Holmes-Like Tremor in Ataxia With Oculomotor Apraxia Type 2

Maria Chiara D’Amico, MD,1,* Iole Borrelli, MD,2 Holta Zhuzhuni, MD,2 Aurelio D’Amico, MD,2 Roberta Di Giacomo, MD,2

Luca Mancinelli, MD,2 Valeria di Tommaso, MD,2 Antonio Di Muzio, MD,2 Marco Onofrj, MD1

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).1–3 International case

series described extrapyramidal signs, such choreoathetosis,

dystonia, and head or postural tremor.1–4

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, aggra-

vated 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, incon-

stant 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 crea-

tine 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 move-

ment 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 ele-

vated creatine phosphokinase (290 U/L). Electrocardiogram was

unremarkable.

Nerve conduction studies demonstrated absent compound

motor action potential from peroneus communis nerve bilater-

ally and absent sensory action potential from sural nerves.

Motor nerve conduction of the right ulnaris nerve showed mild

increased distal latency and decreased amplitude. Electromyo-

graphy revealed denervation in every examined muscle. A diag-

nosis 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 neuro-

imaging (Fig. 1).

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, typi-

cal 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.

1Department of Neuroscience and Imaging, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy; 2Neurology Clinic, “SS. Annunziata”Hospital, Chieti, Italy

*Correspondence to: Dr. Maria Chiara D’Amico, Clinica Neurologica, Ospedale “SS Annunziata”, VII Livello Corpo A, Via dei Vestini, 66100Chieti, Italy; E-mail: mariachiara.damico@libero.it

Keywords: Ataxia with oculomotor apraxia type 2, Holmes-like tremor, polyneuropathy.Relevant disclosures and conflicts of interest are listed at the end of this article.Received 10 March 2014; revised 12 May 2014; accepted 25 May 2014.Published online 28 July 2014 in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/mdc3.12070

© 2014 International Parkinson and Movement Disorder Society261

doi:10.1002/mdc3.12070

CASE REPORT

CLINICAL PRACTICE

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 meno-

pause2,3; hypogonadotrophic hypogonadism1 or ovarian failure;9

increased total cholesterol;2 and elevated immunoglobulin

levels.2 Increased CK levels were also reported.1–3

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 treat-

ment. 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 worsen-

ed 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. Writ-

ing 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

DisclosuresFunding 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.

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7. Nanetti L, Cavalieri S, Pensato V, et al. SETX mutations are a frequentgenetic cause of juvenile and adult onset cerebellar ataxia with neuropa-thy and elevated serum alpha-fetoprotein. Orphanet J Rare Dis 2013;8:123.

8. Criscuolo C, Chessa L, Di Giandomenico S, et al. Ataxia with oculo-motor apraxia type 2. A clinical, pathologic and genetic study. Neurology2006;66:1207–1210.

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Supporting InformationA 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 atro-

phy, 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 con-

stantly appears in the right arm. The movement on the right is

more visible when the patient gesticulates while talking.

Figure 1 Axial T2-weighted brain MRI showing midbrain. No lesionof red nucleus was revealed by the neuroimaging.

262 MOVEMENT DISORDERS CLINICAL PRACTICEdoi:10.1002/mdc3.12070

Holmes-Like Tremor in a Case of AOA2CASE REPORT