M ETACH ROMATIC
LEU KODYSTROPHY:
CLINICAL,
HISTO..
CHEMICAL,
AND
CEREBROSPINAL
FLUID
ABNORMALITIES
Richard J. Allen, M.D., James J. McCusker, M.D., and
Wallace W. Tourtellotte, M.D., Ph.D.
Departments of Pediatrics, Pathology, and Neurology, University of Michigan Medical School,
Ann Arbor, Michigan
This work was supported in part by a training grant from the Childrens Bureau to the Department of Pediatrics, a United States Public Health Service training grant (#CRT-5083), and the National Multiple Sclerosis Society.
Presented in part before the American Pediatric Society, May 2-3, 1961, Atlantic City, New Jersey.
Dr. McCusker is a National Cancer Institute Trainee.
ADDRESS: (R.J.A.) University of Michigan Medical Center, Ann Arbor, Michigan.
629
PEDIATRICS, October 1962
T
HE PIIINIA1IY PURPOSE of tilispublica-tion is to report some unique findings in a patient \Vitil metachromatic
leukodys-trophy. Late in tile course of the disease a
typical cilerry red spot” with a surrounding white halo became apparent on
ophthal-nloscopic examination. Also, an analysis for
cerebrospinal fluid and serum lipids was
ac-comphshed prior to death. Postmortem
ex-amination with histocilemical techniques
permitted proper classification; the
correla-tion of these findings with the chemical
allalVsiS of the cerebrospinal fluid will be
attempted.
Up to 1960 only 10 pathologically verified cases of infantile metachromatic
leukodys-tropiw ha(1 been reported.1 However, as
\Vitil most uncommon diseases, increased
awareness may lead to more frequent
clini-cal diagnosis. Also, tile place of this disease among the inborn errors of metabolism is
Ilot fully appreciated; our findings may sup-port this concept.
REVIEW OF THE LITERATURE
A great number of publications have been written on this disease. Only a brief
review of the literature will be presented here. Tilis disorder was originally de-scribed by Greenfield2 in 1933, and then in
1950 additional cases were reported by
Brain and Greenfield, after the application
of newer histocilemical tecilniques.
In this second report, Brain and Green-field identified metachromatic material not
only in tile central nervous system, hut in
the liver and kidneys, and considered this disease to be a “developmental disorder of the lipid metabolism of the central nervous
system.”
Metachromatic diffuse cerebral sclerosis (leukodystrophy) has been reported to occur
in various age groups,4’ although the in-fantile type (Greenfield’s disease) is best known because there are a larger number
of pathologically verified cases. It is also
one of a group of central nervous system disorders characterized by a widespread loss of myelin and often known as diffuse
cerebral sclerosis. Although occasionally
tile eponym “Schilder’s disease” is used,
there is little justification for this.
Some authors divide diffuse cerebral
seTh-rosis into three groups by employing special
histochemical staining techniques. One of these subgroups includes infantile meta-cilrOmatic leukodystrophy which is charac-terized by tile accumulation of
metachro-matically staining material in the areas of
demyelination.7 While metachromatic ma-terial may be found in other demyelinating diseases, in metachromatic leukodystrophy
the usual sudanophilic lipids are absent from the lesions, except in the Virchow-Robin spaces.6 The characteristic cases are distinguished by an “extraordinary accumu-lation of metachromatic material.”l Also,
no obvious abnormality may be apparent
meta-chromasia may be clearly evident in frozen
38 This metachromatic staining is presumed to be due, in part, to an abnormal
accumulation of cerebroside sulfuric acid
esters (sulfatides), which are ordinarily
found in normal myelin but to a lesser
de-10
Austin is credited with the first
identifica-tion of this disease in a living patient by
examination of the urine sediment for meta-chromatic granules.h1 A renal biopsy was
also done and demonstrated metachromatic material in the renal tubules. On the other hand, Jatzkewitz was the first to
demon-strate that cerebral tissues and kidneys con-tamed increased amounts of sulfatides, and
these observations have since been
con-firmed by several investigators.9’12’7 The metachromatically staining granules in the urine have also been shown to be a
sulfa-tide.172O Austin has suggested that this
accumulation may be indicative of a
“sulfa-tide lipidosis.” Subsequent reports’ “‘ “
sup-port the concept that metachromatic
leuco-encephalopathy is indeed closely related to tile other cerebral sphingolipidoses which are thought to be due to an inborn error of metabolism.
In addition to the metachromatic urine
granules, there are other manifestations in this disorder that are important to the
clinician. The protein in cerebrospinal fluid is characteristically elevated’ while
electro-phoresis of the protein is normal.20 The
early onset of ataxia and hyporeflexia and, in some instances, areflexia has led some to
suspect many disorders characterized by
IlypOtonia, including lower motor neuron disease. Cranial nerve pareses often occur. Fundoscopic examination generally reveals optic atrophy, and to date no other signifi-cant retinal changes have been reported.
Microscopic examination of the eye in older patients \Vitil tilis disease has demonstrated
the deposition of metachromatic substances in ganglion cells, which compares to the abnormal lipid deposits seen in the retina of patients with Tay-Sach’s disease.2’
Neuropathological studies have
demon-strated extensive deposition of
metachro-matic lipid in nerve cells of the brain
stem,’4 while Diezel22 reported a deposition
of metachromatic material in the peripheral nerves similar to that found in the central nervous system. This may account for the clinical evidence of lower motor neuron
disease, for Austin’5 has stated that periph-eral nerves degenerate and
electrornyo-graphic fibrillations are evident.
CLINICAL DATA
D. C. was 22 months of age when lie was
first admitted to the hospital with a history of a fall in which he had struck his head
2 months before. Tilere were no immediate
abnormalities, but one month later a
stra-bismus developed. It was also noted that he had difficulty with his balance. The past medical history and early birth and
devel-opmental history were entirely normal. The family history revealed a normal
6-month-old brother. There was no history of cen-tral nervous system disorders in any mem-ber of tile family. The general physical
find-ings were normal. On neurological
examina-tion the mental function seemed normal for his chronological age. On motor examina-tion he walked unsteadily. His co-ordination was othervise difficult to assess, bilt he
used all extremities equally well. There were no pareses. Sensory examination was limited to normal pinprick perception. Deep
tendon reflexes were equal, but
question-ably positive Babinski responses were noted. Cranial nerve examination revealed
only a right abducens nerve paresis. The fundi, including the maculae and periphery, were normal. The first lumbar puncture was done during this admission (Table I). Skull x-rays revealed a linear fracture in the left
posterior parietal area paralleling the lamb-doidal suture. An electroencephalogram
showed some mild background abnormality
but was not diagnostic. Tile infant was
dis-charged witilout any specific diagnosis.
At 26 months of age tile infant was re-admitted to the hospital because the mother
said that his walking ilad become worse.
He demonstrated a wide based gait and
Pressure
N 0
N 7 IioIl’s
90 001 1000000
TABLE I
RESULTS OF ANALYSIS OF CEREBROSI’INAL FLUID
.lge
(,,io)
(el/v Protein (per ,,,,,,3) (,iig/l(W) ml)
2 erythroeytes
(‘olloidal Serology (a1)bl,li,L 601(1
9() 001llI000()
mastic 011ll()
0
0 +2
160 001 122100()
IIlaStiC 0(8)000
0
34 (‘SF frorei l)rleuIIo- 180 00122’100() 0 +2
ercepiealograen iiiastic 01 ‘2 10
46 N 0.9 l4.7 0(8123100(8) 0 +2
S Ste Tables I I ated I I I for cerehrospituel fluid 1111(1 seruili hpi(l values.
The only difference now in the neurological
examination was a complete absence of all deep tendon reflexes. The plantar responses were primarily that of withdrawal but did
suggest Babinski responses. The abducens
nerve paresis was no longer evident.
Corn-plete ophthalmological examination failed to
reveal any abnormality.
A pneumoencephalogram was done, and
the impression was that of cerebral atrophy on the left with localized dilation of the occipital horn. A rnyelogram ruled out a cervical cord lesion. An electromyogram was done because of marked hypotonia and
weakness but was normal. A biopsy of the
left gastrocnemius muscle proved to be
nor-mal. A second electroencephalogram mdi-cated deterioration since the last one, and suggested the presence of a severe diffuse disturbance of cerebral function.
At 32 months of age the boy was unable
to walk by himself. The gait was flatfooted, with marked genu recurvatum bilaterally.
An interesting change had taken place in the child’s lower extremities in that there
appeared to be a loss of muscle volume,
es-pecially below the knees. In the lower ex-tremities there was definite scissoring and heel cord shortening. Passive movements
re-vealed increased spastic tone throughout.
He now demonstrated a terminal tremor on
reaching for objects. Sensory examination
was limited to the normal perception of pin. All deep tendon and superficial reflexes were
absent. Typical bilateral Babinski’s were present. Nystagmus was present on lateral gaze bilaterally. The fundi, including the maculae, were perfectly normal at this time.
At 34 months of age the patient was ad-mitted to the hospital because of lethargy and vomiting. His neurological status had
continued to show a progressive downhill
course. He still appeared to be well
nour-ished and well developed, but he had now
lost bladder control and was also losing the ability to speak. There was a change in his personality, for he was less interested
in his surroundings and was having many “staring episodes.” He showed a decreased response to any stimulation, but would get
irritable at times and resist examination.
He lay in a rigid position with his legs ad-ducted and feet plantar flexed. Nuchal
rigidity was present. Any voluntary effort to move the upper extremities resulted in marked tremor; this was thought to be the
result of severe ataxia. The deep tendon reflexes were absent throughout and the toes were in the constant extensor position. There was a question of decreased visual acuity. The pupils were dilated but reacted
sluggishly to light direefly and consensually.
The disks and maculae were normal. The
TABLE II
LIPIDS PER 100 MILLILITERS OF CEREBROSPINAL FLUID
. .
Determination Normal Values
Avg (± S.D.)
Meta-chromatic
Leuko-dystrophy
Total phospholipids
(m M/100 mI)* Cephahins Lecithins Sphingomyehins
Recovery of lipid
phosphorus (%)
521 (840-702) 142 ( 63-221)
228 (118-338)
119 ( 60-178)
93 ( 73-113)
1198 (I)t
621 (I)
..
511 (I)
79 (N)
Nonphosphorus sphin-go lipids (m M/I00
ml) 94 ( 0-206) 129 (N)
Total cholesterol
(IL gm/100 ml)
Free (%)
395 (218-572) 33 ( 15- 51)
1192 (I)
28 (N)
Total lipids
(jzgm/lOOml) 1252(766-1738) 6148(I)
“Neutral fats”
(pg/100 ml) 417 ( 0-902) 3958 (I)
* mM indicates micromoles times 1,000.
t (N), (I), and (D) indicate, respectiVely, no
signifi-cant difference, significant increase, and significant decrease.
% recovery of lipid phosphorus equals summation of cephalins+Iecithins+spingomyelins times 100
di-vided by total.
in the midline. It was impossible to evaluate the extraocular movements or nystagmus.
A
third
electroencephalogramapproxi-mately 14 months after the onset of his
illness indicated further diffuse
deteriora-tion. An examination in the Department of Ophthalmology failed to reveal any ab-normality of the disks or maculae. A second pneumoencephalogram indicated
general-ized mild dilation of the lateral ventricles
with a slight predominance of left ventricu-lax enlargement. The cerebrospinal fluid
was also analyzed (Table I).
At 46 months of age the head measured 53.7 cm, which is between 2 and 3
stand-aid deviations above normal for a boy of
this age. He constantly whined and cried
but no longer spoke. He had generalized
increased muscle tone throughout, and it
was virtually impossible to straighten his
flexed right arm or to bend his left. He
assumed a position of opisthotonos at all times. His legs were generally extended and internally rotated. Surprisingly the re-flexes could be obtained in moments of
re-laxation, but were markedly increased, and
there was bilateral heel cord shortening and bilateral Babinski’s. He appeared to be
blind. The pupils were widely dilated and responded poorly, if at all, to light.
On funduscopic examination he had a
definite “cherry red spot” with a macular
halo of greyish-white coloring. He was seen
by an ophthalmologist who confirmed these
retinal changes, and a cerebral lipoid stor-age disorder was considered, such as Tay-Sach’s disease. A bone marrow aspiration
was done and found to be normal. The
cerebrospinal fluid examination was
re-peated (Tables I & II) to obtain a lipid profile.
LABORATORY DATA
Routine blood and urine examinations were normal throughout the various hospi-tal admissions. Results of five cerebrospinal
fluid studies done from 22 to 46 months of
age are shown in Table I. Cerebrospinal fluid and serum lipid profiles2s were done
under fasting conditions 3 months prior to death. In general, the cerebrospinal fluid
was marked by an increased protein
con-tent and a “rnidzone” colloidal gold curve; these abnormalities tended to increase dur-ing the period of observation.
The lipid fractions (Table II) indicated approximately a twofold increase of total phospholipids with cephalins, and
sphingo-myelin about equally elevated. The
non-phosphorus sphingolipid compartment was
normal; the cerebroside sulfuric acid esters
are contained in this fraction. Lipid sulfur analysis has not yet been carried out on this fraction. Furthermore, a threefold
in-crease in total cholesterol, a fivefold
TABLE III
LIPIDS PER 100 MILLILITERS OF SERUM
ARTICLES
633in “neutral fats” was noted. All these have been compared to young normal adult
cere-brospinal fluid fractions.23 The serum lipid data are shown in Table III. The values were
within normal limits except for an increase
in tile flonpilosphoruS sphingolipids (nine-fold above the average).
AUTOPSY FINDINGS
On gross examination the body was that
of a physically retarded and cachectic white
boy, with moderate enlargement of the head and marked atrophy of the muscles of the
extremities. The brain revealed a moderate
internal hydrocephalus involving the whole
ventricular system, an area of recent soften-ing with central hemorrhage involving the tip of tile left temporal lobe, and a marked
diffuse increase in firmness of the central
white matter of the cerebrum. A lumbar
spina bifida occulta was present. The spinal cord appeared to be normal. A bilateral
confluent lobular pneumonia was present in
the lungs. The rest of the viscera were
grossly normal.
Materials and Methods
The brain and spinal cord were fixed in
Cajal’s bromformalin, the other organs in
neutral 10% formalin. The histochemical
tests (begun within one month after death) were carried out on frozen sections of cilromated, gelatin-embedded tissue. In
order to demonstrate that the abnormal de-posits were, at least in part, lipid, corn-panion blocks of tissue from winch the lipid had been extracted with pyridine
after formalin-fixation served as controls and were stained simultaneously with the sections of non-extracted tissue. Tile main
tissues used for the histochernical study in-eluded cerebral cortex and white matter, pons, cerebellar folia, spinal cord with
nerve roots, kidney, and liver. Certain
im-portant histocilemical stains (periodic-acid-Schiff, tohuidine blue, and Sudan black B) were also performed on paraffin sections of nonchromated blocks of the above tissues
and frozen sections of other tissues. For
. .
Determination Normal Values
Avg (±S.D.)
Meta-chromatic
Leuko-dystrophy
Total phosphohipids (mj.uM/100 ml)
Cephahins Lecithins Sphingomyehins Recovery of Lipid
Phosphorus (%)
250 (180-820)
26 ( 13- 39)
182(131-233) 53 ( 35- 71)
105 ( 72-128)
211 (N) 61 (1)
159(N) 94 (1)
149 (1)
Nonphosphorus sphin-gohipids (mM/100
ml) 26 ( 0- 63) 226 (1)
Total cholesterol
(ig/100 ml)
Free (%)
180 (1 14-244) 30 ( 19- 41)
199 (N)
28 (N)
Total lipids (g/100 ml) 875 (483-1267) 763 (N)
“Neutral fats”
(g/100 ml) 299 ( 57-531) 225 (N)
Total proteins (gm/100
ml) 7.43(623-8.73) 8.62(N)
the most part, standard histochemical
stain-ing methods were ti221
Findings
Microscopic examination of the histo-chemical tests and stains revealed the typi-cal findings of the metachromatic type of diffuse cerebral sclerosis (leukodystrophy);
i.e., severe and diffuse demyelinization of the brain, with numerous granular to foamy metachromatic, periodic-acid-Schiff (PAS)
positive, weakly “sudanophilic” glia through-out the white matter, metachromatic, PAS
positive but strongly “sudanophilic” smaller but more foamy glia in the perivascular Virchow-Robin spaces and rnetachromatic PAS positive, deposits in the liver and kid-neys. A more detailed summary of the histochernical stains is given in Table IV.
The lack of rnyelmn appeared to be
FIG. 1. Cerebral white matter; oil red 0 stain. Fic. 3. Pons. (PAS-hematoxylin stain; paraffin
sec-Note the strongly “sudanophilic” perivascular glia, tion; x 185)
weakly “sudanophilic” nonperivascular glia and the lack of myehin. (Frozen section, X 90)
FIG. 2. Cerebral white matter; toluidine blue stain. The material in the ganghion cells was
inter-stain. Many strongly metachromatic (magenta; preted as an abnormal metachromatic deposit and
black in photograph) glia but no myelin present. not Nissi substance or lipochrome pigment. (Frozen
(Frozen section, X 180) section, X 175)
moderate but patchy in tile pons (Fig. 3) and spinal cord (Fig. 4). A fibrous gliosis was prominent in the cerebral white matter.
In the spinal cord the demyelmnization was
most marked in the dorsolateral funiculus
and the lateral fasciculus cuneatus at the
upper thoracic level but more generalized
at the sacral level. A moderate number of metachromatic, PAS positive cells were found within both the anterior and posterior
nerve roots of tile spinal cord. The myelmn
in these roots, although light-staining,
ap-peared to be intact. A few cells containing metacilrornatic material were identified in
myelinated nerves in skin and small
in-testine. Tile ganglion cells of the spinal
cord and pons were laden with a meta-chromatic, PAS positive, moderately sudan-ophilic material which did not appear to be lipochrorne pigment. The Purkinje cells of
tile cerebellum contained traces of similar
material but the ganglion cells of the cere-bral cortex contained none. Abundant
meta-cilromatic, PAS positive material was also
found deposited within periportal granular macrophages and bile (luctS afl(I to a lesser
degree periportal hepatic cord cells in the liver (Fig. 5) and in the straight tui)ules
Stuifl
.\onj)eri- Pen- (ha in Ganglion Periportal
,. .. vascular
‘l(J,1I/l(afl(e ,.
. Cilia of
vascular
, .
(ilia of 1yridine
‘
1xtracted
Cells of
.
iSpi nal Phago-cytes of
CNS CNS l’issue Cord Liver
I nroi red
Kidizey
Tubules
Schultz cholesterol For cholesterol and its I to + 3 to 4+ esters
tein
. . .. 1+
635
TABLE IV
SUMMARY OF 1IISTOCIIEMI(AL STAINING REACTIONS
$udan IV in ace- Oil soluble fat (J%( tOIle-etlIIIIIOl
1to2+ 4+ .. 3- . No selective
staiiuitg5
Oil red 0 in isopro- Oil sOlUl)l(.’ fat (lVC
)tI0l IIl(l propyl-cue glycol
1to + 4+ 0 to 1+ 2 to 3+ + No selective
staillillg*
Sudan l)lack B in Oil soluble fat (lye ethanol an(l
l)roPy’l-ene glycol
lto3+ 4+ Otol+ 3+ 2 to 4+ No selective
staining5
Ilydrolyzed Nile blue A
Neutral fat red, other Bluish- Red
lipids blue” purple
0to light I)ark
blue l)lue
l)ark 1)ark blue (red
blue tinge in
collect-ing tubules)
Baker’s aci(l hema- For phospholipid 1+ ± 0 0 to 1+ 0 No selective
staining5
Basic netachro-i,atic dyest
Sulfated carbohydrates 0 to 4+
etc; Illetacholllatic”
4+ 0 4+ 4+ 4+
I)irect Scuff For free aldehydes; con-trol for other Schiffs
Otol+ Otol+
Peracetic acid For ethylene groups in
Scliiff unsaturate(l fatty acids,
etc.u
Otol+ Otol+ 2 to 3+ 1+ No selective staining5
Periodic acid Schiff Detects sugars, amino-sugars, unsaturated
fatty acids”
lto4+ lto4+ lto4+ 4+ 3+ 4+ in collecting tubules, 2+ iii cortical tubules
S Light, diffuse staining of cortical tubules and, to a lesser extent, medulla. t Toluidine blue, cresyl violet, thionin, and Unna’s methylene blue.
practically all of the collecting tubules in
tile kidney (Fig. 6). Except as mentioned above, no metachromatic material was found within skin, small intestine, spleen, adrenal gland, or lung.
Paraffin sections yielded almost complete lack of metachrornasia with toluidine blue,
moderate reduction in the intensity of
staining with Sudan black B, but practically the same degree of staining with PAS as on frozen sections. There was no reduction
in the PAS stain after saliva digestion. Oligodendroglia could not be identified in
tile affected areas.
COMMENT
The clinical course of this child was not unlike that originally described by
Green-field’ and more recently summarized by
unde-FIC. 5. Periportal area of liver; toluidine blue stain.
Numerous phagocytes laden with metachromatic
matcrial. ( lrozcn section, approximately
x
400)scribed. This further suggests a similarity
to tile neurolipidoses. Thus, tile “cherry red spot” may occur not only in Tay-Sach’s
dis-ease and Niernann-Pick’s disease, but also
111 metachromatic leukodystrophy. It has
also been seen in some atypical
degenera-tive central nervous system 27
\Vhule tile central nervous system rnyelin
breaks down ill this disorder or is not
prop-erly laid down, great amounts of metachro-matic lipid can be found in the liver (Fig. 5), kidney (Fig. 6), retinal ganglion cells,
and some have even found tilis material
ill tue gallbladder, adrenal medulla,’ ‘ and
tile leukocytes of tile peripileral blood and
hone marrow.’5 Furthermore, a few cells containing metachromatic material in the
myelinated nerves in the skin and small
intestine were found in this patient. Some
authors ilave even suggested that a biopsy
of peripheral nerves may assist in the
diag-20 28 The deposition is obviously very
widespread, but none can be found in
cere-bral ganglion cells. Within the central
nerv-oils system sudanophilic lipids (neutral lip-ids and cholesterol) were largely perivascu-lar in location (Figs. 1 & 2) while the
meta-chromatic lipid, in part at least, a cere-broside sulfatide, was away from the blood vessels in the areas of demyelmnation.
To our knowledge the cerebrospinal fluid lipids have not previously been studied in
this disorder. Compared to normal adults,
there is an increase in all compartluents of
the cerebrospinal fluid lipi(Is j)cr 100 ml of
cerebrospinal fluid, except for the
non-phosphorus sphingolipicls, which ‘cre
nor-mal. The cerebrospinal fluid SCCI11S to reflect
in particular tile peri\tscular neutral 1ipd and cholesterol deposition.
The normal nonphospiiorus spi ii ugolipids, the fraction which contains ic sulfatides,
may be the result of a flumi)er of factors. Since this fraction aba) contains other sphingolipids it is possible that the
sul-fatides are increased and the others are decreased with a normal net result. Fur-tilermore, it is possible that the sulfatides are deposited in tile brain or metabolized
to other lipids with tile result that the
cerebrospmnal fluid value is not increased.
The perivascular sudanophilia suggests that
the sulfatides may reach tile blood vessels in a different form. Almost in every instance
where direct tissue analysis has been eni-ployed, the white matter sulfatide content has been considerably increased.’ “
Cere-brospinal fluid sulfatides have as yet to
be quantitatecl or related to the clinical
20
We have compared these cerebrospinal fluid findings to those foulld in
pathologi-cally verified Tay-Sach’s disease and Nie-mann-Pick’s disease. In the forliler there
is a specific increase in tile nollpilosphorus
sphingolipids, and in the latter tile
sphingo-FIG. 6. Cortex of kidney; toliiidine blue stain. Note
ARTICLES
6:37
myelins are increased. The changes in the
cerebrospinal fluid lipid profile in
metachro-nlatic leukodystrophy appear to he more
generalized. Tile high total protein in
meta-chromatic leukodystrophy, in contrast to
Tay-Sach’s disease and Niemann-Pick’s
dis-ease, may suggest that the blood brain bar-ncr is defective. This has been silown to
result in an increase of all cerebrospinal
fluid lipids.
The mecilanism for the generalized
de-position of lipid material not only in the central nervous system but also in visceral organs and peripheral nerves in unclear.
Also the origin of the rnetachromasia is not entirely understood. However, because of widespread rnyelin destruction or lack of proper formation this disorder is known as
a leukodystrophy, and most authors favor
this 230 The nosologic position
of the leukodystrophies is not entirely clear,
but it has been suggested that they
repre-sent disorders characterized by a disturb-ance of rnyelin anabolism.31 Diezel2 sug-gested that in the sphingolipidoses, as well
as in leukodystrophy, there is a genetic
en-zyme defect which leads to the accumula-tion of certain lipids within the myelin sheaths as well as ganglion cells. An ac-cumulation of gangliosides, which is char-acteristic of tile infantile form of amaurotic
idiocy (Tay-Sach’s disease) has also been demonstrated in familial leukodystrophy’
and subsequently confirmed by Edgar,34 who suggests that leukodystrophy is a
dis-turbance of sphingolipid metabolism that
chiefly involves the myelmn sheath.
SUMMARY
A cilild has been reported with ilistO-chemically proven rnetachromatic
leuko-dystrophy. Central nervous system
degen-eration began at the age of 20 months and continued to the time of death at tile age of 49 months. Prior to death a “cherry red
spot” became evident in the retina and is the only known instance of this finding. This
adds to the evidence that metachromatic
leukodystrophy is one of the neurolipidoses,
but the metabolic defect apparently affects
primarily the cerebroside sulfuric acid
esters. Repeated analyses of cerebrospinal fluid demonstrated an elevated total pro-tein and a “midzone” gold curve. Lipid
analysis of serum and cerebrospinal fluid
demonstrated findings which are discussed
in detail and correlated to tile
histocilemi-cal changes. In addition, comparisons are
made with the cerebrospinal fluids in Tay-Sach’s and Niemann-Pick’s disease. This too revealed important differences between
the various netirolipidoses.
REFERENCES
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2. Creenfield, J. C. : A form of progressive
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in-fantile metachromatic ieuco-encephalopathy, with primary degeneration of the
inter-fas-cicular oligodendroglia. Brain, 73:291, 1950.
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5. Norman, R. M. : Diffuse progressive
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6. Greenfield, J. C., et al.: Neuropathology.
Balti-more, Williams & Wilkins, 1958, p. 459. 7. Blackwood, W. : The histological classification of diffuse demyelinating cerebral sclerosis, in Cerebral Lipidoses: A Symposium, edited
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Sci-entific Publications, 1957, p. 1. 8. Haii, H. F., and LaVeck, C. D. :
Metachro-matic leuko-encephalopathy : review with
il-lustrative case report. PEDIATRICS, 22:1064, 1958.
9. Hagberg, B., et al.: Late infantile
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Acknowledgment
We wish to gratefully acknowledge the kindness
of Dr. Richard Schneider, of the Department of Neurosurgery, for bringing this patient to our
