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Adult type of leukodystrophy. Krabbe's disease?
Adult type of leukodystrophy. Krabbe s disease? F . F . C r u z - S a n c h e z * , J . A . M a r t o s * * *, A . R i v e s * , T. R i b a l t a * , I. F e r r e r * *, a n d A . C a r d e s a *
Introduction Summary K. Krabbe described in 19161 a form of infantile leukodystrophy characterized by the presence of clusters of globoid cells in the brain white matter 2. Further studies proved that the deficient activity of lysosomal galactocerebrosidebeta-galactosidase is the primary deficit in this form of leucodystrophy 3. Therefore, this fact discloses a deficient synthesis of myelin with acumulation of galactocerebroside in non-neural mesodermal cells 4-5. Up to now, there have been described two neurological variants in the clinical presentation of Krabbe's disease: the infantile and the late infantile-juvenile form 6. Another form which has been described in two cases is the adult one. However, the existence of this form has been questioned 6-9. The present paper records an adult patient who developed progressive neurological and psychyatric disorders. Neuropathological examination showed a globoid cell leukodystrophy examination showed a globoid cell leukodystrophy which was confirmed by immunohistochemistry.
Case report The patient was a 24 year-old beggar who was accepted in a Charity's Institution due to his
A 24-year-old man developed progressive dementia in seven years. The patient suffered a severe bronchopneumonia and eventually died few days later. Brain coronal sections showed a soft gray-brownish discoloration of white matter of centrum ovale but the subcortical arcuate fibers and the interne capsule were preserved. Microscopically, the white matter showed marked loss of myelin and oligodendrocytes, abundant hypertrophic astrocytes and numerous "globoid cells". The latter showed strong positivity in immunostains for a mouse monoclonal antigalactocerebroside antibody. The presence of these cells in the brain white matter might be the morphological basis to classify the present case as one of Krabbe's Leukodystrophy. Key words: Leukodystrophy, Krabbe's leukodystrophy, galactocerebroside
extreme indigency and to the progressive appearance of mental impairment and sphincterian incontinence. Also, it was impossible to obtain familiar and personal medical history. H e was nursed for two years in that institution; during this time the patient lost his capability of constructing sentences and the answers were mostly monosyllabic; he had forgotten the characters of the alphabet and the ability of reading. Two years later, he showed an important dis-
Departments of Pathology of the Hostpiral Clinico y Provincial* (Barcelona), and Hospital Principes de Espa~a* * (Hospitalet de Llobregat), and Service of Pneumology* * * of Hospital Clfnico y Provincial (Barcelona) Address for correspondence and reprint requests: F.F. Cruz-Sanchez, MD., Virgen de Nuria 19; 5~ 2 a, 08400 Granollers (Barcelona), Spain. Accepted 7.5.90 Clin Neurol Neurosurg 1991. Vol. 93-3
217
connection and lack of interest for his environment, m e m o r y loss and conformistic behavior. Repetitive maneuvres were a conspicuous feature and he exhibited a compulsive inclination to introduce objects into his mouth. H e moved slowly and draggering. The neurological examination showed, at this time, the following facts: the deep tendon reflexes were normal and the cutaneous plantar reflexes were in flexion; the muscular tone and strength were preserved. Oculomotor responses were normal and cerebellar signs were absent. However, he had a severe prefrontal release syndrome. The fundoscopic examination revealed no abnormalities. Routine analytical tests in serum, urine and CSF were normal; ceruloplasmin and copper levels in serum were normal; tests for syphilis were negative. Amino-acids, mucopolysacharides and sulphatides in urine were negative. The E E G showed only sligth non-specific abnormalities. Brain scan disclosed cortical cerebral atrophy and enlargement of the cerebral ventricles. The patient was then discharged to a Psychiatric Centre where he survived for five years. Cerebellar signs, convulsive disorders and visual loss were not recorded to occur throughout this period. At the age of 31 years he was admitted to another Hospital because of bilateral bronchopneumonia. The patient was severely ill and unresponsive; he was hypertonic and the deep tendon reflexes were slightly hyperreactive bu the Babinski sign was not elicited. In spite of antibiotic therapy the patient died four days later.
Figure 1: Coronal section of brain showing diffuse irregular areas of degeneration of white matter (arrows) with conservation of the U fibers (arrow heads). (These areas disclosed a soft-grey-brownish discoloration). Also notice pronounced subcortical atrophy. 218
Method
Autopsy was performed within 24 hours of death and the brain was fixed in 10% formalin for 3 weeks. Coronal sections of both hemispheres, cerebellum and brainstem were performed and respresentative samples from most of the brain areas were e m b e d d e d in paraffin. The following stains were used: hematoxylin and eosin ( H E ) , luxol fast blue, and periodic acid-schiff (PAS). Acidic cresyl violet and Sudan were performed in n o n - e m b e d d e d material. The peroxudase-antiperoxidase (PAP) method 1~was used for a polyclonal antibody for glial fibrilary acidic protein ( G F A P ; from Dakopatts Ltd). The indirect two stage m e t h o d 11was used for a mouse monoclonal anti-galactocerebroside (gal C) antibody 12(hybridoma supernatant, 1:10). As a positive control for anti-Gal C we used a tissue culture of oligodendrocytes extracted from young rat brains. We also used paraffin embedded tissue from two patients with an infantile form of Krabbe's disease. For G F A P we used two astrocytomas. Results
Autopsy revealed a severe bronchopneumonia. The brain was small, weighed 1070 g. and showed a moderate diffuse cortical atrophy. Coronal sections showed a soft-gray-brownish discoloration of white matter of the centrum ovale (Fig. 1) but the subcortical arcuate fibers
P
Figure 2: Abundant globoid cells in a diffuse pattern (A) and in a perivascular location (B) within the white matter of the centrum semiovale (HE x 80).
(a line of 2 mm thickness) and the internal capsule were preserved. The white matter of brainsteam and cerebellum were not macroscopically impaired. Microscopically, the cortex showed a moderate loss of neurons. The white matter showed marked loss of myelin and oligodendrocytes, abundant hypertrophic astrocytes and numerous large eosinophilic cells with one or up to three nuclei ("globoid cells"). These cells were diffuselly distributed (Fig. 2A) or grouped in clusters around blood vessels (Fig. 2B), measured 40 to 50 microm in diameter and were PAS positive. Some astrocytes and globoid cells stained faintly with Sudan dyes. Methacromasia
with acid cresyl violet was not seen. Perivascular infiltrates by polymorphs or by lymphocytes were not found. Some clusters of globoid cells and a sligth loss of oligodendrocytes were found in the white matter of brainstem and cerebellum. However, very few loci of demyelination were observed. The dentate and the inferior olive nuclei did not show any histologycal changes. We did not find significant alterations in peripheral nerves (sural and pneumogastrics) nor in the adrenal glands. The immunohistological study with anti-gal C showed a strong positivity of globoid cells grouped in clusters and also in those that were diffusely distributed (Fig. 3A). Similar stain of 219
Figure 3A: Anti-Gal C immunostain showing strongly positivity of globoid cells (arrows) (Indirect two-state method x 60, inset x 140).
Figure 3B: Positive control for the immunostaining with anti-Gal C in a case of an infantile form of Krabbe's disease. Note a strong positive in a globoid cell (indirect-two-stage method x 500).
both adrenal glands and peripheral nerve were negative. A positive control from a patient with the infantile form of Krabbe's disease was also used (Fig. 3B). Discussion
The pathological findings in our case indicate that it is a leukodystrophy ~3. The presence of numerous characteristic globoid cells in the cerebral white matter is the morphological basis for a diagnosis of Krabbe's globoid cell leukodystrophy (KLD) 3 and is in keeping with other descriptions 1-2,9. There has been some controversy over the origin of globoid cells 14-15but it is now clear that they are macrophages arising from non-neural mesodermal cells 5. The production of these cells is specifically confined to one type of lipid injected experimentally in rat brains 16. Galactoce220
rebroside appears to be the only compound capable of inducing the histological globoid cell reaction 17. Galactocerebroside is a sphingosine, a fatty acid and galactose, precursor of sulphatide which is present in myelin sheath and oligodendroglial cells3,18. Histochemical techniques allowed some authors to suggest the presence of acid glycolipids 19 in both human and experimental induced globoid cells as well as activity for acid phosphatase and dehydrogenase 3,2~ However, there are no specific histochemical reactions which recognized the high concentration of galactocerebroside in these cells. In our case, we have used a mouse monoclonal antibody for galactocerebroside which has not been previously reported on KLD. This antibody is a cell-type specific marker of oligodendrocytes initially used to study the development of these cells in tissue cultures u. The strong positivity of globoid cells for this
antibody indicate the high concentration of galactocerebroside in these globoid cells. Clinical manifestations in our case were of progressive neurological deterioration including dementia. The age at the onset was quite atypical for KLD. However, adult onset in other forms of leucodystrophy has been reported such as in the methacromatic leucodystrophy 2'24 and in the adult type (type IV) of Pelizaeus Merzbarcher disease 25'26. Progressive intellectual deterioration is a constant feature in these forms of leucodystrophy. Adult forms of K L D have been described in old cases. Verhaart et al. 17 described a case of a 30 year-old mand and Guillain et al. 8 another one in a 37 year-old man. Clinically, in both cases, the symptoms were of motor and bulbar disturbances but dementia was not recorded. Histologically, there were well demarcated symmetrical areas of demyelinitation similar to those observed in multiple sclerosis. Therefore, the classification of the cases as K L D has been questioned 6'13'27. Hagberg et al. 6 described two different forms in KLD: the infantile and the late infantile-juvenile. This author separated neurological variants according to the clinical presentation. A variant which first manifested with monosymptomatic dementia combined with psychotic traits has been reported in a 10 year-old boy 28. T o our knowledge, the present case is the first proved case of K L D of adult onset. In a revision of Krabbe's disease in Sweden, Hagberg (1984) 6 concluded that the classical type and the late infantile-juvenile type of K L D are separate disease entities and suggested that the differences in presentation might be due to variabilities in central nervous system (CNS) impairment. Our case showed only CNS affection with predominant lesions in the white matter of the centrum ovale. These findings could explain the late slow-progressive onset as well as the clinical manifestations which did not suggest the diagnosis of K L D . Thus, our case would confirm the existence of an adult type of K L D and might prove the variabilities in the features of CNS involvement.
Acknowledgements We acknowledge Dr. Mark Noble from The Ludwig Cancer Research Institute (London) for his generous supply of the anti-Gal C.
References 1 2
3
KRABBE K. A new familial, infantile form of diffuse brain-sclerosis. Brain 1916; 39:74-114. C O L L I E R J , G R E E N F I E L D J G . The encephalitis periaxialis of Schilder. A clinical and pathological study, with an account of two cases, one of which was diagnosed during life. Brain 1924; 47:489-519. SUZUKIK, SUZUKiY. Galactosylcereamide lipidosis: Globoid cell leukodystrophy (Krabbe's disease). In: The metabolic basis of inherited disease. STANBURYJB, WYNG A A R D E N J B , F R E D R 1 C K S O N U S , G O L D S T E I N JL~ B R O W N M S
(eds). 5th edition. McGraw-Hill. New York 1983, pp. 857-880. 4 BACHHAWATBK, AUSTINJ, ARMSTRONGO. A cerebroside sulphotranferase deficiency in a human disorder of myelin.Biochem J 1967; 104:15c-17c. 5 A U S T I N J H , L E H F E L D T D , M A X W E L L W . Experimental "globoid bodies" in white matter and chemycal analyses in Krabbe's disease. J Neuropath Exp Neurol 1961; 20:284-5. 6 HAGBERGB. Krabbe's Disease: clinical presentation of neurological variants. Neuropediatrics 1984; 16:11 s. 15s. 7 VERHAART WJC. Zur Markdegeneration im Gehirn bei Siiuglingen.Z.ges. Neurol Psychiat 1933; 147:76-91. 8 G U 1 L L A I N G , B E R T R A N D I, G R U N E R J. S u r u n type anatomo-clinique sp6cial de leuco-enc6phalite a nodules morul6s gliog6nes. Rev Neurol 1941; 73:401.414. 9 V O L K W B , A D A C H I M. Diffuse cerebral sclerosis. Krabbe type. In: Leukodystrophies and poliodystropies. Handbook of Clinical Neurology. VlNKENPJ, BRUYNGW (eds). North Holland Publishing Co. New York 1970, vol 10, pp. 67-93. 10 STERNBERGERLA. The unlabelled antibody peroxidaseantiperoxidase method. In; WILEYJ (ed). Immunohistology. Chichester, 1979; pp. 297.321. 11
W A R N K E R A , G A T T E R K C , F A L I N I B~ H I L D R E T H STUN RE, PULFORD
K, CORDELL
P, W O O L -
J, COHEN B, WOLF-PEE-
TERS C DE, MASON nx. Diagnosis of human lymphoma with monoclonal antileukocyte antibodies. N Eng J Med 1983; 309:1275-1281. 12
RANSCHT B, CLAPSHAW PA, PRICE J, NOBLE M, SEIFERT W.
Development of olygodendrocytes and Schwann ceils studied with a monoclonal antibody. Proceedings of the National Academy of Sciences (USA) 1982; 79:27092713. 13 P O S E R C M , V A N B O G A E R T L. Natural history and evolution of the concept of Schilder's diffuse sclerosis. Acta Psychiat Scand 1956; 31:285-331. 14 PEIFFERJ. Zur formalen Genesen der Globoidzellen bei der diffuse Sklerose vom Typus Krabbe. Arch Psychiat Z ges Neurol 1956; 195:446-465. 15 C H R I S T E N S E N E , M E L C H I O R J C , A N D E R S E N H . Diffuse infantile familial sclerosis (Krabbe type). Acta Psychiat Scand 1960; 35:431-9. 16 O L S S O N Y , S O U R A N D E R P, S V E N N E R H O L M L. Experimental studies on the pathogenesis of leukodystrophies I. The effect of intracerebraUy injected sphingolipids in the rat's brain. Acta Neuropath (Berl) 1966; 6:153-163. 17 AUSTIN JH, LEHFELDT D. Studies in globoid (Krabbe) leukodystrophy. III. Significance of experimentally-produced globoid-like elements in rat white matter and spleen. J Neuropath Exp Neurol 1965; 24:265-289. 18 Y A K O V L E V P , L E C O U R S A R . The myelogenetic cycles of regional maturation of the brain. In: Regional development of the brain in early life. MINKOWSKI A (ed). Blackwell. Oxford 1967; p. 3. 19 DIESELPB. Histochemische Untersuchungen an den Glo-
221
boidzellen der famili/iren infantilen diffusen Sklerose vom Typus Krabbe. Virchows Arch Path Anat 1955; 327:206-228. 2O
NELSON E, AUREBECK G, OSTERBERG K, BERRY J, JABBOUR JT, BORNHOFEN J. U l t r a s t r u c t u r a l
and chemical
21
studies on Krabbe's disease. J Neuropath Exp Neurol 1963; 22:414-434. WALLACE BJ, ARONSON SM, VOLK W. Histochemical and biochemical studies of globoid cell leukodystrophy (Krabbe's disease). J Neurochem 1964; 11:367-376.
22
GOEBEL H H, ARGYRAKIS A , SHOMOKAWA K, SEIDEL D,
HEIPERTZR. Adult metachromatic Leukodystrophy. Eur Neurol 1980; 19:294-307. 23
SEIDEL D, HEIPERTZ R, GOEBEL HH, DUENSING I, PILZ H.
Adult metachromatic leukodystrophy. Eur Neuro11980; 19:288-293.
222
2A
WRIGHT GDS, PATEL MK, MIKEL J. A n a d u l t o n s e t m e t a -
chromatic leukodystrophy with dominant inheritance and normal arylsulphatase A levels. J Neurological Sci 1988; 87:153-166. 25 SEITELBERGERF. Pelizaeus-Merzbacher disease. In: VINKEN PH, BRUYNGW (eds). Handbook of Clinical Neurology. North-Holland. Amsterdam 1970, vol 10, pp. 150202. 26 LAKE BD. Lisosomal defiencies. In: ADAMS HJ, CORSELLIS JAN, DUCHEN LW (eds). Greenfield's Neuropathology. Edward Arnold Publishers. London 1984; pp. 530-4. 27 NORMAN RM, OPPENHEIMER D R, TINGLY AH. Histological and chemical findings in Krabbe's leukodystrophy. J Neurol Neurosrug Psychiat 1961; 24:223-232. 28 VADJA P, KOPECKY S. Juvenilna forma globoidnej leukodistrofie (Krabbe). Bratisl lek Listy 1979; 71:77-504.
Introduction Summary K. Krabbe described in 19161 a form of infantile leukodystrophy characterized by the presence of clusters of globoid cells in the brain white matter 2. Further studies proved that the deficient activity of lysosomal galactocerebrosidebeta-galactosidase is the primary deficit in this form of leucodystrophy 3. Therefore, this fact discloses a deficient synthesis of myelin with acumulation of galactocerebroside in non-neural mesodermal cells 4-5. Up to now, there have been described two neurological variants in the clinical presentation of Krabbe's disease: the infantile and the late infantile-juvenile form 6. Another form which has been described in two cases is the adult one. However, the existence of this form has been questioned 6-9. The present paper records an adult patient who developed progressive neurological and psychyatric disorders. Neuropathological examination showed a globoid cell leukodystrophy examination showed a globoid cell leukodystrophy which was confirmed by immunohistochemistry.
Case report The patient was a 24 year-old beggar who was accepted in a Charity's Institution due to his
A 24-year-old man developed progressive dementia in seven years. The patient suffered a severe bronchopneumonia and eventually died few days later. Brain coronal sections showed a soft gray-brownish discoloration of white matter of centrum ovale but the subcortical arcuate fibers and the interne capsule were preserved. Microscopically, the white matter showed marked loss of myelin and oligodendrocytes, abundant hypertrophic astrocytes and numerous "globoid cells". The latter showed strong positivity in immunostains for a mouse monoclonal antigalactocerebroside antibody. The presence of these cells in the brain white matter might be the morphological basis to classify the present case as one of Krabbe's Leukodystrophy. Key words: Leukodystrophy, Krabbe's leukodystrophy, galactocerebroside
extreme indigency and to the progressive appearance of mental impairment and sphincterian incontinence. Also, it was impossible to obtain familiar and personal medical history. H e was nursed for two years in that institution; during this time the patient lost his capability of constructing sentences and the answers were mostly monosyllabic; he had forgotten the characters of the alphabet and the ability of reading. Two years later, he showed an important dis-
Departments of Pathology of the Hostpiral Clinico y Provincial* (Barcelona), and Hospital Principes de Espa~a* * (Hospitalet de Llobregat), and Service of Pneumology* * * of Hospital Clfnico y Provincial (Barcelona) Address for correspondence and reprint requests: F.F. Cruz-Sanchez, MD., Virgen de Nuria 19; 5~ 2 a, 08400 Granollers (Barcelona), Spain. Accepted 7.5.90 Clin Neurol Neurosurg 1991. Vol. 93-3
217
connection and lack of interest for his environment, m e m o r y loss and conformistic behavior. Repetitive maneuvres were a conspicuous feature and he exhibited a compulsive inclination to introduce objects into his mouth. H e moved slowly and draggering. The neurological examination showed, at this time, the following facts: the deep tendon reflexes were normal and the cutaneous plantar reflexes were in flexion; the muscular tone and strength were preserved. Oculomotor responses were normal and cerebellar signs were absent. However, he had a severe prefrontal release syndrome. The fundoscopic examination revealed no abnormalities. Routine analytical tests in serum, urine and CSF were normal; ceruloplasmin and copper levels in serum were normal; tests for syphilis were negative. Amino-acids, mucopolysacharides and sulphatides in urine were negative. The E E G showed only sligth non-specific abnormalities. Brain scan disclosed cortical cerebral atrophy and enlargement of the cerebral ventricles. The patient was then discharged to a Psychiatric Centre where he survived for five years. Cerebellar signs, convulsive disorders and visual loss were not recorded to occur throughout this period. At the age of 31 years he was admitted to another Hospital because of bilateral bronchopneumonia. The patient was severely ill and unresponsive; he was hypertonic and the deep tendon reflexes were slightly hyperreactive bu the Babinski sign was not elicited. In spite of antibiotic therapy the patient died four days later.
Figure 1: Coronal section of brain showing diffuse irregular areas of degeneration of white matter (arrows) with conservation of the U fibers (arrow heads). (These areas disclosed a soft-grey-brownish discoloration). Also notice pronounced subcortical atrophy. 218
Method
Autopsy was performed within 24 hours of death and the brain was fixed in 10% formalin for 3 weeks. Coronal sections of both hemispheres, cerebellum and brainstem were performed and respresentative samples from most of the brain areas were e m b e d d e d in paraffin. The following stains were used: hematoxylin and eosin ( H E ) , luxol fast blue, and periodic acid-schiff (PAS). Acidic cresyl violet and Sudan were performed in n o n - e m b e d d e d material. The peroxudase-antiperoxidase (PAP) method 1~was used for a polyclonal antibody for glial fibrilary acidic protein ( G F A P ; from Dakopatts Ltd). The indirect two stage m e t h o d 11was used for a mouse monoclonal anti-galactocerebroside (gal C) antibody 12(hybridoma supernatant, 1:10). As a positive control for anti-Gal C we used a tissue culture of oligodendrocytes extracted from young rat brains. We also used paraffin embedded tissue from two patients with an infantile form of Krabbe's disease. For G F A P we used two astrocytomas. Results
Autopsy revealed a severe bronchopneumonia. The brain was small, weighed 1070 g. and showed a moderate diffuse cortical atrophy. Coronal sections showed a soft-gray-brownish discoloration of white matter of the centrum ovale (Fig. 1) but the subcortical arcuate fibers
P
Figure 2: Abundant globoid cells in a diffuse pattern (A) and in a perivascular location (B) within the white matter of the centrum semiovale (HE x 80).
(a line of 2 mm thickness) and the internal capsule were preserved. The white matter of brainsteam and cerebellum were not macroscopically impaired. Microscopically, the cortex showed a moderate loss of neurons. The white matter showed marked loss of myelin and oligodendrocytes, abundant hypertrophic astrocytes and numerous large eosinophilic cells with one or up to three nuclei ("globoid cells"). These cells were diffuselly distributed (Fig. 2A) or grouped in clusters around blood vessels (Fig. 2B), measured 40 to 50 microm in diameter and were PAS positive. Some astrocytes and globoid cells stained faintly with Sudan dyes. Methacromasia
with acid cresyl violet was not seen. Perivascular infiltrates by polymorphs or by lymphocytes were not found. Some clusters of globoid cells and a sligth loss of oligodendrocytes were found in the white matter of brainstem and cerebellum. However, very few loci of demyelination were observed. The dentate and the inferior olive nuclei did not show any histologycal changes. We did not find significant alterations in peripheral nerves (sural and pneumogastrics) nor in the adrenal glands. The immunohistological study with anti-gal C showed a strong positivity of globoid cells grouped in clusters and also in those that were diffusely distributed (Fig. 3A). Similar stain of 219
Figure 3A: Anti-Gal C immunostain showing strongly positivity of globoid cells (arrows) (Indirect two-state method x 60, inset x 140).
Figure 3B: Positive control for the immunostaining with anti-Gal C in a case of an infantile form of Krabbe's disease. Note a strong positive in a globoid cell (indirect-two-stage method x 500).
both adrenal glands and peripheral nerve were negative. A positive control from a patient with the infantile form of Krabbe's disease was also used (Fig. 3B). Discussion
The pathological findings in our case indicate that it is a leukodystrophy ~3. The presence of numerous characteristic globoid cells in the cerebral white matter is the morphological basis for a diagnosis of Krabbe's globoid cell leukodystrophy (KLD) 3 and is in keeping with other descriptions 1-2,9. There has been some controversy over the origin of globoid cells 14-15but it is now clear that they are macrophages arising from non-neural mesodermal cells 5. The production of these cells is specifically confined to one type of lipid injected experimentally in rat brains 16. Galactoce220
rebroside appears to be the only compound capable of inducing the histological globoid cell reaction 17. Galactocerebroside is a sphingosine, a fatty acid and galactose, precursor of sulphatide which is present in myelin sheath and oligodendroglial cells3,18. Histochemical techniques allowed some authors to suggest the presence of acid glycolipids 19 in both human and experimental induced globoid cells as well as activity for acid phosphatase and dehydrogenase 3,2~ However, there are no specific histochemical reactions which recognized the high concentration of galactocerebroside in these cells. In our case, we have used a mouse monoclonal antibody for galactocerebroside which has not been previously reported on KLD. This antibody is a cell-type specific marker of oligodendrocytes initially used to study the development of these cells in tissue cultures u. The strong positivity of globoid cells for this
antibody indicate the high concentration of galactocerebroside in these globoid cells. Clinical manifestations in our case were of progressive neurological deterioration including dementia. The age at the onset was quite atypical for KLD. However, adult onset in other forms of leucodystrophy has been reported such as in the methacromatic leucodystrophy 2'24 and in the adult type (type IV) of Pelizaeus Merzbarcher disease 25'26. Progressive intellectual deterioration is a constant feature in these forms of leucodystrophy. Adult forms of K L D have been described in old cases. Verhaart et al. 17 described a case of a 30 year-old mand and Guillain et al. 8 another one in a 37 year-old man. Clinically, in both cases, the symptoms were of motor and bulbar disturbances but dementia was not recorded. Histologically, there were well demarcated symmetrical areas of demyelinitation similar to those observed in multiple sclerosis. Therefore, the classification of the cases as K L D has been questioned 6'13'27. Hagberg et al. 6 described two different forms in KLD: the infantile and the late infantile-juvenile. This author separated neurological variants according to the clinical presentation. A variant which first manifested with monosymptomatic dementia combined with psychotic traits has been reported in a 10 year-old boy 28. T o our knowledge, the present case is the first proved case of K L D of adult onset. In a revision of Krabbe's disease in Sweden, Hagberg (1984) 6 concluded that the classical type and the late infantile-juvenile type of K L D are separate disease entities and suggested that the differences in presentation might be due to variabilities in central nervous system (CNS) impairment. Our case showed only CNS affection with predominant lesions in the white matter of the centrum ovale. These findings could explain the late slow-progressive onset as well as the clinical manifestations which did not suggest the diagnosis of K L D . Thus, our case would confirm the existence of an adult type of K L D and might prove the variabilities in the features of CNS involvement.
Acknowledgements We acknowledge Dr. Mark Noble from The Ludwig Cancer Research Institute (London) for his generous supply of the anti-Gal C.
References 1 2
3
KRABBE K. A new familial, infantile form of diffuse brain-sclerosis. Brain 1916; 39:74-114. C O L L I E R J , G R E E N F I E L D J G . The encephalitis periaxialis of Schilder. A clinical and pathological study, with an account of two cases, one of which was diagnosed during life. Brain 1924; 47:489-519. SUZUKIK, SUZUKiY. Galactosylcereamide lipidosis: Globoid cell leukodystrophy (Krabbe's disease). In: The metabolic basis of inherited disease. STANBURYJB, WYNG A A R D E N J B , F R E D R 1 C K S O N U S , G O L D S T E I N JL~ B R O W N M S
(eds). 5th edition. McGraw-Hill. New York 1983, pp. 857-880. 4 BACHHAWATBK, AUSTINJ, ARMSTRONGO. A cerebroside sulphotranferase deficiency in a human disorder of myelin.Biochem J 1967; 104:15c-17c. 5 A U S T I N J H , L E H F E L D T D , M A X W E L L W . Experimental "globoid bodies" in white matter and chemycal analyses in Krabbe's disease. J Neuropath Exp Neurol 1961; 20:284-5. 6 HAGBERGB. Krabbe's Disease: clinical presentation of neurological variants. Neuropediatrics 1984; 16:11 s. 15s. 7 VERHAART WJC. Zur Markdegeneration im Gehirn bei Siiuglingen.Z.ges. Neurol Psychiat 1933; 147:76-91. 8 G U 1 L L A I N G , B E R T R A N D I, G R U N E R J. S u r u n type anatomo-clinique sp6cial de leuco-enc6phalite a nodules morul6s gliog6nes. Rev Neurol 1941; 73:401.414. 9 V O L K W B , A D A C H I M. Diffuse cerebral sclerosis. Krabbe type. In: Leukodystrophies and poliodystropies. Handbook of Clinical Neurology. VlNKENPJ, BRUYNGW (eds). North Holland Publishing Co. New York 1970, vol 10, pp. 67-93. 10 STERNBERGERLA. The unlabelled antibody peroxidaseantiperoxidase method. In; WILEYJ (ed). Immunohistology. Chichester, 1979; pp. 297.321. 11
W A R N K E R A , G A T T E R K C , F A L I N I B~ H I L D R E T H STUN RE, PULFORD
K, CORDELL
P, W O O L -
J, COHEN B, WOLF-PEE-
TERS C DE, MASON nx. Diagnosis of human lymphoma with monoclonal antileukocyte antibodies. N Eng J Med 1983; 309:1275-1281. 12
RANSCHT B, CLAPSHAW PA, PRICE J, NOBLE M, SEIFERT W.
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