Isolated head tremor is a frequent clinical presentation with a diverse etiology that can be challenging to establish. The differential diagnosis often includes cervical dystonic tremor, essential tremor, and various cerebellar diseases. We present a case of a male patient presenting with isolated head tremor diagnosed with ataxia with vitamin E deficiency (AVED).
Case Report
A 42‐year‐old male of Han Chinese ethnicity presented with involuntary head shaking since his early twenties, which progressively worsened and extended to his upper limbs. Factors such as stress and anxiety appeared to intensify the tremor, which persisted even when he was lying down. Alcohol had no mitigating effect, and a family history of similar symptoms was absent.
He had previously been diagnosed with essential tremor at another medical institution. Various therapeutic interventions, including propranolol (90 mg/day), gabapentin (0.9 g/day), clonazepam (1 mg/day), trihexyphenidyl (6 mg/day), and botulinum toxin, were administered, but yielded little improvement. Deep brain stimulation (DBS) targeting the ventral intermediate (VIM) nucleus of the thalamus resulted in some benefit, but post‐surgery dysarthria led to device removal at the patient's behest. Therefore, further programming adjustment was not made. Consequently, he sought further evaluation at our hospital.
Neurological examination (Video 1) demonstrated dystonic head tremor, bilateral postural hand tremor predominantly affecting the right hand, and mild impairment of the tandem gait. Notably, no bradykinesia, muscle rigidity, or Babinski sign was observed. Eye movements, strength, reflexes, proprioception, and other sensory modalities were preserved. Brain magnetic resonance imaging (MRI) did not reveal any structural abnormalities or atrophy (Fig. 1). Nerve conduction study indicated mild neuropathy, particularly a reduced sensory conduction velocity in the left superficial peroneal nerve.
Video 1.
The video shows a 42‐year‐old male exhibiting dystonic head tremor and bilateral postural hand tremor, predominantly affecting the right hand. The head tremor was characterized by an irregular, jerky pattern with variable amplitude. Partial suppression was possible by turning the head toward one side and touching the lower face, whereas voluntary movements exacerbated the tremor, which is consistent with the features of a dystonic tremor. Neurological examination also revealed mild impairment in the tandem gait.
FIG. 1.
Brain magnetic resonance imaging of the patient showing no obvious structural abnormalities (artifacts noted because of head tremor).
Laboratory tests revealed a low serum vitamin E (α‐tocopherol) level (1.61 mg/L; normal range = 5.5–17.0 mg/L). The results of additional assessments, including thyroid function, serum ceruloplasmin, ferritin, and vitamin B12 level, were within normal ranges. Whole genome sequencing identified biallelic mutations in the TTPA gene [c.575G>A (p.R192H), c.358G>A (p.A120T)], both classified as likely pathological in accordance with The American College of Medical Genetics and Genomics criteria. 1 These mutations segregated in the patient's family (Fig. 2).
FIG. 2.
Genetic analysis of the patient's family. (A) Pedigree of the patient's family, illustrating the inheritance pattern. (B) Sanger sequencing confirming that both parents were heterozygous carriers of the TPPA mutation.
Considering the symptoms and genetic findings, a diagnosis of AVED was established. Subsequently, we initiated vitamin E supplementation at a dosage of 1200 mg/day. Following this intervention, serum vitamin E levels were restored to normal (last recorded level: 9.0 mg/L). After 1 year of consistent vitamin E supplementation, the patient's condition remained stable.
Discussion
AVED is a rare autosomal recessive neurodegenerative disorder caused by defects in the TTPA gene, resulting in reduced serum vitamin E levels and varying in presentation and severity. 1 , 2 , 3 Whereas the majority of AVED patients present with cerebellar ataxia, 4 our patient showed only mild impairment of the tandem gait and no signs of cerebellar atrophy in brain MRI scan. His mild phenotype may be explained by the identified missense mutations, which differ from those causing severe childhood‐onset AVED. 4
Head tremor is present in ~40% of AVED patients. 5 Dystonic tremor may occur in AVED, but is seldom reported to be a predominant presenting feature. Previous case reports have described AVED patients presenting with isolated dystonia or dystonic tremor before developing ataxia. Becker et al 6 reported two siblings with initial cervical dystonia and dystonic head tremor, of whom only the younger sister showed improvement in their head tremor after vitamin E treatment, whereas the older brother developed irreversible ataxia due to delayed diagnosis. Zhang et al 7 described a 32‐year‐old Chinese female whose symptoms remained stable, but did not improve over 2 years of vitamin E therapy, which is similar to our patient. Our case highlights that AVED should be considered when diagnosing head tremor, even in the absence of typical cerebellar signs. AVED is a treatable condition that is often under‐recognized, particularly in regions such as Asia, where it is rare. Early intervention with high‐dose vitamin E supplementation may prevent disease progression and improve symptoms.
To our knowledge, no studies have reported the use of DBS specifically for AVED, although two cases of DBS for abetalipoproteinemia has been documented. Abetalipoproteinemia is an autosomal recessive disorder that also results in vitamin E deficiency and presents with neurological deficits, including tremors and ataxia. Mammis et al 8 described a 41‐year‐old male with abetalipoproteinemia treated with bilateral VIM DBS for disabling tremors. Significant improvements in tremor of extremities and slight improvements in head tremor were noted after 8 months. More recently, Cortier et al 9 reported a 53‐year‐old male with abetalipoproteinemia and refractory intentional tremor treated by VIM DBS. The excellent response to VIM DBS supports DBS as a potential therapy for medically refractory tremors in vitamin E‐deficient diseases. Conversely, our patient did not respond well to DBS. A potential reason for our patient's poor outcome was the lack of DBS programming adjustments after implantation. Further research is warranted to determine optimal targeting and long‐term outcomes.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution: (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
J.L.: 1A, 1B, 1C, 3A.
Z.L.: 1C, 3A.
N.J.: 1B, 1C, 3B.
X.Z.: 1C, 3B.
W.L.: 1C, 3B.
Disclosures
Ethical Compliance Statement: The study was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine. Written informed consent was obtained from the patient. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: This study was supported by the Science Technology Department of Zhejiang Province (2019C03017). No potential conflict of interest was reported by the authors.
Financial Disclosures for the Previous 12 Months: The authors declare no additional disclosures to report.
Acknowledgments
We express our gratitude to the patient for granting permission to publish this information and to Dr. Piu Chan, MD, PhD, and Dr. J.K. Chhetri, MD, for their invaluable assistance in presenting this case at the 2023 Asian and Oceanian Parkinson's Disease and Movement Disorders Congress Video Tournament. We also thank Mitchell Arico from Liwen Bianji (Edanz) (https://www.liwenbianji.cn) for editing the language of a draft of this manuscript.
Relevant disclosures and conflict of interest are listed at the end of this article.
Jiaxiang Li and Zhiru Lin contributed equally to this manuscript.
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