Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:293-296 293 Late onset Krabbe's leukodystrophy: J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.4.293 on 1 April 1991. Downloaded from a report of four cases

Megan Phelps, Jean Aicardi, Marie-Therese Vanier

Abstract Patients and methods Four cases of late-onset Krabbe's Four cases of late onset Krabbe's leukodystro- leukodystrophy had varying clinical phy were seen in the neurology unit of the features. One sibling became wheel- H6pital des Enfants Malades (Paris) between chair-bound while another leads an June 1984 and November 1988. Between active working life. The computed November 1979 and November 1989 six cases tomography (CT) scan of a third patient of the classic infantile form were identified, showed occipital demyelination with making a total of ten cases of Krabbe's contrast enhancement identical to that leukodystrophy. seen in an adrenoleucodystrophy. The Leucocytes and skin fibroblast cultures were fourth was the only patient with obtained according to standard procedures. peripheral neuropathy. All patients had Total homogenates, prepared as previously enzyme activity comparable to the clas- described,6 served as the enzyme source. (3H- sic infantile-onset form. 6-galactose)-Galactosylceramide (500 Bq/ nmol) with nevronic acid as the uniform fatty acid7 was provided by Professor Lars Globoid cell leukodystrophy was originally Svennerholm and Docent Jan-Eric Mansson, described in 1916 by Krabbe as a familial University of Goteborg, Sweden. Galacto- infantile form of diffuse brain sclerosis, with a sylceramidase activity was determined using a late onset form also described. With the micromethod,75 slightly modified to meet the establishment of the enzyme deficiency (galac- optimal conditions with this particular sub- tosylceramidase) in 1970 by Suzuki and strate.7 Each sample contained 5-9 jug enzyme Suzuki' the diagnosis may be confirmed by protein, 2-5 nmol substrate, 60 nmol sodium determining enzyme activity as well as the taurocholate, 6 nmol oleic acid in 20 pl of histopathology. Among the approximately 200 0.05 mol/l, pH 4-2, acetate buffer, and was cases of Krabbe's leukodystrophy described incubated at 370C for two hours. in the literature we know of 19 cases of Control values were those of patients with http://jnnp.bmj.com/ enzymatically proven late-onset Krabbe's neurological disorders or lysosomal diseases leukodystrophy. other than Krabbe's disease, randomly selec- The heterogeneity of the clinical presenta- ted from analyses performed during the tion and the investigational profile of the late period 1984-90. The results in the four late- onset form of Krabbe's leukodystrophy is onset cases of Krabbe's disease are compared becoming more apparent. The presenting with those in 32 patients with the classic symptoms may include difficulty in walking, infantile form of the disease diagnosed in the

decreased visual acuity, irritability and other laboratory during the same period. on September 26, 2021 by guest. Protected copyright. Unite de Neurologie, behavioural changes. Investigation in the late D6partement de Pediatrie, Hopital onset form may reveal abnormal cerebral CT Necker Enfants scan, abnormal visual evoked responses and Malades, Paris slowed nerve conduction velocities, normal or Case 1 M Phelps elevated CSF protein and characteris- J Aicardi slightly This girl is the second of two children born to tic inclusions in nerve and skin biopsies. first cousins. Her mother has had Laboratoire de Portuguese Neurochimie, These may be present in almost any combina- two spontaneous abortions. She was born at Fondation Gillet- tion. term weighing 2-63 kg with a head circum- Marcel MErieux, Five families with siblings that have been ference of 33 cm. Apart from a febrile convul- Centre Hospitalier Lyon-Sud H6pital affected have been observed in the literature.23 sion at 2 years 11 months, she had been well Sainte-Eug6nie, Loonen2 has described 17 cases from the until the age of four years and nine months. France literature and one additional case, but it There was no other relevant family history. M-T Vanier appears that the descriptions of Crome et al4 Three months before admission to hospital Correspondence to: and Hanefeld et al5 are the same three cases. the mother had noticed that the child was Dr Aicardi, Unite de Our describes four patients with Neurologie, Departement de study irritable, reluctant to leave her and had dif- Pediatrie, H6pital Necker enzymatically proven late-onset Krabbe's ficulty in seeing. Enfants Malades, 149 Rue de leukodystrophy, and includes a brother and had con- Sevres, 75743, Paris Cedex On admission at five years she 15, France sister. The striking difference in clinical siderably decreased visual acuity, a divergent Received 6 April 1990 features between two siblings with the late strabismus, normal fundoscopic examination, and in revised form onset form has not, to our knowledge, been Rossolimo 3 July 1990. brisk deep tendon reflexes, bilateral Accepted 12 July 1990 reported. responses but absent Babinski reflexes. She 294 Phelps, Aicardi, Vanier

Figure Cerebral CT scan J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.4.293 on 1 April 1991. Downloaded from of Case I a) Without enhancement showing hypodensity around the posterior horns of the I lateral ventricles b) After contrast injection, showing enhancement of the splenium corpus callosum.

was ambulant and intellectually unimpaired, 2 2 kg with a head circumference of 32 cm. although very timid. The CT scan showed Apart from measles at eight months she had bilateral hypodensities of the white matter been well until the age of eight years. There adjacent to the occipital horns of the lateral was no other relevant family history. ventricles and contrast enhancement of the Six months before admission she began to splenium, suggesting an adrenoleukodystro- have difficulty walking and at school. Her phy (fig). Long chain fatty acids were normal. parents also noted a change in behaviour with Nerve conduction velocities and an elec- increasing aggression. Clinical examination at troretinogram were normal. Visual evoked admission showed marked hypertonicity and potentials were markedly abnormal. CSF hyperreflexia of the lower limbs and bilateral examination was normal. Babinski responses. The upper limbs showed Krabbe's leukodystrophy was diagnosed on minor dysdiadochokinesis and intention the basis of a marked decrease in galactosyl- tremor. There were no other cerebellar signs. ceramidase activity in peripheral blood leu- Cerebral CT scan, visual and auditory cocytes and skin fibroblasts. Enzyme activity evoked potentials and the electroretinogram measured in the mother's leucocytes showed were normal. The CSF showed a normal cell http://jnnp.bmj.com/ an intermediate value consistent with a count with an elevated protein at 0 63 g/l and heterozygote state9 (table). an electrophoresis pattern consistent with a At follow up at 5 years 6 months the patient transudate. The electromyogram showed was unable to walk, sit alone or speak. She evidence of distal denervation and nerve con- was able to follow a light and had spastic duction velocities were slowed, consistent tetraplegia. with a peripheral neuropathy. A sural nerve

biopsy showed lightly packed myelin and on September 26, 2021 by guest. Protected copyright. tubular inclusions in the Schwann cell cyto- Case 2 plasm of myelinated fibres suggesting This girl was the last of five children whose Krabbe's leukodystrophy. Also present in the parents are first cousins, once removed. She non-myelinated fibres were pseudocrystalline was born at 37 weeks gestation weighing inclusions similar to those described in Refsum disease. Krabbe's leukodystrophy was confirmed by the marked decrease in galac- Table Galactosylceramidase activity in leucocytes and cultured skinfibroblasts tosylceramidase activity in the leucocytes and Leucocytes Skin fibroblasts skin fibroblasts (table). (Activity expressed as microkatal/kg protein) At 10 years and eight months her Case 1 0-03 0-07 paediatrician indicated that she had stopped Case 2 0.05 0.09 walking and there had been a marked intellec- Case 3 0-05 009 Case 4 ND 0-06 tual deterioration. Mothercase 1 0-19 ND Mother cases 3 and 4 0-31 ND Father cases 3 and 4 0 39 ND Controls 0-70 (0-36)* 0-89 (055)* Case 3 (n = 100) (n = 20) Infantile Krabbe's disease 0 04 (0 02)* 0-06 (0 02)* This girl was the third of four children born (n= 24) (n= 19) Parents of patients with infantile to non-consanguineous parents. She was born Krabbe's disease 0-41 (0-24)* ND at term weighing 31 kg. She was well until (n = 44) the age of five years when a decrease in visual ND = not determined; * = mean (SD); n = number of individuals studied. acuity was noted. At six years and six months Late-onset Krabbe's leukodystrophy-a report offour cases 295

she suffered a progressive left hemiplegia and a ther demonstrate the heterogeneity of the late J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.4.293 on 1 April 1991. Downloaded from slow intellectual deterioration began. onset form of Krabbe's globoid cell leukodys- On admission at 12 years, nine months she trophy. Patient 1 presented with visual was wheelchair-bound with fixed contractures problems and a CT scan suggesting an at the elbows, knees and hips and an inap- adrenoleukodystrophy, while patient 2 propriately euphoric affect. She had marked presented with a spastic diplegia, and some facial grimacing and her movements were minor cerebellar signs. The contrast in the severely dystonic, with an athetoid component clinical condition of the siblings, patients 3 in the hands and feet. There was marked and 4, is striking with the younger girl con- hypertonicity and hyperreflexia of all four fined to a wheelchair and institutionalised limbs and bilateral Babinski responses. Her while her brother continues a normal life, voice was almost unintelligible although some despite the comparable enzymatic abnor- words were still comprehensible. She under- malities and CT images. Interestingly, neither stood simple commands. She reacted to and patient has progressed clinically or followed a light, although at fundoscopy her radiologically for some years. Such discrepan- discs were pale. cies in the late-onset form, even within a Nerve* conduction studies and elec- family, pose difficulties for advising prognosis. tromyogram were normal, as was the One clinical feature not previously evident cerebrospinal fluid. The electroretinogram in reported cases is the dystonic movements showed an increased latency on red light described in case 3. At admission seven years stimulation, indicative of a predominantly after onset of symptoms these movements central retinal disturbance. The visual evoked were striking, involving mainly the face, potentials were abnormal but could not be hands and feet. explained by the retinal disturbance. The Consistent with a previous report'0 the CSF cerebral CT scan showed bilateral rounded protein in the three patients who had spinal hypodense areas in the upper parietal white fluid examination showed a normal protein matter and poor grey-white differentiation. A concentration in two cases and a mildly skin biopsy showed numerous nerve endings elevated value in the other. without specific inclusions, and an excess of In only one of the patients (case 2) was glycogen either free or within mitochondria. there EMG evidence of a peripheral Krabbe's leukodystrophy was diagnosed by neuropathy and the peripheral nerve biopsy decreased activity of galactosylceramidase performed was interesting in that not only did in the leucocytes and skin fibroblasts. The it demonstrate inclusions classically described patient's parents showed galactosylceramidase in biopsies of patients with Krabbe's leuko- leucocyte activity at an intermediate dystrophy" but also showed inclusions remin- heterozygote level (table). iscent of those seen in Refsum disease.'2 The At follow up at 15 years and nine months significance of this is not clear. the situation was unchanged with the patient These four patients showed a severe remaining wheelchair-bound, euphoric and deficiency of galactosylceramidase activity, intellectually impaired. with values less than 10% of the mean normal

value. There was no significant difference bet- http://jnnp.bmj.com/ Case 4 ween the levels of residual activities observed This young man was the older brother (by in infantile or late-onset patients which differs three years) of patient 3. Following the diag- from the findings of Loonen et al.2 Similar nosis of Krabbe's disease in his sister he was results were also observed in cases 3 and 4, seen in the outpatient clinic at the age of 16 despite the clinical dissimilarity in these two years and five months. siblings. The question of a pseudodeficiency in From the age of five years he had had minor case 4 could be ruled out since both parents difficulty in walking, was easily fatigued, un- showed galactosylceramidase activities within on September 26, 2021 by guest. Protected copyright. able to run long distances, and had a the expected range for heterozygotes. decreased visual acuity that was uncorrected All four cases had had cerebral CT scans at by glasses. Otherwise he continued to lead a varying times after the onset of symptoms, normal life. Clinical examination revealed with the scan of patient 2 (six months after the brisk tendon reflexes more pronounced in the onset of symptoms but not repeated) being lower limbs, ankle clonus and bilateral Babin- normal. This has previously been described in ski reflexes. The optic discs were pale but not the late-onset form.'0 The CT scans of atrophic. He was intellectually normal. patients 3 and 4 show small identically dis- Cerebral CT scan demonstrated symmetric tributed low density white matter changes rounded hypodensities in the upper part of despite the obvious clinical disparity. The the centrum semi-ovale in the parietal regions. most interesting of the CT scans is that of Galactosylceramidase activity in the leuco- patient 1, with its occipital hypodense areas cytes was considerably decreased, comparable and contrast enhancement of the corpus with that of his sister. Follow up at the age of callosum, an appearance previously thought to 19 years found that there had been no worsen- be specific for adrenoleukodystrophy"3 and not ing of symptoms and, in contrast to his wheel- reported in Krabbe's leukodystrophy. chair-bound institutionalised sister, he works These clinical and investigative findings fur- regularly as a baker. ther contribute to the picture of late-onset Krabbe's leukodystrophy as a heterogeneous Discussion disease, despite enzyme activity comparable to These four enzymatically confirmed cases fur- the classic infantile variety. 296 Phelps, Aicardi, Vanier J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.4.293 on 1 April 1991. Downloaded from We thank Professor J Mikol for examining the nerve biopsy of 7 Mansson JE, Svennerholm L. The use of galactosyl- patient 2. ceramides with uniform fatty acids as substrates in the diagnosis and carrier detection of Krabbe disease. Clinica Chimica Acta 1982;126:127-33. 1 Suzuki Y, Suzuki K. Globoid cell leukodystrophy (Krabbe's 8 Svennerholm L, Vanier MT, Hakansson G, Mansson JE. disease): Deficiencyofgalactocerebroside B-galactosidase. Use of leukocytes in diagnosis of Krabbe disease and Proc Nat Acad Sci USA 1970;66:302. detection of carriers. Clinica Chimica Acta 1981;112: 2 Loonen MCB, Van Diggelen OP, Janse HC, Kleijer WJ, 333-42. Arts WF. Late-Onset globoid cell leukodystrophy (Krab- 9 Vanier MT, Svennerholm L, Mansson JE, Hakansson G, be's leukodystrophy). Clinical and genetic delineation of Boue A, Lindsten J. Prenatal diagnosis of Krabbe disease two forms and their relation to the early-infantile form. and detection ofcarriers. Clinical Genetics 1981;20:79-89. Neuropediatrics 1985;16:137-42. 10 Vos AJM, Joosten EMG, Gabreels-Festen AAWM, 3 Bohles H, Schlenk R, Harzer K. Die unterschiedliche Gabreels FJM, Verspreet FAM. An atypical case of klinische Symptomatik der Globoidzell-Leukodystrophie infantile globoid cell leukodystrophy. Neuropediatrics (M. Krabbe) in einer Familie. Monatsschrift ffur Kinder- 1983;14:1 10-12. heilkunde 1981;129:303-6. 11 Lyon G, Jardin L, Aicardi J. Etude au microscope electron- 4 Crome L, Hanefeld F, Patrick D, Wilson J. Late onset ique d'un nerf peripherique dans un cas de leukodystro- globoid cell leukodystrophy. Brain 1973;96:841-8. phie de Krabbe. J Neurolog Sci 1971;12:263-74. 5 Hanefeld F, Wilson J, Crome L. Die juvenile Form der 12 Fardeau M, Engel WK. Ultrastructural study of a peripheral Globoidzell-Leukodystrophie. Monatsschrift ffr Kinder- nerve biopsy in Refsum's disease. J Neuropath Exper heilkunde 1973;121:293-4. Neurol 1969;28:278-94. 6 Vanier MT, Revol A, Fichet M. Sphingomyelinase activities 13 Aubourg P, Diebler C. Adrenoleukodystrophy-its diverse of various human tissues in control subjects and in CT scan appearances and an evolutive or phenotypic Niemann-Pick disease. Development and evaluation of a variant: The leukodystrophy without adrenal insuf- microprocedure. Clinica Chimica Acta 1980;106:257-67. ficiency. Neuroradiology 1982;24:33-42. http://jnnp.bmj.com/ on September 26, 2021 by guest. Protected copyright.