Holmes‐Like Tremor in Ataxia With Oculomotor Apraxia Type 2

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive cerebellar ataxia associated with axonal sensorimotor neuropathy, inconstant oculomotor apraxia, and increased serum concentration of alpha‐fetoprotein (AFP).1, 2, 3 International case series described extrapyramidal signs, such choreoathetosis, dystonia, and head or postural tremor.1, 2, 3, 4

Here, we present a case of AOA2 affected by severe mixed tremor resembling Holmes’ tremor.5

A 50‐year‐old woman, affected by a cerebellar syndrome since she was 14, developed progressive, involuntary, rhythmic, and wide movements of the left arm occurring at rest, aggravated by holding a posture and, further, during voluntary movements. It also affected the head, which also presented an independent tremor. The right arm manifested a minor, inconstant tremor. Assessments with the Tremor Research Group Rating Scale, according to a recent report,6 showed resting tremor in the left arm equal to 3, postural 3.5, and kinetic 4; head tremor was equal to 2. In the right arm, the score was for resting tremor 1, postural 3, and kinetic 2. Dystonic position of hands was associated (see Video 1).

Family history evidenced consanguinity: Paternal grandfathers of the parents were brothers.

At the age of 14, the first evaluation showed mild pyramidal signs, dysmetria in the upper and lower limbs, ataxic gait, and loss of deep tendon reflexes. Brain CT was normal. Serum creatine kinase (CK) was normal (22 U/L). The disease advanced, and she became wheelchair bound in her mid‐thirties.

Neurological examination revealed nystagmus in every gaze position, dysarthric speech, head tremor, dystonic position of the hands, weakness of distal muscles of the limbs, areflexia, bilateral absence of cutaneous plantar reflex, dysmetria of upper and lower limbs, loss of vibratory and position sensation, distal atrophy in the lower limbs, foot drop, and distal and symmetric superficial hypoesthesia of the legs and bilateral pes cavus. Standing and deambulation were impossible.

Oculomotor apraxia (i.e., inability to coordinate the movement of the head and eyes toward a target with delayed achievement by the eyes) was also observed.2

Routine biochemistry was normal, except for slightly elevated creatine phosphokinase (290 U/L). Electrocardiogram was unremarkable.

Nerve conduction studies demonstrated absent compound motor action potential from peroneus communis nerve bilaterally and absent sensory action potential from sural nerves. Motor nerve conduction of the right ulnaris nerve showed mild increased distal latency and decreased amplitude. Electromyography revealed denervation in every examined muscle. A diagnosis of axonal sensory‐motor neuropathy was established.

Brain MRI showed global cerebellar atrophy, dilatation of the fourth ventricle, and microvascular leucopathy in cerebral hemispheres. No lesions of midbrain were evidenced by neuroimaging (Fig. 1).

Figure 1.

Axial T2‐weighted brain MRI showing midbrain. No lesion of red nucleus was revealed by the neuroimaging.

EEG showed a frontal intermittent rhythmic delta activity. Visual‐evoked potentials were normal for paracentral stimuli, whereas responses to central stimuli were unreliable. This might be a result of the inability to gaze at the visual stimulus, rather than to optic neuritis. Auditory‐evoked potentials were normal. No macular or retinal lesions were found.

Neuropsychological testing revealed global performances in the lower limits of normality.

AFP was detected and showed an elevated level (76.10 ng/mL). Subsequently, identification of homozygous mutation in the SETX gene confirmed the diagnosis of AOA2. It was a frameshift mutation recently described also in another Italian patient.7

AOA2 seems to be the most common cause of autosomal recessive cerebellar ataxia in adults after Friedreich's disease.2

The involuntary movement presented by the patient was interpreted as Holmes‐like tremor. Indeed, it occurred at rest, increased in amplitude with posture and during goal‐directed movements, and was associated with dysmetria. However, typical Holmes’ tremor is considered to result from lesion of the cerebellothalamic and nigrostriatal pathways,5 which were not revealed by brain MRI in the present case (Fig. 1). Dopamine transporter single‐photon emission CT could not be performed because of movement artefacts.

The severity of movement disorders in AOA2 tends to remain stable.2 Yet, in an Italian clinical, pathological, and genetic study, choreiform head movements associated with truncal dystonia and head tremor disappeared with the disease's progression.8

Other variable clinical symptoms independent of the central nervous system were reported in the literature: early menopause2, 3 hypogonadotrophic hypogonadism1 or ovarian failure;9 increased total cholesterol;2 and elevated immunoglobulin levels.2 Increased CK levels were also reported.1, 2, 3

In this patient, the age of menopause was not remembered and cholesterolemia was normal during treatment with statins. No elevated levels of immunoglobulins were found.

The tremor did not benefit from any pharmacological treatment. Levetiracetam 500 mg twice a day was the last treatment tried, according to a recent report suggesting possible efficacy in Holmes’ tremor,10 but was withdrawn after a few weeks because of evident inefficacy. The tremor progressively worsened in the following 2 years (see Video 2).

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

M.C.D.A.: 1C, 3A

I.B.: 1C

H.Z.: 1C

A.D.A.: 1C

R.D.G.: 1C

L.M.: 1C

V.D.T.: 1C

A.D.M.: 1C, 3B

M.O.: 3B

Disclosures

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report.

Supporting information

A video accompanying this article is available in the supporting information here.

Video 1. Head tremor. Dystonic position of the hands and bilateral tremor while maintaining a posture, mainly in the left arm, where it persists at rest; right dysmetria while performing finger‐to‐nose test, and the test is unattainable with the left arm because of worsening of the tremor. Lower limbs: distal atrophy, foot drop, pes cavus, and postural tremor.

Video 2. Six months after the first evaluation: persistent bilateral postural tremor, and the finger‐to‐nose test shows a slightly wider amplitude of the movement on the left and an increased intention tremor on the right. Resting tremor constantly appears in the right arm. The movement on the right is more visible when the patient gesticulates while talking.