ltal. J. Neurol. ScL 11:57-59, 1990

Late onset globoid leukodystrophy: unusual clinical and CSF findings Rolando S.*, Cremonte M.*, Leonardi A.** * Cattedra e Divisione di Neuropsichiatria Infantile, Istituto G. Gaslini, Universit~ di Genova. ** Clinica Neurologica, Universit&di Genova

During a febrile upper respiratory tract illness this 4 year old boy developed left hemiparesis, which progressed to loss of walMng and even of sittingfinally to tetraplegia. The cerebrospinal fluid protein pattern showed blood-brain barrier damage with additional intrathecal lgG synthesis. The symptoms responded to steroid therapy but resumed and worsened on withdrawal. Only late, when visual evoked potentials and nerve conduction velocity proved to be impaired, was Krabbe disease diagnosed on the assay of culturedfibroblasts for galactocerebroside-beta-galactosidase. We discuss the significance of possible endogenous production of lgG in the CNS.

Key-Words: Globoid cell leukodystrophy - - Krabbe disease - - CSF immunoglobulins

~u~on Globoid cell leukodystrophy (Krabbe disease) is an autosomal recessive metabolic disorder due to the absence or marked reduction of galactocerebroside-beta-galactosidase. Several clinical forms of the disease are known. Whether the clinical heterogeneity represents a genetic heterogeneity is still unclear [3,4].

Case report A previously normal 4 year old child began, during an upper respiratory febrile infection, to show weakness of the left side of the body followed within a few days by the involvement of the fight leg. He lost the ability to walk. 15 days after the onset, dysarthric speech and motor impairment of the upper limbs became evident. He was admitted to the local hospital; CT was normal; CSF examination showed a mild hyperproteinorrachia with normal cell count. A Schilder disease was suspected and treatment Received 30 April 1989 - Accepted 30 September 1989

with hydrocortisone c 0,5 mg/Kg/day) for one month apparently led a progressive improvement: the child began to walk unsupported, with a spastic gait. Suspension of the steroid therapy was followed by a sudden worsening. Two months after onset the patient was admitted to our hospital: he presented spastic tetraplegia with a fight prevalence, markedly dysarthric speech and sialorrhea. The child could neither sit nor stand. Mentation was apparently normal. Adrenoleukodystrophy, metachromatic leukodystrophy, vascular and space-occupying lesions were ruled out by laboratory examinations. CSF and serum IgG and albumin were determined by radial immunodiffusion: the CSF/serum ratios of both proteins, plotted on Reiber's graph showed blood-CSF barrier damage, with an additional IgG production in the nervous systema. Tourtellotte's and Reiber's formulas both confirmed an endogenous synthesis o f l g G (Table

I). Treatment with ACTH was followed by a new improvement of the symptomatology: reduction of 57

The Italian Journal of Neurological Sciences

TABLE

tient's neurological status began to deteriorate with tetraplegia and mental regression; visual evoked responses were abnormal and moter nerve conduction was slow (common peroneal nerve 30 m/sec). The CT showed a diffuse cortical atrophy and slight reduction of the white matter attenuation. Galactocerebroside-beta-galactosidase activity on cultured fibroblasts was: 0,78 lxmoli/mg/h (normal values: 4-12,2 ~tmoli/mg/h).

I

CSF FINDINGS Protein gr% Pandy Glucose rag% Cells/mm s CSF AIb mg% S AIb mg% CSF IgG mg% S IgG mg% CSF/S AIb x 10s CSF/S IgG x 10s IgG index Tourtellotte formula Reiber formula Isoelectric focusing Myelin basic protein

0.570 + (+) - 57 2 (leukocytes) 44.5 4190 7.7 765 10.62 10.06 0.947 17.85 mg/24 h 3.44 absence of oligoclonal bands 2.8 ug/ml (max 3 Izg/ml)

Discussion The deficiency of galactocerebroside-beta-galactosidase leaves no doubt that this boy is affected by gioboid cell leukodystrophy. This diagnosis was made late in the course of the disease. In fact the acute onset, during a febrile illness and the initial lateralization of the pyramidal signs suggested an inflammatory disorder. In view of this clinical suspicion we evaluated a possible increase of the CSF immunoglobulins, utilizing Reiber's graph [7], which allows the identification of auto-

the dysarthria and the spasticity; possibility of sitring unsupported and walking with aid. The improvement was nevertheless short-lived and a month later, while still on ACTH therapy, the pa1 Fig. 1.

Normal range 2. Blood - CSF barrier dysfuction 3. Blood - CSF barrier dysfunction with disproportionately increased IgG quotient 4. Blood - CSF barrier dysfunction with additional "[gG locally produced 5. Locally synthesized IgG fraction without blood - CSF barrier dysfunction *Personal case

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Rolando S.: Late onset globoid leukodistrophy

cthonous IgG production in the CNS. According to this graph, our case falls in the range of"blood-CSF barrier dysfunction with additional IgG locally produced in the CNS" (Fig. 1). An IgG index of 0.947, and the results of Tourtellotte's [10] and Reiber's formulas['/] confirm the occurrence of IgG synthesis in the CNS. The validity of these formulas, even in presence of blood-C.SF barrier impairment has recently been confirmed by Tourtellotte [11]. We are not aware of similar CSF findings in other cases of late onset Krabbe's disease, where the CSF is usually reported to be normal [2, 5]. In a few cases hyperproteinorrachia has been described but no increase of immunoglobulins ]6, 4]. The possibility of a CSF IgG increase is mentioned only by Adams and Lyon [1] in early infantile Krabbe disease, but the frequency and the significance of this finding are obscure. Whether the CNS can react to a metabolic disorder through an inflammatory mechanism is not known. The presence of inflammatory infiltrates [I 2, 8] in perivascular areas in the brain of patients

affected by Krabbe disease could be consistent with this hypothesis. In two other cases of Krabbe disease, aged 13 and 17 months (onset of symptoms: 4 and 7 months) we performed a similar study. Both of these cases fell in the range of "dispropionate type of bloodCSF barrier dysfunction" according to Reiber [7]. The normality of the IgG index and Tourtellotte's and Reiber's formulas was against the possibility of an endogenous synthesis of IgG. The different CSF pattern in our cases can be due to the different clinical forms of the disease: the first is a late acute onset case; the other two are early infantile, long standing cases. We conclude stressing the necessity of taking into account the possibility of globoid cell leukodystrophy in every child presenting subacute focal neurological signs, especially of the pyramidal or cerebellar type, associated with optic atrophy or impaired visual evoked responses and slight mental deterioration. The finding of a CSF increase of IgG should not rule out the possibility of Krabbe disease.

Sommario Gli autori riportano lo studio clinico e biochimico di un caso di malattia di Krabbe tardiva. L'esordio acuto dei sintomi neurologici, dopo una affezionefebbrile respiratoria, il profilo immunochimico del liquor con produzione locale di IgG e la risposta iniziate al trattamento con A C T H hanno fatto supporre una genesi infiammatoria. E stata tuttavia diagnosticata in seguito una malattia di Krabbe.Gli Autori discutono brevemente il significato di una possibile produzione di IgG nel Sistema Nervoso Centrale in questo caso.

Address reprint requests to: Dr. Susanna Rolando Neuropsichiatria Infantile, Istituto G. Gaslini, via 5 Maggio, 16100 Genova References

[!] ADAMSIL D., Lyon G: Neurologyof hereditary metabolic diseases of children MacGraw-Hill Book Co, New York, 1982. [2] CROMELet at: Late onset globoidcellleukodystrophy Brain 96:841 1973. [3] HAGBERDB: Krabbe's disease: clinical presentation of neurological variants Neuropediatrics 15 (suppl. 1): 1 I, 1984. [4] KOLODNYE H et at.: Late onsetgloboid cellleukodystrophyAnn. Neurol. 8:219,1980 [5] LOONENM C Bet al: Late onset globoid cell leukodystrophy (Krabbe's Disease) Clinical and genetic delineation of twoforms and theirrelation to the early infantileform Neuropediatrics 16:137,1985. [6] MALONEM Jet at: Globoidleukodystrophy. Clinical and enzymatic studies Arch. Neurol. 32:606,1975 [7] REIBER H: The discrimination between different blood-CSF barrier dysfunction and inflammatory

reactions of the CNS by a recent evaluation graphfor the protein profile of cerebrospinalfluid J. Neurol. 224:89, 1980 [8] SuzuKI K, SUZUKIY: Galactosylceramidelipidosis: globoid cell leukodystrophy (Krabbe's disease) In: "The metabolic basis of inherited disease" Stanbury J B et al. eds., MacGraw-HiU Book Co, New York, p. 857 (1983. [9] TmLINOG, et at: Principlesof albumin and IgG analyses in neurological disorders. Part I (Establishment of reference values) Scand. J. Clin. Lab. Invest. 37:385, 1977. [10] TOURTELLOTI'EX et at: Multiple sclerosis. Measurement and validation of central nervous system IgG synthesis data Neurology 30:240, 1980 [11] TOURTELLOTEEW e t at: The basis of intra-bloodbrain-barrierlgGsynthesisAnn. Neurol. 17:21,1985 [12] VOLK BW, ADACHI M: Diffuse cerebral sclerosis. Krabbe type In: "Diffuse cerebral sclerosis. Krabbe type In: "Handbook of Clinical Neurology" V'mken P J and Bruyn G Weds. North Holland Publ. Co, Amsterdam, Vol. 10, p. 67, 1970

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