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Journal of the Neurological Scie

Short communication

Dysautonomic achalasia in two siblings with Sandhoff disease

Michele Pellegrini a, Enza Zicari b, Maria Teresa Dotti b, Antonio Federico b,*

a Digestive Surgery Unit, Department of Surgery and Surgical Specialities, University of Siena, Italyb Department of Neurological and Behavioural Sciences, Unit of Neurometabolic Diseases, University of Siena, Viale Bracci 2, 1-53100 Siena, Italy

Received 6 April 2005; received in revised form 26 October 2005; accepted 1 November 2005

Available online 13 December 2005

Abstract

Two siblings in their sixth decade with chronic Type II GM2 gangliosidosis developed progressive dysphagia in addition to chronic motor

neuron disease and autonomic nervous system (ANS) involvement. Esophageal achalasia was diagnosed in both patients. It is suggested that

this esophageal motor disorder may be a manifestation of the neurovegetative system disorder due to alteration of ganglioside metabolism.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Achalasia; Dysautonomia; Esophageal motor disorders; Sandhoff disease; Type II GM2 gangliosidosis; Autonomic nervous system

1. Introduction

The etiology of achalasia, a motor disorder of the

esophagus characterized by functional obstruction to the

passage of swallowed solids and liquids, is still uncertain.

Genetic, autoimmune and infectious factors may cooperate in

causing degenerative changes in esophageal nerve fibres [1].

Esophageal achalasia may also be secondary to extra-

digestive disorders. Patients with neurological diseases may

complain of gut motility abnormalities and achalasia is

reported as a consequence of ANS alterations [2].

Autonomic nervous system involvement and achalasia

are aspects of Allgrove’s syndrome, a rare infantile disorder

characterized by achalasia cardia, alacrimia, adrenocortical

insufficiency and autonomic dysfunction [3]. In addition,

cases of this esophageal motor disorder have been reported

in patients with Fabry disease, an X-linked inborn error of

glycosphingolipid metabolism, and hereditary cerebellar

ataxia [4,5].

This is the first report of dysautonomic achalasia in two

siblings with Sandhoff disease, a rare inherited disorder of

ganglioside metabolism, caused by deficiency of the

lysosomal enzymes, h-hexosaminidase A and B [6].

0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.jns.2005.11.001

* Corresponding author. Tel.: +39 0577 585763; fax: +39 0577 40327.

E-mail address: federico@unisi.it (A. Federico).

2. Case report

The neurological phenotype of two brothers with unrelat-

ed parents has been described in previous papers [7,8].

Low leucocyte total hexosaminidase activity was found

in both and a diagnosis of GM2 gangliosidosis was made in

the early 1980s.

No history of gastrointestinal surgery, pharmacological

treatment, alcohol use or smoking was reported.

2.1. Case 1

This 50-year-old man was referred to our hospital with a

two-year history of progressive dysphagia for solids and

liquids and chest pain. Physical examination was unremark-

able. Neurological signs included evidence of autonomic

dysfunction with sweating impairment, loss of libido and

pili loss. Functional evaluation of cardiovascular parameters

(heart ratio, electrocardiographical changes in R-R interval

and blood pressure variations in head-tilt-table test, deep

breathing test and Valsalva manoeuvre) suggested impaired

cardioregulatory activity, prevalently of parasympathetic

type.

An esophagram revealed moderate esophageal dilation,

with a smoothly tapered and narrowed distal end. Upper

endoscopy showed normal esophageal mucosa and dilatated

esophageal lumen, associated with a tight narrow unob-

nces 241 (2006) 107 – 109

Table 1

Interpretation of abnormal autonomic function tests found in our two patients with Sandhoff disease

Test Predominant autonomic

function tested

Normal Borderline Abnormal Sibling 1 Sibling 2

Valsalva ratio Parasympathetic >1.21 1.11–1.20 <1.10 1.00 1.05

Deep breathing test (max–min heart rate beats/min) Parasympathetic >15 11–14 <10 9 9

Heart rate response to standing (30 :15 ratio) Parasympathetic >1.04 1.01–1.03 <1.00 0.98 0.96

Interpretation of tests was based on the works of Bajaj et al. [19].

M. Pellegrini et al. / Journal of the Neurological Sciences 241 (2006) 107–109108

structed gastro–esophageal junction. This tract was easily

passed with the endoscope, and gastric and duodenal

mucosa appeared normal. Diagnosis of achalasia was

confirmed by conventional esophageal pull-through ma-

nometry [9] that revealed absent peristalsis of the distal two-

thirds of esophagus, absent relaxation of the lower

esophageal sphincter (LES) on swallowing and an elevated

LES pressure (50 mm Hg). No motility alterations were

found in the proximal one-third of the esophagus. The

patient underwent pneumatic dilation [10] under fluoro-

scopic control, achieving complete symptomatic relief and

the ability to eat and drink without difficulty.

2.2. Case 2

This 59-year-old brother of case 1 was hospitalised in our

department at the age of 57 because of increasing dysphagia

for solids.

As in case 1, neurological examination showed slightly

ataxic gait, progressive weakness, distal atrophy of the limbs,

fasciculations and paresthesia of the extremities associated

with dysautonomic symptoms (sweating impairment and loss

of libido and pili loss). As in his brother, a functional cardiac

examination revealed a prevalently parasympathetic pattern

of cardiovascular activity (Table 1). Barium swallow showed

typical findings of achalasia. The patient was unable to

tolerate esophageal manometry. Endoscopy confirmed dilat-

ed and atonic esophagus, without evidence of mucosal

inflammation, and a puckered, closed lower esophageal

sphincter, which was readily passed with the endoscope.

Biopsies in the distal esophagus were unremarkable and the

gastric and duodenal mucosa had normal endoscopic

appearance. Pneumatic dilation under fluoroscopic control

was performed with good symptomatic and radiographic

results. The patient resumed eating without difficulty.

3. Discussion

In 1962 Tyce and Brough first reported two brothers with

a neurological syndrome characterized by cerebellar ataxia,

bilateral optic atrophy, speech disorder and mental retarda-

tion associated with achalasia [11].

In the present paper we report esophageal achalasia in

two brothers with Sandhoff disease, an inherited neuro-

metabolic disorder due to a mutation in the HEX B gene

(5q13) which causes hexosaminidase A and B deficiency

and accumulation of GM2 gangliosides in neuronal and

non-neuronal tissues [12].

Our patients had a late-onset, slowly progressive

neurological phenotype with mild ataxia, fasciculations,

peripheral neuropathy and autonomic nervous system

involvement. They had evidence of autonomic dysfunction

including sweating impairment, loss of libido and pili loss

[13]. Functional evaluation of cardiovascular parameters

suggested prevalently parasympathetic alteration of cardior-

egulatory activity (Table 1).

Gastrointestinal manifestations of autonomic dysfunction

are widespread and include esophageal dysmotility, gastro-

paresis, diarrhea, constipation and fecal incontinence [14].

Moreover, in our cases, gastrointestinal manifestations of

dysautonomia included impaired esophageal motility. The

esophageal motor impairment, manifesting as achalasia, was

demonstrated in the brothers by means of barium swallow

and upper endoscopy. In the younger brother the diagnosis

was confirmed by the esophageal manometry that showed

absence of esophageal body peristalsis and no LES

relaxation on swallowing. During base-line and follow-up,

endoscopic and radiological examinations let us rule out

malignancies as the possible cause of esophageal impair-

ment and symptoms. No other gastrointestinal manifesta-

tions were present.

Cashman et al. [15] and Federico et al. [13] first reported

neurovegetative disorders in patients with GM2 gangliosi-

dosis. The presence of severe motor diarrhea, due to a

decreased transit time in a morphologically normal colon, in

a patient with Sandhoff disease indicated digestive dysau-

tonomic involvement in this inherited neurometabolic

disease [16]. This correlation was confirmed by histological

investigations showing typical intralysosomal storage of

membranous cytoplasmic bodies in myenteric neuronal cells

of adults with hexosaminidase deficiency [13,16].

We hypothesize that altered esophageal motility and LES

relaxation found in the patients here reported may be due to

deficient release of transmitters by the altered autonomous

nervous system innervating the esophagus. In fact, gangli-

oside accumulation in the myenteric neuronal cells may lead

to a myenteric inflammation with ganglionitis and subse-

quent ganglion cell loss and neural fibrosis. The end-result

of these changes may be a selective loss of postganglionic

inhibitory neurons containing nitric oxide (NO) and

vasoactive intestinal polypeptide (VIP) [17]. The loss of

the inhibitory function results in an altered esophageal

motility and LES function. If postganglionic cholinergic

M. Pellegrini et al. / Journal of the Neurological Sciences 241 (2006) 107–109 109

neurons are spared, unopposed cholinergic stimulation leads

to high basal LES pressure, as showed in our case. We were

not able to demonstrate ganglioside accumulation in the

esophageal specimens. Nevertheless, we believe that dys-

autonomic achalasia should be considered the gastrointes-

tinal presentation of Sandhoff disease in both patients for the

following reasons: i) the probability to have concomitantly

in two patients two independent and rare disorders such as

dysautonomic achalasia and Sandhoff disease seems very

weak; ii) ganglioside storage outside the central nervous

system and specifically in the digestive ganglion cells has

been documented [16] and iii) gastrointestinal symptoms

have been already reported in patients with gangliosidosis

[16].

The molecular pathogenesis of adult forms of GM2

gangliosidosis is still under discussion. Different allelic

mutations in one gene locus may lead to extremely different

clinical forms of the same biochemical variant [18]. Cases

with infantile, juvenile and adult onset have been described

and different manifestations listed [12].

In some cases of Sandhoff disease, autonomic nervous

system involvement is significant and, as shown in our

patients, may include achalasia, an additional worsening

factor of disability.

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