Case report

Laryngeal dystonia in xeroderma pigmentosum

Ayako Mutoa,b, Akira Matsuia, Yoshiaki Saitoa,b,*, Hiroko Iwamotoa, Kaori Kanekoa,b,

Kaori Masukoa, Yuri Chikumarua, Kazuyo Saitoa, Seiji Kimuraa

aDepartment of Pediatrics and Pediatric Neurology, Yokohama Ryo-iku Medical Center,

557-2 Ichizawa-cho, Asahi-ku, Yokohama 241-0014, JapanbDepartment of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan

Received 26 November 2004; received in revised form 19 January 2005; accepted 8 March 2005

Abstract

We report on three patients with xeroderma pigmentosum group A (XPA) who showed laryngeal stridor in their 20s. The stridor appeared

on feeding and emotional excitation, was exaggerated during respiratory infection and was life-threatening on some occasions. Adduction of

the vocal cords during inspiration, observed by laryngoscopy, confirmed laryngeal dystonia in all cases. This type of focal dystonia may be

characteristic in XPA and requires special attention during the management of these patients to avoid serious complications.

q 2005 Elsevier B.V. All rights reserved.

Keywords: Xeroderma pigmentosum; Larynx; Vocal cord; Focal dystonia; Stridor

1. Introduction

Xeroderma pigmentosum (XP) is a genetic disorder

where the repair mechanism of damaged DNA is defective.

It is characterized by hypersensitivity of the skin to

sunlight, an increased risk of skin cancer and progressive

neurological impairment [1]. There are several comple-

mentation subgroups of this disease, defined by cell-fusion

studies. Group A (XPA), caused by mutations of XPAC

gene, is the most common in Japan and shows the most

severe clinical form including mental deterioration,

cerebellar ataxia, spasticity, sensorineural deafness and

peripheral neuropathy [1].

We describe three cases of XPA with laryngeal dystonia

that resulted in a marked inspiratory stridor. There is

nonspecific neurological impairment and widespread patho-

logical changes in the brain of XPA patients [1]. However,

we suggest in this paper that laryngeal dystonia may be

characteristic in this disorder with advancing age.

0387-7604/$ - see front matter q 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.braindev.2005.03.004

* Corresponding author. Address: Department of Child Neurology,

Faculty of Medicine, Institute of Neurological Sciences, Tottori University,

36-1 Nishi-cho, Yonago 683-8504, Japan. Tel.: C81 45 352 6551;

fax: C81 45 352 6553.

E-mail address: saitoyo@fb3.so-net.ne.jp (Y. Saito).

2. Case report

All three patients were diagnosed with XPA based on

clinical features, reduced ultraviolet-induced unscheduled

DNA synthesis and the inability to complement reference

group A cells. They showed hypersensitivity to sunlight,

pigmentation and freckles on the skin, malignancy of skin

or conjunctiva and neurological deterioration from late

childhood (Table 1). Intermittent stridor appeared at 20–25

years of age, when magnetic resonance (MR) imaging

showed diffuse atrophy of the cerebral and cerebellar

cortex and the brainstem in each case (Fig. 1). At this age

they had spastic tetraplegia with decreased deep tendon

reflex and myoclonia in the upper limbs. Their mouths

were open and pharyngeal reflex was decreased to varying

degrees.

2.1. Patient 1

A 26-year-old woman with sunlight hypersensitivity

during infancy was diagnosed with XPA at 3 years of age.

Her younger brother (patient 3) suffered from the same

disorder. Initial psychomotor development was normal until

2 years of age but then deteriorated progressively. She

attended special education classes during school age.

Auditory impairment appeared at the age of 10 and ataxic

gait was noted at 13 years of age. Epileptic seizures

Brain & Development 27 (2005) 598–601

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Table 1

Age of onset (in years) of symptoms of neurological deterioration in xeroderma pigmentosum group A patients

Patient Gender Auditory

disturbance

Ataxia Epilepsy Dysarthria Swallowing

disability

Inability

to walk

Incontinence Inspiratory

stridor

1 F 9 13 14 13 23 22 20 20

2 M 10 N 24 N 24 23 23 25

3 M 6 9 12 9 19 18 19 20

N, not specified.

A. Muto et al. / Brain & Development 27 (2005) 598–601 599

occurred during adolescence but disappeared after treatment

with valproic acid. The patient became incontinent and was

unable to walk by 22 years of age.

At 20 years of age, inspiratory stridor appeared during

respiratory infections. This stridor gradually became

prominent and often occurred at feeding and emotional

excitation. These episodes usually lasted from 10 s to

several minutes. However, after respiratory infection or

vomiting they could persist from a few hours up to a couple

of days. This resulted in a marked dyspnea that required

transient tube feeding. During periods of stridor, closing of

the vocal fold during inspiration and opening during

expiration was observed by laryngoscopy (Fig. 2A and B).

Focal laryngeal dystonia was diagnosed based on this

paradoxical movement of the vocal fold.

The patient suffered from pneumonia with marked

hypoxia due to laryngeal stridor at 26 years of age. We

tried tracheal intubation but could not insert the tube beyond

the narrow glottis due to spasm of the laryngeal muscles.

Tracheotomy was not approved by the patient’s parent. We

consulted with otorhinolaryngologists to attempt electro-

myographical recording of the laryngeal muscles and

botulinum toxin injection [2]. They advised against these

invasive and difficult procedures as complications, such as

fistula formation, could occur. Episodic stridor continued

after recovery of pneumonia.

Fig. 1. MR imaging of patient 2. (A) Atrophy of the cerebral cortex and dilatat

cerebellar cortex and brainstem are seen here.

2.2. Patient 2

A 27-year-old man was diagnosed with XPA at 2 years of

age and shows progressive deterioration from the age of 3.

Swallowing difficulty appeared at 24 years of age and he has

been tube-fed since the age of 25. Episodic inspiratory

stridor became prominent during this period. Laryngoscopy

showed that the vocal fold closed during inspiration and

half-opened during expiration. He showed marked dyspnea

due to an exacerbation of this stridor and was intubated

during a respiratory infection. He was re-admitted to our

hospital after tracheotomy. At this time the vocal cord

remained in the half-open position and the respiration- and

swallowing-related motion of the vocal fold was poor.

When we transiently closed the valve of the tracheal

cannulae several times, the glottis closed during each

inspiration (Fig. 2C and D), but laryngeal stridor was not

significant.

2.3. Patient 3

This 21-year-old man is a younger brother of patient 1.

Daytime drowsiness and swallowing disturbance appeared

at 19 years of age. Around this age laryngeal stridor also

occurred transiently during feeding, excitation and upper

respiratory infection. Closing of the vocal fold during

ion of lateral and third ventricles are noted. (B) Moderate atrophy of the

Fig. 2. Laryngoscopic findings of each patient (patient 1: A and B, patient 2: C and D, patient 3: E and F). (A) During inspiration, the vocal cords (arrows) are

adducted and the glottis is closed. (B) During expiration, the vocal fold is partly open. Since the glottis is retracted downwards during inspiration, epiglottis and

glottis are observed closer in the visual field compared to A. Vocal fold adduction (C and E) and abduction (D and F) during inspiratory and expiratory phase

are also observed in patients 2 and 3.

A. Muto et al. / Brain & Development 27 (2005) 598–601600

inspiration and opening during expiration was observed by

laryngoscopy (Fig. 2E and F).

3. Discussion

Inspiratory stridor observed in the present XPA cases

resulted from the narrowing of the vocal fold during

inspiration. This was due to a change in the timing of the

contraction of vocal cord adductor muscles during the

respiratory cycle. Such a phase shift can be regarded as focal

dystonia of laryngeal muscles [3–6]. Intralaryngeal muscles

are innervated by recurrent and superior laryngeal nerves

whose motor neurons are located in the nucleus ambiguus

and have respiration-related activities [7]. They can be

classified as ‘inspiratory’ (vocal cord abductor) and

‘expiratory’ (vocal cord adductor) muscles based on their

activation pattern during the quiet breathing cycle. The

inspiratory muscles, i.e. posterior cricoarytenoid and

cricothyroid muscles, contribute to airway patency during

inspiration. The expiratory muscles including the thyroar-

ytenoid (TA) may regulate laryngeal resistance during

expiration [7]. However, expiratory muscles in the laryngo-

pharyngeal region can contract during inspiration in some

conditions including gasping [8] and at arousals after

obstructive sleep apnea [9]. Focal laryngeal dystonia with

such an inspiratory activation of adductor muscles, along

with resultant stridor, has been reported in patients with

A. Muto et al. / Brain & Development 27 (2005) 598–601 601

Parkinson’s disease [3], multiple system atrophy (MSA)

[4], idiopathic or drug-induced multifocal dystonia [5],

and sequelae of Japanese encephalitis with basal ganglia

lesions [6].

This report provides for the first time a description that

laryngeal dystonia is most characteristic in the later course

of XPA and that it can be life-threatening. Neuropatholo-

gical studies on brains of XPA patients have described the

loss of neurons in the cerebral and cerebellar cortex, the

basal ganglia, the substantia nigra, the medulla oblongata

and the spinal cord [1]. Such an involvement of multiple

systems results in a collection of neurological complications

in XPA patients, which gives an impression of nonspecific

deterioration. Increased oxidative stress [10] has been

suggested as the mechanisms of neuronal death, but their

role in the pathology of specific anatomical structure has not

been well-established. On the other hand, homovanillic

acid, a dopamine metabolite, is decreased in the cerebro-

spinal fluid of XP patients [1]. This may be related to the

dysfunction of the nigro-striatal pathway, which can

contribute to laryngeal dystonia, as is seen in Parkinson’s

disease. Dysfunction of inhibitory neurotransmitters in the

brainstem is also assumed to cause inspiratory TA muscle

activity in MSA [4]. Involvement of such specific pathways

may be the cause of laryngeal dystonia in XPA patients at a

specific age.

The facilitation of vocal cord adduction during inspi-

ration by occlusion of tracheotomy in patient 2 supports the

hypothesis that inspiratory TA activity in MSA patients is

augmented by negative airway pressure [4]. Application of

continuous positive airway pressure is effective in suppres-

sing inspiratory TA activation in MSA patients [4]. This

may be worth trying in the management of XPA patients

with laryngeal dystonia, particularly when tracheotomy is

not approved by parents. Currently, laryngeal dystonia is

not well known among pediatric neurologists. However, we

should be aware of this condition in relation to patients with

XPA and perhaps other neurological disorders involving the

nigro-striatal pathway and brainstem structures.

Acknowledgements

We thank Dr Masaharu Hayashi for his encouragement in

preparing this article.

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