ltal. J. Neurol. Sci. 13:617-619, 1992
Metachromatic leukodystrophy: on an atypical case Zambrino C.A.*, Balottin U.*, Minelli A.**, Rossi G.*, Lanzi G.* * D i v i s i o n e di N e u r o p s i c h i a t r i a I n f a n t i l e - I R C C S F o n d a z i o n e Istituto N e u r o l o g i c o "C. M o n d i n o " Universit~ di P a v i a ** Istituto di B i o l o g i a G e n e r a l e e G e n e t i c a M e d i c a - Universitgl di P a v i a
-
We describe an atypical case of juvenile metachromatic leukodystrophy. Motor conduction velocity was still within the normal range 3 years after clinical onset, in contrast to what is commonly found in this disease. Another unusual feature is the normal level of CSF protein. These data are discussed in the light of the sural nerve biopsy findings, which revealed only slight impairment.
Key Words: Metachromatic leukodystrophy - - CSF protein - - motor conduction velocity
Introduction Impairment of the peripheral nervous system is
known to be a characterizing feature of the clinical and histopathological pattern of metachromatic leukodystrophy (MLD) [3, 7]. Electrophysiologically, motor conduction velocity (MCV) is reduced right from the early stages and the sensory potentials are decreased in amplitude with lengthening of the peak latencies. In some subjects these abnormalities may even precede onset of the clinical signs [1, 2, 10]. MLD is very rare and mostly affects adults, in whom the MCV remains within normal limits even at advanced stages of the disease. For this reason a juvenile case with normal MCV as late as 3 years after onset of the disease seems worth reporting.
Case report This child, born to nonconsanguineous parents by normal delivery, came to observation at the age of 6t/2 years. Her psychomotor development had been normal up to about age 6, when she began to show hyporeactivity to stimuli and reduced Received 23 April 1991 - Accepted 30 April 1992
awareness of her surroundings. The following months saw gradual loss of sphincter control, tiptoe gait, inability to go up and down stairs, reduced mobility of the left arm, deterioration of cognition with loss of the ability to write, which she had acquired, dyslalia and at times echolalia. Neurological examination showed, in addition, slight hypotonia of the lower limbs and brisk tendon reflexes. The symptom complex gradually worsened until one year after onset the child had difficulty in grasping objects and was incapable of utilizing them; speech was reduced to a few phonemes with dysarthric, scanning articulation and severely reduced comprehension. Dysphagia was also present together with ataxic gait and dysmetria. Examination showed increased muscle tone in all limbs with hyperextension of the arms and dinner fork posture of the hands, hyperextension of the lower limbs and talipes equinus; tendon reflexes were brisk and ankle clonus and Babinski sign elicitable. The signs and symptoms remained relatively stationary during the second and third years of the disease apart from a reduction of trophism and the occasional appearance of a spontaneous Babinski. A C T scan 6 months after clinical onset imaged a 617
The Italian Journal of Neurological Sciences
TABLE I. Time since Max MCV SCV (m/ onset in (m/sec) sec) right months common sural nerve peroneal nerve* 6 12 15 24 36
51 47.9 44.4 37.02 40.6
52 47.9 49 ~ 46.6
--33 31.08 42
NV: 36-64 non determined for technical reasons
diffuse hypodensity of the white substance of the semioval centers, especially at the frontal horns of the lateral ventricles. The entire ventricular system and cisterns were larger than normal. A repeat scan done 12 months later showed a further increase in the volume of the ventricular system and cisterns but no change in the rest of the pattern. Five assessments of the MCV in the common peroneal nerve were made at different times together with studies of antidromal sensory conduction velocity (SCV) in the fight sural nerve, as shown in Table I. An evaluation of MCV in the right median nerve 36 months after onset was within normal limits. The somatosensory evoked potentials were determined on the right median nerve 12 months after onset: the cortical response showed normal latencies of the first components with desynchronization of the rest of the response. The clinical pattern, especially the sequence of normal psychomotor development for a few years - - slowing - - arrest - - regression clearly pointed to a storage disorder. Then assay of the activities of some lysosomal enzymes a year after onset of the first symptoms both on leukocytes and fibroblasts revealed a selective deficiency of arylsulfatase A (ARSA) activity, which clinched the diagnosis of MLD. The ARSA determination by the method of Galijaard yielded the following results: leukocytes: patient 6.1, father 148.1, mother 168.5, nv 191.64_+4; fibroblasts: patient 2.17, nv 509.82_+194.0. All activities are expressed in nM/mg/hr. The control enzymes (B-galactosidase, hexosaminidases A and B) were normal both for patient and for the parents. The ARSA activity levels found in the parents were higher than expected for obligate heterozygotes, but the ARSA: B-gal ratio was as expected for heterozygotes for MLD: father 0.46, mother 0.51, controls 0.85, expected value for MLD heterozygotes 0.42. Routine serum and blood tests and CSF parameters were normal, as was isoelectric focusing 6 618
months after onset. A biopsy of the right sural nerve, not performed until 5 years after onset because of parental opposition, yielded a mild pattern with rare metachromatic cytoplasmic inclusions, evidence of de- and re-myelination. Ultrastructural examination revealed lysosomal inclusions for Tuffstone bodies; the myelin sheaths of numerous axons were reduced in thickness and sometimes showed increased space between the interperiodic lines. Discussion The case described here undoubtedly presents some peculiarities. The clinical features were atypical: hypotonia and areflexia, characteristics of peripheral neuropathy, were absent while signs of spasticity were present. Further, as shown in the table, the MCV of the common peroneal nerve was only a little on the low side 24 months after onset but still within the normal range and the SCV of the sural nerve was within normal limits. Right from the beginning the distal latencies were slightly increased (5.7 m/sec at 6 months to 6.4 m/sec at 36 months; normal range 4-5.8). These electroneurographic findings contrast with the pattern seen in typical forms of the disease, in which the MCV is decreased in all cases of late infantile MLD [2, 4, 5, 6] and in most patients with juvenile and adult forms [2, 11]. This is due to the peripheral nerve involvement with segmental demyelination and deposition of metachromatic granules in the Schwann cells caused by the alteration with consequent interference with the metabolism of the sulfatides and with myelin maturation [3, 9]. Peripheral nerve involvement that occurs very early, as shown by the MCV changes in the presymptom'atic stages of the disease (adult form) [10]. The sural nerve biopsy sample in our case showed mild impairment in line with the mild SCV alteration. The unusual feature of latency lengthening observed earlier, compatible with phenomena of dying back type axonal degeneration, is more simply a possible index of close distal localization of the processes of demyelination and remyelination in t~ae absence of the characteristic segmental demyelination found in other atypical forms of storage diseases [13]. Another finding at variance with the features of classic cases of juvenile MLD is the normality of the CSF protein level 6 months after onset. Although we have no subsequent data, this finding does differ from the reported CSF protein levels of over 100 mg% in early onset juvenile forms. As Choen pointed out, the increase in CSF protein might reflect the degree of demyelination. There are very few published cases at all like ours.
Zombrino C.A: Aopical metachromatic leukocivstrophy
Tonnesen [12] reported a case described as atypical of a 7 year old girl with normal M C V and no progression of symptoms, reduced A R S A and increased urinary excretion of sulfatides but, oddly enough, a sulfatide loading test within normal limits. Fullerton [5] reported a case of onset at 6 years with progressive dementia and unchanged
M C V , highly atypical clinically and diagnosed post mortem. Other cases appear in the series of MacFaul [8]. There remains the question whether these atypical forms express a genetic and b i o c h e m i c a l polymorphism or, more simply, the clinical variability of an otherwise homogeneous disorder.
Sommario Gli autori descrivono un caso atipico di Leucodistrofia M e t a c r o m a t i c a di tipo giovanile. A 3 anni di distanza dall'esordio clinico la V d C motoria b risultata ancora nella norma, in contrasto con quanto comunemente osservabile in tale patologia. Altro dato inusuale ~ la norrnalitgt del livello delle proteine nel CFS. Tali dati vengono discussi anche alla luce dei risultati della biopsia di nervo surale, che rivela solo modesta compromissione.
Address reprint requests to: Dott. Carlo Alberto Zambrino Divisione di Neuropsichiatria Infantile Via Palestro, 3 - 27100 Pavia
References [1] BUCHTAL F., ROSENFALKA.: Sensory potentials in polyneuropathy. Brain 94:241-262, 1971. [2] CLARK J.R., MILLER R.G., VIOGOFF J.M.: Juvenile onset rnetachromatic leukodystrophy: biochernical and electrophysiologic studies. Neurology 29:346-3.53, 1979. [3] DAYAN A.D.: Peripheral neuropathy of rnetacrornatic leukodystrophy: observation on segmental dernyelination and rernyelination and the intracellular distribution of sulphatide. J. Neurol. Neurosurg. Psychiatry 30:311-318, 1967. [4] FRENCHJ.H., GRAZIANIL.J., PAPIN J.: Metachrornatic leukodystrophy: clinical aspects. Neurology 15:293, 1965. [5] FULLERTONP.M.: Peripheral nerve conduction in rnetachromatic leukodvstrophy. J. Neurol. Neurosurg. Psychiatry 27:100-109, 1964. [6] HABERLANDC., BRUNNGRABERE., WITTING L. e[ al.: Juvenile rnetachromatic leukodystrophy: case report with clinical, histopathological, ultrastructural and biochemical observatios. Acta Neuropathol. 26:93-106, 1973.
[7] HAGBERG B.: Clinical symptoms, signs and tests in metachromatic leukodystrophy. In: Folch P.J., Baver H. (Eds) Brain lipids and lipoproteins and the leukodystrophies, pp. 134-136, 1963. [8] MACFAUL R., CAVANAGH W., LAKE B.O. et al.: Metachromatic leukodystrophy: review of 38 cases. Arch. Dis. Child. 52:168-175, 1982. [9] PERCY A.K., McKMANN G.M.: The biochemistry of myelin and the leukodystrophies. In: Vinken, Bruyn G.W. Eds. Handbook of Clinical Neurology. North Holland Publ. pp. 134-149, 1970. [10] PLIZ H., HOpF H.C.: A preclinical case of late adult rnnetachromatic leukodystrophy? J. Neurol. Neurosurg. Psychiatry 35:360, 1972. [11] SEIDELet al.: Late-onset metachromatic leukodystrophy: diagnostic problem elucidated by case report. J. Neurol. 226:119-124, 1981. [12] TONNESEN T. et al.: An anusualform of ARS-A deficiency combined with sulfatide-excretion and a normal sulfatide-loading. Acta Paediatr. Scand. 72:837-841, 1983. [13] Vos A.J.M., JOOSTEN E.M.G. et al.: An ao'pical case o f infantile Globoid Cell Leukodystrophy. Neuropediatrics 14:110-112, 1983.
619
Metachromatic leukodystrophy: on an atypical case Zambrino C.A.*, Balottin U.*, Minelli A.**, Rossi G.*, Lanzi G.* * D i v i s i o n e di N e u r o p s i c h i a t r i a I n f a n t i l e - I R C C S F o n d a z i o n e Istituto N e u r o l o g i c o "C. M o n d i n o " Universit~ di P a v i a ** Istituto di B i o l o g i a G e n e r a l e e G e n e t i c a M e d i c a - Universitgl di P a v i a
-
We describe an atypical case of juvenile metachromatic leukodystrophy. Motor conduction velocity was still within the normal range 3 years after clinical onset, in contrast to what is commonly found in this disease. Another unusual feature is the normal level of CSF protein. These data are discussed in the light of the sural nerve biopsy findings, which revealed only slight impairment.
Key Words: Metachromatic leukodystrophy - - CSF protein - - motor conduction velocity
Introduction Impairment of the peripheral nervous system is
known to be a characterizing feature of the clinical and histopathological pattern of metachromatic leukodystrophy (MLD) [3, 7]. Electrophysiologically, motor conduction velocity (MCV) is reduced right from the early stages and the sensory potentials are decreased in amplitude with lengthening of the peak latencies. In some subjects these abnormalities may even precede onset of the clinical signs [1, 2, 10]. MLD is very rare and mostly affects adults, in whom the MCV remains within normal limits even at advanced stages of the disease. For this reason a juvenile case with normal MCV as late as 3 years after onset of the disease seems worth reporting.
Case report This child, born to nonconsanguineous parents by normal delivery, came to observation at the age of 6t/2 years. Her psychomotor development had been normal up to about age 6, when she began to show hyporeactivity to stimuli and reduced Received 23 April 1991 - Accepted 30 April 1992
awareness of her surroundings. The following months saw gradual loss of sphincter control, tiptoe gait, inability to go up and down stairs, reduced mobility of the left arm, deterioration of cognition with loss of the ability to write, which she had acquired, dyslalia and at times echolalia. Neurological examination showed, in addition, slight hypotonia of the lower limbs and brisk tendon reflexes. The symptom complex gradually worsened until one year after onset the child had difficulty in grasping objects and was incapable of utilizing them; speech was reduced to a few phonemes with dysarthric, scanning articulation and severely reduced comprehension. Dysphagia was also present together with ataxic gait and dysmetria. Examination showed increased muscle tone in all limbs with hyperextension of the arms and dinner fork posture of the hands, hyperextension of the lower limbs and talipes equinus; tendon reflexes were brisk and ankle clonus and Babinski sign elicitable. The signs and symptoms remained relatively stationary during the second and third years of the disease apart from a reduction of trophism and the occasional appearance of a spontaneous Babinski. A C T scan 6 months after clinical onset imaged a 617
The Italian Journal of Neurological Sciences
TABLE I. Time since Max MCV SCV (m/ onset in (m/sec) sec) right months common sural nerve peroneal nerve* 6 12 15 24 36
51 47.9 44.4 37.02 40.6
52 47.9 49 ~ 46.6
--33 31.08 42
NV: 36-64 non determined for technical reasons
diffuse hypodensity of the white substance of the semioval centers, especially at the frontal horns of the lateral ventricles. The entire ventricular system and cisterns were larger than normal. A repeat scan done 12 months later showed a further increase in the volume of the ventricular system and cisterns but no change in the rest of the pattern. Five assessments of the MCV in the common peroneal nerve were made at different times together with studies of antidromal sensory conduction velocity (SCV) in the fight sural nerve, as shown in Table I. An evaluation of MCV in the right median nerve 36 months after onset was within normal limits. The somatosensory evoked potentials were determined on the right median nerve 12 months after onset: the cortical response showed normal latencies of the first components with desynchronization of the rest of the response. The clinical pattern, especially the sequence of normal psychomotor development for a few years - - slowing - - arrest - - regression clearly pointed to a storage disorder. Then assay of the activities of some lysosomal enzymes a year after onset of the first symptoms both on leukocytes and fibroblasts revealed a selective deficiency of arylsulfatase A (ARSA) activity, which clinched the diagnosis of MLD. The ARSA determination by the method of Galijaard yielded the following results: leukocytes: patient 6.1, father 148.1, mother 168.5, nv 191.64_+4; fibroblasts: patient 2.17, nv 509.82_+194.0. All activities are expressed in nM/mg/hr. The control enzymes (B-galactosidase, hexosaminidases A and B) were normal both for patient and for the parents. The ARSA activity levels found in the parents were higher than expected for obligate heterozygotes, but the ARSA: B-gal ratio was as expected for heterozygotes for MLD: father 0.46, mother 0.51, controls 0.85, expected value for MLD heterozygotes 0.42. Routine serum and blood tests and CSF parameters were normal, as was isoelectric focusing 6 618
months after onset. A biopsy of the right sural nerve, not performed until 5 years after onset because of parental opposition, yielded a mild pattern with rare metachromatic cytoplasmic inclusions, evidence of de- and re-myelination. Ultrastructural examination revealed lysosomal inclusions for Tuffstone bodies; the myelin sheaths of numerous axons were reduced in thickness and sometimes showed increased space between the interperiodic lines. Discussion The case described here undoubtedly presents some peculiarities. The clinical features were atypical: hypotonia and areflexia, characteristics of peripheral neuropathy, were absent while signs of spasticity were present. Further, as shown in the table, the MCV of the common peroneal nerve was only a little on the low side 24 months after onset but still within the normal range and the SCV of the sural nerve was within normal limits. Right from the beginning the distal latencies were slightly increased (5.7 m/sec at 6 months to 6.4 m/sec at 36 months; normal range 4-5.8). These electroneurographic findings contrast with the pattern seen in typical forms of the disease, in which the MCV is decreased in all cases of late infantile MLD [2, 4, 5, 6] and in most patients with juvenile and adult forms [2, 11]. This is due to the peripheral nerve involvement with segmental demyelination and deposition of metachromatic granules in the Schwann cells caused by the alteration with consequent interference with the metabolism of the sulfatides and with myelin maturation [3, 9]. Peripheral nerve involvement that occurs very early, as shown by the MCV changes in the presymptom'atic stages of the disease (adult form) [10]. The sural nerve biopsy sample in our case showed mild impairment in line with the mild SCV alteration. The unusual feature of latency lengthening observed earlier, compatible with phenomena of dying back type axonal degeneration, is more simply a possible index of close distal localization of the processes of demyelination and remyelination in t~ae absence of the characteristic segmental demyelination found in other atypical forms of storage diseases [13]. Another finding at variance with the features of classic cases of juvenile MLD is the normality of the CSF protein level 6 months after onset. Although we have no subsequent data, this finding does differ from the reported CSF protein levels of over 100 mg% in early onset juvenile forms. As Choen pointed out, the increase in CSF protein might reflect the degree of demyelination. There are very few published cases at all like ours.
Zombrino C.A: Aopical metachromatic leukocivstrophy
Tonnesen [12] reported a case described as atypical of a 7 year old girl with normal M C V and no progression of symptoms, reduced A R S A and increased urinary excretion of sulfatides but, oddly enough, a sulfatide loading test within normal limits. Fullerton [5] reported a case of onset at 6 years with progressive dementia and unchanged
M C V , highly atypical clinically and diagnosed post mortem. Other cases appear in the series of MacFaul [8]. There remains the question whether these atypical forms express a genetic and b i o c h e m i c a l polymorphism or, more simply, the clinical variability of an otherwise homogeneous disorder.
Sommario Gli autori descrivono un caso atipico di Leucodistrofia M e t a c r o m a t i c a di tipo giovanile. A 3 anni di distanza dall'esordio clinico la V d C motoria b risultata ancora nella norma, in contrasto con quanto comunemente osservabile in tale patologia. Altro dato inusuale ~ la norrnalitgt del livello delle proteine nel CFS. Tali dati vengono discussi anche alla luce dei risultati della biopsia di nervo surale, che rivela solo modesta compromissione.
Address reprint requests to: Dott. Carlo Alberto Zambrino Divisione di Neuropsichiatria Infantile Via Palestro, 3 - 27100 Pavia
References [1] BUCHTAL F., ROSENFALKA.: Sensory potentials in polyneuropathy. Brain 94:241-262, 1971. [2] CLARK J.R., MILLER R.G., VIOGOFF J.M.: Juvenile onset rnetachromatic leukodystrophy: biochernical and electrophysiologic studies. Neurology 29:346-3.53, 1979. [3] DAYAN A.D.: Peripheral neuropathy of rnetacrornatic leukodystrophy: observation on segmental dernyelination and rernyelination and the intracellular distribution of sulphatide. J. Neurol. Neurosurg. Psychiatry 30:311-318, 1967. [4] FRENCHJ.H., GRAZIANIL.J., PAPIN J.: Metachrornatic leukodystrophy: clinical aspects. Neurology 15:293, 1965. [5] FULLERTONP.M.: Peripheral nerve conduction in rnetachromatic leukodvstrophy. J. Neurol. Neurosurg. Psychiatry 27:100-109, 1964. [6] HABERLANDC., BRUNNGRABERE., WITTING L. e[ al.: Juvenile rnetachromatic leukodystrophy: case report with clinical, histopathological, ultrastructural and biochemical observatios. Acta Neuropathol. 26:93-106, 1973.
[7] HAGBERG B.: Clinical symptoms, signs and tests in metachromatic leukodystrophy. In: Folch P.J., Baver H. (Eds) Brain lipids and lipoproteins and the leukodystrophies, pp. 134-136, 1963. [8] MACFAUL R., CAVANAGH W., LAKE B.O. et al.: Metachromatic leukodystrophy: review of 38 cases. Arch. Dis. Child. 52:168-175, 1982. [9] PERCY A.K., McKMANN G.M.: The biochemistry of myelin and the leukodystrophies. In: Vinken, Bruyn G.W. Eds. Handbook of Clinical Neurology. North Holland Publ. pp. 134-149, 1970. [10] PLIZ H., HOpF H.C.: A preclinical case of late adult rnnetachromatic leukodystrophy? J. Neurol. Neurosurg. Psychiatry 35:360, 1972. [11] SEIDELet al.: Late-onset metachromatic leukodystrophy: diagnostic problem elucidated by case report. J. Neurol. 226:119-124, 1981. [12] TONNESEN T. et al.: An anusualform of ARS-A deficiency combined with sulfatide-excretion and a normal sulfatide-loading. Acta Paediatr. Scand. 72:837-841, 1983. [13] Vos A.J.M., JOOSTEN E.M.G. et al.: An ao'pical case o f infantile Globoid Cell Leukodystrophy. Neuropediatrics 14:110-112, 1983.
619
