Diarrhea and autonomic dysfunction in a patient with hexosaminidase B deficiency (Sandhoff disease)

Diarrhea and Autonomic Dysfunction in a Patient With Hexosaminidase B Deficiency (Sandhoff Disease) ROBERT MODIGLIANI,* MARC LEMANN,* SERGE B. MELANCON,* JACQUELINE MIKOL,§ MICHEL POTIER,? MARCELLO SALMERON,* GERARD SAID,li and PIERRE POITRAS” *Department of Gastroenterology, Hbpital St-Louis, Paris, France; ‘Medical Genetics, Hopital SW-Justine, Montreal, Quebec, Canada: “Department of Neurology, Hopital Kremlin Sicetre, Paris, France; §Department of Pathology and INSERM U53, Paris, France; and ‘Department of Gastroenterology, Hopital St-Luc, Montreal, Quebec, Canada

The causal factors and the physiopathology of motor diarrhea are still unclear. This case report describes a 60-year-old white man with severe diarrhea for more than 10 years and minor signs of autonomic dysfunction. Extensive investigation showed that small intestinal motility and absorption were normal but that accelerated colon transit precluded water and solute absorption from the large bowel. Orthostatic hypotension, sexual dysfunction, and loss of sweating suggested dysfunction of the autonomous nervous system, which was confirmed by reduced plasma concentra tions of norepinephrine and dopamine. Rectal biopsy specimens showed enlarged enteric ganglion cells filled with lipidic material. Levels of total hexosaminidase and hexosaminidase B in plasma, white blood cells, and fibroblasts were decreased, as found in Sandhoff disease. The pedigree of the proband’s family showed several affected and heterozygous individuals, detected by examination of total hexosaminidase and hexosaminidase B levels in plasma. Among the five homozygous subjects, three had a clinical picture of diarrhea and orthostatic hypotension since the age of 50. Therefore, hexosaminidase B deficiency should probably be regarded as a cause for dysautonomia; dysfunction of the gastrointestinal tract, manifested by motor diarrhea or esophageal dysmotility, could be the initial and prevalent presentation of dysautonomia.

D

ysfunction

describes tract

the functional

in a patient

initial mia.

of the autonomic

causal factor for diarrhea.lW3

and most The

without

patient

alterations

complaining obvious also had

the usual clinical

ease such as blindness,

nervous The present

system

is a

case report

of the gastrointestinal

of chronic

presentation

hexosaminidase manifestations

diarrhea

as the

of his dysautonoB deficiency of Sandhoff

dis-

mental retardation, or motor deterioration caused by the accumulation of lipid material in cortical, cerebellar, or spinal tissues.* However, available evidence suggests that dysautonomic diarrhea in our patient was a manifestation of the enzymatic deficiency.

Case Report The patient, a white non-Jewish Canadian man, comof chronic diarrhea since the age of 50. The diarrhea

plained appeared

in 1977,

thereafter. hours,

worsened

He passed

both

during

7-10

in 1980, watery

the day (especially

meals) and at night with frequent ate, and diffuse

abdominal

and remained

nonbloody during

or soon after

soiling. Intermittent,

pain

stable

stools per 24 moder-

led to cholecystectomy

for

gallstones in 1980 without any clinical improvement. The patient lost 17 kg since the onset of his disease and complained of progressive weakness. Extensive investigations 1984 (six hospitalizations).

were performed between 1980 and Daily stool weight averaged 1 kg,

Determination

of fecal fluid osmolarity

gested

diarrhea

osmotic

(osmolarity

After fasting for 72 hours, diarrhea volume.

The following

and electrolytes

sug-

> ENa+] + lK+)

X 2).

decreased

investigations

to half the usual

gave normal

results: se-

rum hemoglobin; white blood cells count; serum electrolytes; renal and liver function tests; oral glucose tolerance test; serum y-globulins and immunoelectrophoresis; screening ence of laxatives or diuretics; stool examination

for the presfor ova and

parasites; upper gastrointestinal endoscopy and colonoscopy with abdominal ultrasound and computed tomographic scans; basal and maximal

gastric acid outputs;

tests; fecal fat (except

in one instance

D-XylOSe

and Schilling

where it reached

10.1

g/24 h); brush border disaccharidase activity; pancreatic bicarbonate secretion under secretin stimulation; jejunal juice bacteriological count; and extensive hormonal levels of thyroid hormones, vasointestinal

workup (circulating polypeptide, calcito-

nin, gastrin, serotonin, neurotensin, pancreatic polypeptide, motilin, somatostatin, cortisol, and urinary 5-HIAA). Cl4 breath excretion after ingestion of labeled cholylglycine was slightly premature (3 hours after ingestion; normal, 4-6 hours), and Cl4 total breath excretion over 6 hours was increased (9.3% of the ingested dose; normal < 4.0%). Barium enema could not be performed adequately because, despite optimal collaboration from the patient, no barium could be introduced beyond the splenic flexure without inducing very

0 1994 by the American Gastroenterological 00185085/94/$3.00

Association

776

MODIGLIANI

strong

colonic

Empirical

ET AL.

GASTROENTEROLOGY

contractions

treatment

free diets, metronidazole, creatic enzymes, peramide

and irresistible

with

lactose-,

cholestyramine,

or prednisone

slightly

reduced

In 1984, the patient

need to defecate.

sucrose-,

and/or

fructose-

indomethacin,

produced

no benefit.

pan-

to Saint-Lazare

hyporeflexia

and decreased

both legs and arms. Mental functions questioning,

the patient

and dizziness occasionally

usually leading

reported

thermic

to a syncopal

attack;

warm weather with loss of sweating;

of

of faintness position

but

(2) intolerance

(3) impaired

to

sexual func-

tion from 1975 and complete impotence since 1978; and (4) mild urinary stress incontinence. Two 72-hour fecal fat collections gave values of 15.7 and 6.0 g/24 h (normal

< 7.0 g).

Duodenal

test meal.

lipase output

was normal

after a Lundh

Results of colonoscopy with ileoscopy and jejunoscopy were normal. The multiple gastrointestinal biopsy specimens were unremarkable with no amyloid deposits. Rectal biopsy specimens suggested

an abnormal

feature to be discussed

later.

Special Studies Stool analysis. Stool volume measured

during

a standardized

and composition

diet and during

hours of a 4-day fast. Each stool was immediately (-- 18°C). During

the standardized

were

the last 48 refrigerated

diet, mean daily volume of

stools reached 1077 mL. The fecal concentration of Na+, K+, and volatile fatty acids was 95, 40, and 52 mmol/L; osmolarity of stool water was 411 mOsm/kg; sulfate, phosphate, and magnesium

and pH was 5.8. Fecal concentrations were nor-

mal, and phenolphtalein was undetected. Over a 15-day period, the number of stools averaged 8.7 + 1.76 (mean t SD) per

the 24-hour

and K’ levels remained

stable (106 and 45 mmol/L,

respec-

to 7.8.

Small intestinal fluid movement. Net and solute transport

were measured

(range,

did not pass any

rates of fluid

by triple lumen technique>

from a plasmalike electrolyte solution (Na+, 135 mmol/L; K+, 5 mmol/L; Cl-, 110 mmol/L; HCOS-, 30 mmol/L; and polyethylene glycol [PEG] 4000, 5 g/L) and from a glucose saline solution (glucose, 65 mmol/L; NaC, 105 mmol/L; Kf, 5 mmol/ L; Cl-‘, 110 mmol/L; and PEG, 5 g/L). Water and solute jejunal absorption from the plasmalike electrolyte solution and from the glucose saline solution was normal. Ileal fluid and solute output was assessed by the slow marker perfusion technique.’ The 24-hour slow marker perfusion studies showed normal fluid and solute outputs in the terminal ileum (immediately above the ileocecal junction) as follows: fluid, 2534 mL/24 h (normal range, 765-2940); Na+, 306 mmo1/24 h (normal range, 242-583); K+, 22.8 mmoU24 h (normal range, 18.2-35.2); glucose, 4.47 g/24 h (normal range, l-9.1); and

period

while the fluid reaching

the

Gastrointestinal motility evaluation. The transit time of the whole gut was assessed by monitoring the fecal excretion of ingested carmine red and ES’Cr] Cl3 Carmine red appeared in the stool 55 minutes after its ingestion (normal range, 18-48 hours). Fecal excretion of ingested f”Cr] Cl, was also extremely rapid; the marker appeared in the stool within 1 hour, and 67.4% and 81.2% of the ingested dose were excreted 6 and 10 hours after ingestion, respectively (normal controls do not excrete any radioactivity within this time range). After ingestion of 20 radiopaque pellets, the first marker was passed in 3 hours (normal range, 6-54 hours), and 80% of the markers was excreted within 23 hours (normal range, 24-80 hours). Small intestinal transit time assessed by the lactulose breath test was normal, with the increase in Ha excretion occurring 3 hours 15 minutes after ingestion of the sugar. The progression of a double isotope-labeled meal (In”’ liquid phase ““Tc solid phase) from the stomach to the colon was assessed as previously described.’ The scintigraphic study showed a normal gastric emptying of liquids but a frank delay in the emptying rate of the solid material. The profile of cecal filling with the liquid phase marker was normal, suggesting a normal small intestinal transit time. However, a marked propulsive response of the colon to eating was present on this test, with transfer of most of the radioactivity from the cecoascending to the rectosigmoid area within the first postprandial hour. The evaluation of intestinal transit is summarized in Table 2.

Table 1. Evaluation

of Intestinal

24 hours. During fasting, stool volume and osmolarity decreased to 535 mL/24 h and 242 mOsm/kg, respectively. Na+ tively), and stool pH increased

the patient

Hospital

sensitivity

in the supine

Interestingly,

ileal region was totally aspirated and precluded for entering into the colon. The evaluation of intestinal absorption is summarized in Table 1.

were normal. On specific

(1) few episodes

improving

minutes).

14.91). The ttme for

was 180 minutes

stool during

in Paris. Blood pressure was 120/80 mm Hg when in recumbent position but decreased to 70150 on standing with no increase in pulse rate. Neurological examination showed lower limb tendon

90-307

range, 4.02-

of 50% of [C’*]PEG

No. 3

Only lo-

the diarrhea.

was admitted

starch, 9.34 g/24 h (normal ileal recovery

Vol. 106,

Absorption

Patient Whole gut absorption Stool analysis Weight (g) Eating Fasting Osmolarity (mOsm/kg Na’ (mmo//L) K’ (mmo//L) VFA (mmo//‘L) Fat (g/24 h)

Small intestinal absorption Heal output fluid (mL/24 h) Na+ (mmo//24 h) K’ (rnmo//24 h) Glucose (g/24 h) Starch (A/24 h) VFA, volatile

fatty acids.

Normal value

1077 535 411 95 40 52 6 10.1 15.7

150-250 0 280-300

2534 306 22.8 4.47 9.34

765-2940 242-583 18.2-35.2 1-9.1 4.02-14.9

<7

March 1994

MOTOR DIARRHEA, DYSAUTONOMIA, SANDHOFF DISEASE

Table 2. Evaluation of intestinal

ties were normal.

Transit Normal value

Patient

Basal supine plasma epinephrine

3 5 - 50), but the concentrations

norepinephrine

normal,

acid output 55 min

(46 pg/mL;

evaluation

81.3%

of

showed a normal peristaltic pressure

was increased

complete

3h 23 h

6-54 24-80

195 180

180-240 240-360

180

go-307

the

contractions

no phase III could be documented

sigmoid

colon, electrical of rythmic

of the time; normal potentials

(our patient,

were more frequent is a pattern Schang,

was

normal,

but

a 4-hour observation

Canada).

In the fasting but

stationary

2%

potentials

(our patient,

nonpropagating

15% of the recording sporadic

time; normal

propagating

18/h; normal,

personal

found in patients

communication,

6/h). The de-

failed to induce the postprandial

sigmoid

increase usually seen in normal

subjects.

Neurological

evaluation.

ones

with diarrhea

February

1985).

myoelectrical

Neurological

>

potentials

signals and the increase in propagated

frequently

(J. C. Eating activity

dependent anterior

sensation pattern

examination

aspect of the trunk.

the knee level; perception legs and in the hands. The evaluation Table 3. When standing

of the right

in the number

On electron

or amyloid

fibers/mm2);

showed

that

dense bodies,

and modified

cells contained

pleomorphic

made of irregularly in lysosomes

cytoplasmic

sphingomyelinase, mal. However, creased

body was observed.

(Table

evaluation.

blood

disease. No oligosaccharides

Table 3. Evaluation

of Autonomic

No

No neural cell level.

of P-galactosidase, and hexosamini-

cells, or fibroblasts reported

were detected

by thin-layer

spherical bodies.

from white cells were nor-

4), as characteristically

evaluated

accumulating

at the ultrastructural Levels

and arylsulfatase white

many figures,

pm in diameter,

and lipofuscin

levels of total hexosaminidase

dase B in plasma,

of storage

Most of Schwann l-2

parallel membranes

on the sections studied

Metabolic

gan-

study of the

contained

mitochondria.’

inclusions

from

enteric

1); the same cells also contained

or ovoid dense granular was present

obtained

evidence

the plexuses

of

endoneurial

size, filled of myelinic lipid bodies,

arranged

(Figure

membranous

specimen

The ultrastructural

axons of different

the density

the density

of submucosal

and showed

and

endoneurial

to 36OO/mm*

On a biopsy

enlarged

lesion

to 1670/mm2

the cytoplasm

with usual stainings. specimen

an

examination,

myelinated

glion cells appeared

sural nerve showed

neural

32,600/mm2).

the rectal mucosa,

and

as in motor

significant

area (controls,

biopsy

(sural, saphenous,

microscopic

fibers was reduced 7200

of

tested

myelin

fibers was reduced

dystrophic

integrity

of small-size

were de-

for Sandhoff

in a 24-hour

chromatography,

urine

suggesting

Dysfunction

Pinprick

Vibratory

sensation

was lost up to

sensation

in the

was decreased

in

is summarized

on

sense was preserved.

the patient

dysfunction

moved from the recumbent

his systolic

and diastolic

blood

to the pressure

decreased rapidly (40 and 20 mm Hg, respectively) without elevation of the heart rate. Atropine injection failed to accelerate the cardiac frequency.

Patient

elbow level, and over the

of light touch was decreased

of autonomic

position,

limbs

unmyelinated

material

suggesting

nerve conduction

(+ 5°C and + 50°C) was lost in a length-

up to midthigh,

the feet only; position

reduction

fibers, without

collection

showed normal muscle strength. Tendon reflexes were brisk in the upper limbs and decreased in the lower extremities. Temperature

fibers. A biopsy specimen

Gastric

hypoglyce-

nerves) was normal in sensitive

Rectal biopsy.

signals were of normal amplitude

(our patient

crease in stationary

peroneal

area (controls,

and the amplitude

during

Quebec,

whereas

nerves of the inferior

superficial

of myelinated

sphincter

after insulin-induced

Peripheral

of

and dopamine

180) were deeply reduced.

in various

important

200-400)

to pentagastrin),

vagal nerves.

infiltration.

contractions

appeared

> 10%) and of sporadic

30%) was decreased

h h

activity was recorded by J. C. Schang’

of Sherbrooke,

the frequency

esophageal

The configuration

period. Colonic electrical

mia (17.3 in response

amyelin

to 50 mm Hg, but its relaxation

gastroduodenal

(University

0%

profile. Lower esophageal

on swallowing.

of fasting

h

1 lo-

was 10.6 mEq/h

the gastric

Small intestinal transit time Lactulose breath test (min) (r?‘]Cholylglycine breath test (mifl) lleal recovery of 50% of [C14]PEG infused in jejunum (min)

Manometric

8-48

levels were

normal (40 pg/mL; normal, (
Whole gut transit time Fecal excretion of ingested carmine red 10-h fetal excretion of ingested [?r]C& Fecal excretion of plastic pellets First pellet 80% pellets

777

Blood pressure was not modified

by a

sustained effort (handgrip dynamometer) and was only weakly elevated after arm immersion in ice-cold water. Pupillary response to pilocarpine suggested hypersensitivity to parasympathetic drugs. Urinary bladder and anorectal manometric activi-

Normal value

Blood pressure (mm Hg) decrease on standing Systolic Diastolic Plasma adrenalin (pg/mL) Supine Standing Plasma noradrenalin (pg/mL) Supine Standing Plasma dopamine (pg/mL) Cold pressor test

46 207 (30 No change

200-400 400-800 110-180 Increased blood pressure

Heart rate response to Orthostatism Atropine

No change No change

Increased Increased

50 30

<25
40 52

35-50 70-100

778

Figure L

that

GASTROENTEROLOGY Vol. 106, No. 3

MODIGLIANI Er AL.

(A and 8) Electron micrographs showing pleomorphic lysosomal storage in the cytoplasm of Schwann cells (rectal biopsy).

hexosaminidase

accumulations

activity

material.

characterization

was obtained

other

Briefly,

report.”

showed

was sufficient

of undigested

and described

Northern

Two mutations

gene were identified: to thymidine the intron

IO-/exon

messenger

family

and mature B subunit

5’ gene deletion

located 8 nucleotides 11 junction

individuals,

showing

detected

affecting 2 presents

several

B plasma

from

gene splicing

of the

the pedigree

activity

results were ob-

in peripheral

leukocytes

(data not shown). All affected individuals activity

drolyzed

per minute

erotygotes hydrolyzed

per milliliter

nanomoles

blood

had hexos-

substrate

hy-

of plasma and obligate

het-

between 4.3 and 7.7 nanomoles of substrate per minute per milliliter of plasma (normal plasma

level of hexosaminidase percentage

activity

of hexosaminidase

was more variable, but generally total)

0.9

9.2 and 22.9). The

B in the homozygous

i.e., between

less than

and normal

is between

patient

5% and 30% of total activity,

in the hererozygotes

controls

(13%-36%

Hexosaminidase

(11% -30%

of total).

Patient

Plasma’ WBCb Fibroblastsb

and Percentage

B in Patient’s

Among

of

the

% of B

0.89 3.5 6.5

7.0 29 4

Total 9.2-22.9 11.9-33 51-185

the proband)

pre-

and the two

other homozygotes of the proband suggests

were in apparent could

good health. The mother

not be examined,

she was carrying

the enzymatic

but most

evidence

deficiency.

Evolution The patient

1.7-7.0 2.6-7.0 31-50

WBC, white blood cells. Hexosaminidase activity is expressed in nanomoles of substrate hydrolyzed per minute per milliliter of plasma. bHexosaminidase activity is expressed in nanomoles of substrate hydrolyzed per minute per milligram of protein.

treated

with

codeine

(16 mgldaily).

Treatment

mide

the diarrhea,

which

entirely

stopped

to discontinue

worsened

this drug. Clonidine

the orthostatic

hypotension

for the treatment

of diarrhea.

Addition

In 1987,

the patient

Esophageal

manometry

showed

but the lower esophageal

pressure (50 mm Hg) without matic dilatation

condition

thostatic

hypotension

fludrocortisone

relaxation

manifestations

in stable

with

is controlled

acetate,

or verapamil

both drugs

dysphagia.

esophageal

peristalsis,

increased

resting

on swallowing. this condition.

of his disease,

loperamide,

at any

developed

showed

of the cardia corrected

years after initial

recurred

of anticholinergic

normal

sphincter

syrup

with lopera-

and could not be used

was uneffective.

PneuFifteen

the patient

12- 16 mg/daily.

by elastic support

is Or-

socks and

100 pg/daily.

Discuulon

loidosis.3s’2

% of B

was initially

and then by loperamide

autonomic

of

Tissues Normal controls

Total

(including

with onset at the age of 50. The heterozygotes

Diarrhea Table 4. Total Hexosaminidase

three subjects

hypotension

attempt

of total hexosaminidase

aminidase

less than

of the

and heterozygous

levels. Similar

cained by assaying hexosaminidase

five homozygotes,

sented a clinical picture of diarrhea and orthostatic

and a cytosine

downstream

affected

by examination

and hexosaminidase

in an-

blot analysis

RNA

p subunit messenger RNA. Family history. Figure proband’s

extensively

of the hexosaminidase

a partial

transition

large

biochemical

and Western

low levels of P-subunit

P-protein.

to prevent

Complete

is a well

failure

such

As discussed

rhea can be observed

known as

in

extensively

symptom diabetes3’”

of secondary or

by Camilleri,3

amydiar-

frequently in patients with disorders affecting the extrinsic neural supply to the gut. Dysauconomic diarrhea is usually recognized easily because other symptoms of autonomic failure are patent. In our patient, diarrhea was the main presenting symptom and led to six hospitalizations with extensive digestive investigations before a systematic search for orthostatic hypotension led to the correct diagnosis. Accompanying symptoms of autonomic failure were found only on very specific questioning. One may wonder whether some of the patients

MOTOR DIARRHEA, DYSAUTONOMIA, SANDHOA

March 1994

Figure 2. Pedigree of the pro band (arrow) with total hexosaminidase level in the plasma (nmol~min-l.mL-l) and percentage of hexosaminidase B level. Squares and circles indicate males and females, respectively. Solid and ha/f-so/id figures indicate homozygous and heterozygous status, re spectively. The mother of the proband could not be examined but is assumed to be a carrier.

with large-volume

diarrhea

have autonomic Our findings

failure. provide

the mechanisms

of diarrhea

failure

(Figure

;:,

oj

&

;&

5.7

11%

origin13 do not

testinal glucose,

important

new information

in patients

3). In our patient,

on

with autonomic

the small

intestinal

entering transit

function

showed

and starch into

779

o&doLa

4.3

15Y0

of unknown

0;;

DISEASE

6.5

15%

22%

4.7

the small

were normal.

time was found normal

5.6

19%

that the outputs

leaving

the colon

5.7

30%

of fluid, ions, intestine

Small

before

intestinal

by most tests, although

it

function was considered normal. The jejunum absorbed the fluid, ions, and glucose normally, as shown by the

was probably occasionally accelerated (see cholate breath test), explaining the intermittent slight steatorrhea (10.1 and 15.7 g/24 h). The intermittent and slight dysfunc-

perfusion study. The 24-hour ileal slow marker infusion experiment that evaluated the overall result of small in-

tion of the small bowel appeared for the incapacitating diarrhea.

LES:

insufficient

to account

f pressure 0 relaxation -

STOMACH emptying rate = N

#

INTESTINAL TRANSIT = N

INTESTINAL ABSORPTION = N

Normal rate of H,O (2534 ml/24 hr) and ions entering the colon

STOOLS: 1077 ml/24 hr

figure 3. Schematic representation of the pathophysiological abnormalities of the digestive tract in a patient with motor diarrhea and autonomic deficiency. LES, lower esophageal sphincter.

780

MODIGLIANI

ET AL.

The function turbed.

of the colon was, however,

The colon

the fluid output entering

GASTROENTEROLOGY

was unable

(qualitatively

it. Reabsorbtion

cecum during

and quantitatively

normal)

of the ileal fluid entering experiment

in our patient.

can be assessed by substracting amounts patient

was able to reabsorb Nat/24

Debongnie further fatty

and Phillips

acids

whereas

of the colon

their

the amount

fecal output

of unabsorbed

reabsorb

it received

during

fasting,

as shown

of copious

fecal fluid on fasting,

macrocephaly, manifestations

in the first months

is autosomal

recessive

of life, although

Sandhoff

has been found

by

Our results volatile and

the cecum

hexosaminidase

A and B deficiency.” GM, gangliosidosis

by Navon

et a1.18 Most

spinocerebellar Central

and

nervous

sion) remained

motor

appendectomies of membranous

cytoplasmic

hexosaminidase

A deficiency”;

as

patients

neuron

were

dysfunction.

(intelligence

and viaccumu-

lation in peripheral tissue has been documented. Myenteric neuronal cells obtained by rectal biopsy or at

to com-

regarded

form of

symptoms

in most. Ganglioside

of fluid and ions by the persistence

is

Progressive

have been reviewed

functions

unaffected

disease is

Thirty-five

prominent

lower

system

seen

Dysautonomia

in the adult

with adult-onset

mode.

are often

motor

was increased,

a feature

area, leading motor deteri-

of these diseases

later in life in some patients.

neuropathy

No. 3

and cherry red spots in the retina

of the eye. Transmission Clinical

or spinal retardation,

feature of this syndrome.

sugar (glucose

amounts

mental

not a usual clinical

the colon was unable

the reduced

oration,

cerebellar,

to blindness,

when the

as measured

fatty acids) entering

Furthermore,

in the cortical,

diagnosed

only 25% of the maxi-

in normal subjects.‘*

starch, source of volatile pletely

the ileum

nent

classically

from the

that the colon also malabsorbed

because

was normal.

absorption

1457 mL of water and 203 mEq

capacity

suggest

Colon

diet. It showed that the colon

h. These values represent

mal absorption

the

was the only

fecal outputs

of fluids and ions leaving was on a regular

dis-

reabsorb

the slow marker

way to stop diarrhea

strongly

to adequately

Vol. 106,

patients

showed

had isolated

typical

intralysosomal

storage

bodies in some adults however,

gastrointestinal

with

none of these

symptoms

such as

typical of secretory diarrhea and not previously reported in diarrhea with intestinal hurry.15 Transit time measure-

our patient. constituted

ment by several methods clearly showed a decreased transit time in the colon with extremely rapid postprandial progression of colonic contents. It seems likely that the

deficiency in our patient. In support of this, we consider the following: (1) the chance of having, concomitantly,

main mechanism morphologically

for fluid and ion malabsorption normal

colon was the greatly

speed of transit impairing the normal water, ion, and nutrient metabolites. The profile sigmoid

of myoelectrical

of our patient

activity

is in agreement

by the increased

colonic salvage of

two rare entities such as dysautonomic diarrhea and Sandhoff disease in one single patient seems very weak; (2) peripheral symptoms have been found in other patients who have various diseases with lysosomal lipid accumulation;

recorded

in the

with the mano-

We believe that the dysautonomic diarrhea the clinical presentation of hexosaminidase

central

(3) lipid nervous

of our patient;

substrate

storage

in organs

system was verified and (4) dysautonomia

the

in the rectal mucosa with diarrhea

and

metric and dynamic observations by Bazzocchi et al.” in patients with functional diarrhea; they report decreased

orthostatic hypotension homozygotes.

nonsegmenting contractions, frequent propagating contractions, and absent postprandial response. Increased coionic transit speed in our patients could probably be

McInnes et al. lo identified two mutations of the hexosaminidase B gene in the patient and his family. The two

attributed to a deficient release of inhibitory transmitters (adrenergic and/or others) by the altered autonomous nervous system innervating this organ. Failure of the lower esophageal sphincter to relax upon deglutition could probably also be attributed to an imbalance between the stimulatory and the inhibitory mediators regulating the pressure of this organ. Our patient had hexosaminidase deficiency diagnostic of Sandhoff disease.* Excess ganglioside accumulation in tissue leads to clinical features of Tay-Sachs disease (hexosaminidase A deficiency) or Sandhoff disease (deficiency in the P-subunit of the enzyme leading to hexosaminidase B deficiency and total hexosaminidase deficiency). In these diseases, lipid accumulation is most often promi-

was found

outside

in three of the five

mutations had already been seen in other patients with the Sandhoff phenotype, i.e., a 5’ gene deletion” and a cytosine to thymidine transition 8 nucleotides downstream from the intron lo-exon 11 junction2’ mutations resulting respectively in a severe infantile phenotype and in a juvenile phenotype. The relatively mild and delayed phenotype of our patient may be explained on the basis of tissue-specific variations in the level of properly spliced p subunit messenger RNA leading to the expression of variable levels of the enzyme in different organs. Support for this conclusion is provided by the variable levels of hexosaminidase activity found in various tissues of our patient. A profound deficiency of total hexosaminidase activity (<6% normal) was found in plasma and in cultured skin fibroblasts, whereas the re-

MOTOR DIARRHEA, DYSAUTONOMIA, SANDHOFF DISEASE

March 1994

sidual

activity

was higher

(about

16%

of the normal

control cells) in the white blood cells. No oligosaccharides were detected in 24-hour urine collections from the proband,

supporting

the conclusion

tissues (such as the kidney

that, at least in some

or the brain),

have enough

hexosaminidase

accumulation

of undigested

to an atypical

phenotype.

activity material,

the patient to prevent therefore

may large

leading

References 1. Camilleri M, Malagelada JR, Stanghellini V, Fealey RD, Sheps SG.

2.

3. 4.

5.

6.

7.

8.

9.

10.

Gastrointestinal motility disturbances in patients with orthostatic hypotension. Gastroenterology 1985;88:1852-1860. Camilleri M. Fealey RD. Idiopathic autonomic denervation in 8 patients with functional gastrointestinal disease. A causal association? Dig Dis Sci 1990; 35:609-616. Camilleri M. Disorder of GI motility in neurologic diseases. Mayo Clin Proc 1990; 65:825-846. O’Brien JS. The gangliosidosis. In: Stanbury JB, Wyngaarden JB, Frederickson DS, Goldstein JL, Brown MS, eds. Metabolic basis of inherited disease. New York: McGraw-Hill, 1983:945-972. Modigliani R, Bernier JJ. Effets du glucose sur les mouvements nets et unidirectionnels de I’eau et des electrolytes dans I’intestin grele de I’homme. Biol Gastroenterol 1972;5:165-174. Phillips SF, Gilles J. The contribution of the colon to electrolyte and water conservation in man. J Lab Clin Med 1967;70:686698. Jian R, Najean Y, Bernier JJ. Measurement of intestinal progression of a meal and its residues in normal subjects and patients with functional diarrhea by a dual isotope technique. Gut 1984;25:728-731. Schang JC, Devroede G. Fasting and postprandial myeoelectric spiking activity in the human sigmoid colon. Gastroenterology 1983;85:1048-1053. Lampert PW. A comparative electron microscopic study of reactive, degenerating, regenerating, and dystrophic axons. J Neuropathol Exp Neurol 167; 26:345-368. Mclnnes 6, Potier M, Wakamatsu N, Melancon SB, Klavins MH, Tsuji S, Mahuran DJ. An unusual splicing mutation in the HEXI3

781

gene is associated with dramatically different phenotypes in patients from different racial backgrounds. J Clin Invest 1992; 90:306-314. 11. Bargen JA. Bollman JL, Kepler E. The diarrhea of diabetes and steatorrhea of pancreatic insufficiency. Mayo Clin Proc 1936; 11:737-742. 12. Battle WM, Rubin MR, Cohen S, Snape WJ. GI motility dysfunction in amyloidosis. New Engl J Med 1979;301:24-25. 13. Read NW, Read MG, Krejs GJ, Hendler RS, Fordtran JS. A report of 5 patients with large volume secretory diarrhea but no evidence of endocrine tumor or laxative abuse. Dig Dis Sci 1982;37:193-200. 14. Debognie JC, Phillipps SF. Capacity of the human colon to absorb fluid. Gastroenterology 1978; 74:698-703. 15. Fine KD, Krejs GJ, Fodtran JS. Diarrhea. In: Sleisenger M, Fordtran JS, eds. Gastrointestinal disease. 4th ed. Philadelphia: Saunders, 1989:290-316. 16. Bazzochi G, Ellis J, Villanueva-Meyer, Reddy N, Mena I, Snape JJ. Effect of eating on colonic motility and transit in patients with functional diarrhea. Gastroenterology 1991; 101:1298-1306. 17. Rubin M, Karpati G, Wolfe LS, Carpenter S, Klavins MH, Mahuran DJ. Adult onset neuropthy in the juenile type of hexosaminidase A and B deficiency. J Neurosci 1988;87:103-119. 18. Navon R, Argov Z, Frisch A. Hexosaminidase A deficiency in adults. Am J Med Genet 1986;24:179-185. 19. Yaffe M, Kaback MM, Goldberg M, Miles G, ltabashi H, McIntyre H, Mohandas T. Hexosaminidase-A (Hex-A) deficiency in early adulthood. A new type of GM2 gangliosidosis (abstr). Am J Hum Genet 1978;30:31A. 20. Neote K, Mclnnes KB, Mahuran DJ, Gravel RA. Structure and distribution of an alu-type deletion mutation in Sandhoff disease. J Clin Invest 1990;86:1524-1531. 21 Wakamatsu N, Kobahashi NH, Miyatake T, Tsuji S. A novel exon mutation in human beta hexosaminidase, beta subunit gene affecting the tripe green splice site selection. J Biol Chem 1992;267:2406-2413.

Received November 6, 1992. Accepted October 12, 1993. Address requests for reprints to: Pierre Poitras, M.D., AndrkViallet Clinical Research Center, H6pital St-Luc, 1058 St-Denis, Montreal, Quebec, H2X 3J4 Canada. Fax: (514) 281-2492.