Primary Orthostatic Tremor in 2 Siblings

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312869-sup-v001.htm

Primary orthostatic tremor (POT) is a rare movement disorder characterized by high‐frequency (13–18 Hz), lower limb tremor when standing, unchanged over time.1 Treatment is symptomatic and often unsuccessful. It can be recorded with surface electromyography. A clinical–surface electromyography–gait analysis allows one to evaluate the severity of POT and the efficacy of therapy.2

POT is considered a sporadic disorder: based on patients’ descriptions, less than 5% of patients with POT report a family history of lower limb tremor, whereas 12% present a family history of essential tremor.3

Here we describe the first pair of Italian siblings with clinical and electrophysiological evidence of POT and review previously described familial POT cases.

We describe 2 brothers without other siblings and without a family history of neurological diseases.

Patient 1 complained of tremor in the legs after 10 to 15 seconds of standing and relieved by walking or sitting, progressively worsening since the age of 72. After 10 years, neurological assessment showed bilateral leg tremor after 10 seconds of standing.

Patient 2 reported unsteadiness during standing, with improvement when walking, since the age of 68. After 9 years, neurological assessment revealed stiffness of the legs after 20 seconds of standing.

In both patients, mild postural upper limb tremor was present, without parkinsonian or cerebellar signs. Magnetic resonance imaging showed diffuse brain atrophy, vascular encephalopathy, and dorso‐lumbar spondylosis without myelopathy in both. ¹²³I‐ioflupane single photon emission computed tomography, motor‐evoked potentials, and anti‐glutamic‐acid‐decarboxylase‐antibodies were normal in patient 2.

Clonazepam was ineffective in both cases; the patients refused other treatments. Concomitant treatments were carbamazepine for epilepsy (patient 1) and aspirin, atorvastatin, and carvedilol for ischemic cardiomyopathy (patient 2).

Surface electromyography recordings of the bilateral tibialis anterior and medial gastrocnemius were performed in both patients. In addition, right triceps brachii and lumbar paraspinal muscles were recorded in patient 1. On sitting, no activity was recorded (Video S1, part 1). Immediately after standing, a 16 Hz regular tremor appeared, with alternating bursts in the antagonist muscles and synchronous bursts in the homologous muscles (Video S1, part 2; Fig. 1). On standing while leaning on a chair, the tremor signal amplitude in the lower limbs diminished, while a 16 Hz tremor appeared in the triceps brachii, synchronous with the activity in the tibialis anteriors (Video S1, part 3).

Figure 1.

Surface electromyography recordings of patients 1 (upper) and 2 (lower) show a 15 to 16 Hz lower limb tremor when standing. When standing with support, lower limb tremor amplitude decreases and upper limb tremor amplitude increases (patient 1). See text for recorded muscles. Gas Med, gastrocnemius medialis; L, left; Parasp, paraspinal muscles; R, right; Tib Ant, tibialis anterior.

We performed a review of the literature to identify full descriptions of relatives formally diagnosed with POT. We found previous descriptions of 8 different families (Supplementary Table 1).

In total, including our 2 patients, we identified 9 families (19 cases) with at least 2 members diagnosed with POT by a neurologist. The affected patients were typically siblings, and age at onset was 44 to 73 years, with the exception of 2 brothers with childhood onset.4 Including our cases, 9 of 19 patients (47%) showed a 4 to 8.5 Hz upper limb tremor.

The genetics of POT still remain elusive. A mutation of TWNK was found in a patient with orthostatic tremor and progressive external ophthalmoplegia.5

In conclusion, the siblings described here expand the small group of well‐characterized POT families. A better understanding of familial POT may contribute to clarify the pathophysiology of POT and identify possible causal treatments.

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.

L.V.: 1A, 1B, 1C, 2A, 2C, 3A, 3B

A.B.: 1C, 2B, 3B

G.P.: 1A, 1B, 2A, 2C, 3A, 3B

R.B.: 1C, 2B, 3B

G.L.G.: 2C, 3B

M.V.: 2C, 3B

E.B.: 1A, 1B, 2A, 2C, 3A, 3B

Disclosures

Ethical Compliance Statement: 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. IRB approval was not required. The patients have given written and informed consent for online publication of their data and videos.

Funding Sources and Conflicts of Interest: The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors have nothing to disclose.

Supporting information

Supplementary Material S1. The supplementary material contains detailed methods for the review of the literature, a table (Supplementary Table 1) summarizing the characteristics of our patients and of the previously described cases, and references of the included papers.

Video S1. The electromyography signal of recorded muscles (see text for details) is presented on the left, with the frequency spectrum of each channel. A video recording of the three tests (sitting, standing, standing with support) is presented on the right.