onset of dystonia was 15.8 years. The latency from initial neurological symptom onset to dystonia onset was highly variable, ranging from 0 to 26 years (nine patients included). Dystonia occurred most frequently in the neck (75%), followed by upper limbs (62.5%), lower limbs (50%), trunk (50%), and face (37.5%). Half of the patients developed generalized dystonia (Table 1). Additionally, features of dystonia may be more prevalent than previously recognized in AVED. In one series,3 head tremor has been reported in up to 44% of patients with AVED, and it is possible that at least some of these patients had cervical dystonia with dystonic tremor rather than head titubation.
The mechanism of neurologic dysfunction in AVED is unknown, but neuronal oxidative injury has been hypothesized. Brain imaging demonstrates cerebellar atrophy in up to 50% of cases.3,4 Other brain regions are also affected. Animal models of AVED and post-mortem studies of humans with secondary vitamin E deficiency have shown evidence of degenerative changes in the substantia nigra, posterior column, nerve roots, and peripheral nervous system.6–12 Post-mortem studies of patients with AVED demonstrate loss of cerebellar Purkinje cells, dying back-type posterior column degeneration with spheroids and corpora amylacea, and lipofuscin accumulation.13,14 Ataxia in AVED is likely caused by a combination of cerebellar and posterior column degeneration. Whether dystonia in AVED is attributable to injury of nigrostriatal, cerebellar, or other circuits is uncertain.
High-dose vitamin E supplementation may stop disease progression and, in some cases, result in clinical improvement, especially in patients with shorter disease duration.3,4 Primary prevention in mutation-positive pre-symptomatic patients has also been reported.15 Without treatment, most patients with disease onset during childhood (age <18 years) become wheelchair-bound within 5–20 years of disease onset. The brother in our report started treatment approximately 4 years after symptom onset, when he had developed significant generalized dystonia and ataxia. After 10 months of treatment, he had moderate improvement in hand coordination and speech, but his gait ataxia and dystonia remained unchanged.
The specific response of dystonia in AVED to vitamin E treatment is variable. Dystonia has been reported to improve in two patients,3,5 and most patients with dystonia as a feature of their disease had stabilization or improvement of their other symptoms on high dose vitamin E (Table 1). One patient, however, experienced progressive dystonia despite escalating doses of vitamin E supplementation.16 There are anecdotal reports of dystonia improvement in response to symptomatic treatment with botulinum toxin, trihexyphenidyl,16 and clonazepam.5 The sister in our report clearly improved with trihexyphenidyl treatment. Since AVED may be treatable if diagnosed early, it should be considered in the differential diagnosis of progressive dystonia, particularly when the dystonia is cervical, or is accompanied by head tremor.
1 Funding: None.
2 Financial Disclosures: None.
3 Conflict of Interest: The authors report no conflict of interest.
4 Ethics Statement: All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.
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