Journal of Neurology, Neurosurgery, and Psychiatry, 1980, 43, 934-940

Cherry-red spot myoclonus syndrome anda-neuraminidase deficiency: neurophysiological,pharmacological and biochemical study in an adultS FRANCESCHETTf, G UZIEL, S DI DONATO, L CAIM[*, AND G AVANZfNI

From the Departments of Neurophysiology and Neurometabolic Diseases Istituto Neurologico C Besta,Milan, Italy

SUMMARY A 22 year old patient with non-familial progressive myoclonus, macular cherry-redspot, moderate cerebellar syndrome and normal intelligence is described. The mycolonus beganat the age of 18 years. Focal myoclonus could easily be elicited by voluntary and passive movements,and by touch and electrical stimulation of median nerve. Somatosensory evoked potentials showeda high voltage early component. Jerk-locked averaging of the EEG preceding action myoclonusdetected an otherwise hidden, time-related, EEG spike. The myoclonus responded partially butclearly to L-5 hydroxytryptophan plus carbidopa treatment. Biochemical study showed an

a-neuraminidase deficiency in cultured fibroblasts: the decrease in this enzyme activity was

compared to that found in a patient affected by mucolipidosis III.

A slowly progressing neurological syndrome thatcombines action sensitive and stimulus-sensitivemyoclonus with cherry-red spots at the maculain patients with a-neuraminidase deficiency hasbeen described recently.'-3 In these patients, therewere no dementia or bone deformities, and gen-eralised seizures that occurred in two patientswere easily controlled by antiepileptic therapy.According to Rapin et a12 this peculiar syndromeshould be kept distinct from other more malig-nant storage disorders and progressive myoclonicepilepsies and put in a new class of diseasescharacterised by accumulation of sialidated glyco-peptides and glycolipids in tissues, owing to adeficiency of neuraminidase. Lowden andO'Brien4 have defined as Sialidosis type I theCherry-red Spot Myoclonus Syndrome (CRS-MS)with normal intelligence and a-neuraminidasedeficiency.The present report deals with electrophysio-

logical, pharmacological and biochemical findingsin a case of CRS-MS observed recently.

Address for reprint requests: Dr Silvana Franceschetti, Departmentof Neurophysiology, Istituto Neurologico C Besta, Via Celoria 11,20133 Milan, Italy.

Accepted 11 April 1980

*Institute of Biochemistry, University of Milan, Italy.

Case report

The patient was an Italian male aged 21 years.There was nothing significant in the family history.The patient was cyanotic at birth but his psycho-motor development 'had been normal. At age 13years he had an episode of acute polyarthritis diag-nosed as rheumatic fever. At age 18 years thepatient began to complain of walking clumsily anda few months later he had a short tonic-clonicgeneralised seizure. Neurological examination per-formed at that time showed mild dysmetria andbrisk tendon reflexes.

In the following months his difficulties in stand-ing and walking rapidly became worse with theappearance of muscular jerks that affected all fourlimbs and were exacerbated by voluntary movement.A progressive irregular course eventually led to a con-dition in which the patient was no longer able tocare for himself. When he was admitted to hospitalin December 1978 (at the age of 21 years) neuro-logical examination showed diffuse hypotonia, briskdeep reflexes and bilateral Babinski signs. A mildataxia was evident on finger-nose and heel-knee tests,although evaluation was made difficult by the super-imposed myoclonic jerks. The myoclonic jerks wereabsent at rest but precipitated by any attempt tochange posture or even by a simple request tomove. The focal character of the myoclonus wasevident only at the beginning of the voluntary move-ment owing to its marked tendency to spreadrapidly and end up in repeated massive bilateral

934

Cherry-red spot myoclonus syndrome

jerks. In addition to the action and intention myo-clonus, there was also reflex myoclonus that couldbe triggered by passive movements and tactile stimu-lation. Examination of the ocular funidus showed anormal optic disk and a cherry-red spot in themacular region, more striking in the right eye(fig 1). The results of audiometric examination werenormal. The patient was still able to communicatesatisfactorily with other people, talking very slowlyand using limited mimic movements. He showed nosign of mental impairment.The CT scan was normal. Blood examination

(red and white cell count, erythrocyte sedimentationrate, electrolytes, nitrogen, glucose and bilirubinlevels, SGOT, SGPT, alkaline phosphatase, serumprotein electrophoresis, serum immunodiffusion) wasnormal. In the cerebrospinal fluid cell count, total pro-tein, glucose, chloride, and protein electrophoresisand immunodiffusion were normal; 5-hydroxy-indoleacetic acid level was 35 57 ng/ml (controlsmean value 31-37+4-43). Blood and urinary amino-acids were normal. Assays of arylsulphatase A and,J-galactosidase in the leucocyte also were normal.Electrophysiological findings The EEG and EMGwN-ere recorded from surface electrodes on a 12channel OTE Biomedica polygraph. Scalp electrodeswere placed according to the 10-20 internationalsystem. In addition selected recording samples werestored on FM magnetic tape for averaging of BEGand EMG activity, time-locked to stimuli and tomyoclonic jerks (PDP 11/34 computer system), andfor spectral analysis of EEG (OTE Biomedica Berg-FOURIER Analyzer). For detection of non-obviousEEG correlates of myoclonus, the EEG activitypreceding the myoclonic discharge was analysed byjerk-locked averaging employing a 100 ms analoguedelay-line circuit. An electronic window (Vescovini

935

477-25-28) was employed to trigger the program atthe onset of myoclonic potentials. One hundred andtwenty EEG samples of 250 ms each were usuallyaveraged.

Somatosensory evoked potentials (SEPs) and reflexmyoclonus were elicited by median nerve stimula-tion by paired surface electrodes placed 3 cm aparton the wrist. Square wave pulses of 1 ms durationwere delivered at rate of 05-1 s, the intensity wasadjusted to induce the least detectable motor res-ponse of the opponens muscle. The SEP valuescomputed for 200 bipolar EEG samples wererecorded from central and parietal (C3-P3) regions;the analysis time was 250 ms. Evoked EMG activity(that is reflex myoclonus) was displayed on theoscilloscope and fed into the computer. Sixty res-ponses were usually averaged (analysis time 250 ms).

In the resting condition, the electrophysiologicalrecording did not show anything of particular in-terest. Voluntary and passive movements and tactilestimulation by light touch or tap precipitated vigor-ous focal myoclonic jerks consisting of repetitivebiphasic or polyphasic EMG potential lasting 15-30ms, occurring five to 15 times per second, whichspread rapidly to all the muscles examined eventu-ally leading to a recurrent massive myoclonus (fig 2).Both agonist and antagonist muscles usually wereinvolved. Concomitant EEG bursts of 16-20 Hzactivity were almost always detectable in centraland parietal regions of both sides, in spite of thesuperimposed muscle artifacts.

Case 15

( , _i_z.z _ .. . .r.x. _z_L bicepsR quadR bicepsRtriceps

R biceps

R orb oc 11

R biceps

R triceps m

Fig 1 Fundus oculi (right eye): note macularcherry-red spot (courtesy of Dr Delle Grottaglie).

_ 300,uV2s

l^-, ---R biceps

~~'^' ~ R quodriceps

+- 'lL R biceps

0I R quad riceps

_s300s50ms

Fig 2 Top: EEG-EMG recording of actionmyoclonus evoked by voluntary movement of lowerlimbs. Bottom: EMG recording of action myoclonusfrom paired muscles. Note that the biceps could leador follow the quadriceps according to whether itwas precipitated by voluntary movement of upperlimbs (upper traces) or of lower limbs (lower traces).

4'.,- -.4- .4 4-4),-U-4

S Franceschetti, G Uziel, S Di Donato, L Caimi, and G Avanzini

The characteristics of the EEG correlate weredemonstrated better by jerk-locked averaging whichrevealed that eaoh jerk was time-related to an EEGspike lasting about 30 ms and preceding the musclepotential in the contralateral biceps by 17 ms(fig 3A).

Reflex myoclonus was regularly elicited by electri-cal stimulation of the median nerve as shown infig 3B. The EMG recording in this case showed amore complex wave form than t,hat of action myo-clonus and with longer duration (40-60 ms). A quiteconstant pattern of latency values ranging from 35ms (for proximal muscles of the ipsilateral upperlimb) to 53 ms (for ipsilateral quadriceps) wasobserved, as demonstrated by the averaging of 60responses (fig 4). Note in the same figure that thecontralateral SEP evoked by the same median nervestimulation shows an high voltage (35 jLV) earlycomponent with 21*5 ms latency preceding by 15 msthe EMG potential recorded in the biceps muscle.Pharmacological tests and therapy Pharmaco-logical tests with L-5-hydroxytryptophan (L-5HTP)and clonazepam (CZP) were performed accordingto a protocol previously set up in our department.5L-5HTP (Roche: Ro 3-5940/601) was administeredby intravenous (iv) infusion of 100 mg in 250 ml ofisotonic saline solution (infusion time 60 s) after pre-treatment with carbidopa (Merck Sharpe andDohme) 100 mg given by mouth.

Thirty minutes after the start of the infusion aclearcut reduction of the action myoclonus (fig 5)and the reflex myoclonus was observed resulting inmarked functional improvement. This beneficialeffect lasted four hours. No side effects wereobserved. A similar but more transient effect wasinduced by a single 1 mg dose of CZP givenintravenously.A chronic trial was then started with increasing

oral doses of L-5HTP plus carbidopa, up to 600 and125 mg respectively. These two drugs were simplyadded to the preceding therapy, which was main-tained unchanged. During 12 months of follow-up,the beneficial effects of L-5HTP on action-sensitiveand stimulus-sensitive myoclonus were confirmed.The ensuing improvement in motor performanceincreased the degree of self-sufficiency of the patientin some daily activities such as dressing, washing andeating. So far there has been no sign of loss ofefficacy. Neither clinical nor laboratory side effectshave been observed.Biochemical findings Fibroblasts from normal con-trols, a patient with mucolipidosis III (ML III) andthe CRS-MS patient were grown in Eagle's MEM,supplemented with 10% foetal calf serum aspreviously described.6 Cells were analysed for lyso-somal enzymes and a-neuraminindase activities afterfive to 15 subcultures, seven days after they becameconfluent.Lysosomal enzymes in cultured cells and in culture

medium were analysed as follows: (a) cells werewashed twice with tris-buffered saline (TBS), pH 7-4and trypsinised with 025% trypsin-l 0 mM EDTA,

pH 7-4. The cell pellets were washed twice with TBS.Lysosomal enzymes activities in sonicated cells werethen analysed as previously described7; (b) fibroblastswere washed twice with Eagle's MEM without foetalcalf serum and then incubated overnight with MEMin order to remove serum proteins entrapped in thecell network. The medium was removed and thefibroblasts incubated for 24 hrs at 370 in MEM: the

Case 15

AEEG Jerklocked averaging

of the EEG and EMGBiceps

50msAmpi cal 30,uV

R biceps R thenar R quadriceps

BI~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

50msAmpi cal 300,uV

Fig 3 A: Jerk-locked averaging of the EEG andEMG during action myoclonus showing an EEGspike preceding the muscolar potential by 17 msec.B: Reflex myoclonus evoked by stimulation of rightmedian nerve at the wrist.

Case 15

Median N stim - averaging

L sep

R trapezius

R biceps

R thenar

R quadriceps

20,uV

500,uV

500,uV

750,uV

50mc

Fig 4 A veraging of reflex myoclonus evoked indifferent muscles by stimulation of the right mediannerve at the wrist is compared with contralateralEEG response evoked by the same stimulation(EMG averaging: 60 samples; EEG averaging:200 samples, bipolar recording from C3-P3 leads).

936

B

Cherry-red spot myoclonus syndrome 937

CASE 15

basal 30' af ter L5HTP

bictric

r bic_

quad -_ _ - -

0 4 51t20 2428 32 0 4 8E016 20 4 5J106 20 24 2832 Hz

Fig 5 Effect of LSHTP infusion on action myoclonus evoked by voluntary activation of muscles of lowerlimbs. At bottom of figure: power spectra computed on F3-C3 (upper trace) and C3-P3 (lower trace),showing no remarkable changes in EEG frequency composition. Each trace displays the composition of30 sec sample.

media from three plates for each cell line were

pooled: lysosomal enzymes secreted by culturedfibroblasts were precipitated with 80% (NH4)2SO4centrifuged at 3000 rpm at 4°C in the presence of0 43 mg/ml albumin as a carrier. The precipitateswere suspended in 1 ml of glass redistilled water,dialysed for 24 hr against 500 ml of 0-5 M acetatebuffer pH 5-5, in 0 15 M NaCl, with two changes ofdialysis solution, and then analysed for lysosomalenzymes.Neuraminidase activity in sonicated fibroblasts was

determined under optimal conditions with a-N-acetyl-neuraminylactose (a2-3) as substrate as

recently described.8 Table 1 shows the activities ofa-neuraminidase in the cells of controls, of the MLIII patient and of the CRS-MS patient: a-neura-minidase was markedly reduced, to about 5 % of themean control values in the cells of the two patients.Table 2 shows the activities of five lysosomal

hydrolases in cultured fibroblasts and in the culturemedia from the controls and the two patients. A

marked reduction of the activity of the five hydrolaseswas observed in the cells of the ML III patient, withcorresponding increases in enzyme activity in hisculture medium, except for that of 13-galactosidase;this latter enzyme and the other four hydrolasesmeasured in the cells and in the culture medium ofCRS-MS patient showed activities comparable tothose of controls.

Table 1 Activity of a-neuraminidase in culturedfibroblasts from the two patients and the controls

a-neuraminidase activity

Controls (15) 0-300±0-006Patient CRS-MS 0 020Patient ML III 0-012(Mucolipidosis III)

Activity is expressed as nanomoles a-N-acetyl-neuraminilactose (a 2-3)hydrolysed/mg/protein/hr ± SE. In brackets the number of controlcell lines in duplicate.

Table 2 Activity of lysosomal hydrolases in cultured cells and in culture medium of cells from thepatients and the controls*

Controls CRS-MS patient ML III patient

Cells Medium Cells Medium Cells Mediunm

arylsulphates A 1240±436 (12) 16-5±2-6 (3) 1832 20-6 161 59-2,B-hexosaminidase 8921 ±2610 (12) 87 ±21 (3) 11704 102 2505 324a-mannosidase 259±64 (6) 0-93±0 16 (3) 239 0-20 0 19-6a-fucosidase 217±72 (6) 2 5±04 (3) 229 1 7 19 1 4-81-galactosidase 724±180 (12) 1-29±0-26 (3) 1227 0 75 144 1-37

*Activities are expressed as nanomoles substrates hydrolised/mg protein/hr±S.D. In brackets the number of lines examined in duplicate.

60' after L5HTP

S Franceschetti, G Uziel, S Di Donato, L Caimi, and G A vanzini

Comment

The clinical picture of this patient is strikinglysimilar to that reported by Rapin et al.2 Com-mon to our patient and to the three previouslyreported cases2 are: (1) progressive action andstimulus-sensitive myoclonus with late onset, (2)cherry-red spot at the macula, (3) deficiency ofa-neuraminidase, (4) no evidence of dementia.Our patient shares with the two sisters reportedby Rapin et a!2 an Italian origin.According to Engel et al,9 the electrophysio-

logical findings in this syndrome include: (1) lowvoltage fast EEG background activity; (2) par-oxysmal bursts of bilateral 10-20 Hz positivespikes, time-locked but not topographically re-lated to the myoclonus; (3) changes in SEPamplitude and waveform. Similar but not iden-tical features were present in our patient whoalso showed a low voltage fast EEG backgroundwith paroxysmal bursts which can be betterdefined as "central fast rhythm" according toKelly et all0 rather than as 10-20 positive spikes.By the jerk-locked averaging technique, how-

ever, it was possible to detect a time-locked EEGspike preceding each myoclonic jerk. Accordingto Shibasaki et al," this myoclonus-related cor-tical spike may be due to the same mechanismsunderlying the giant primary SEP (also presentin our patient). Whether or not these twophenomena can be related to a cortical reflextype of myoclonus is not specifically relevant tothe present discussion: the question of cortical-versus-subcortical generators of myoclonus willbe discussed in more detail in another paper nowin preparation, based on a large number ofpatients with various kinds of myoclonus.An interesting point is the effect of L 5HTP

on action-sensitive and stimulus-sensitive myo-clonus in our patient, both in an acute and achronic trial. Beneficial effects of serotonin pre-cursors have been demonstrated far less certainlyin non-postanoxic myoclonus syndromes than inpostanoxic ones.'2-'4 It has been suggested thatlow CSF concentrations of 5HIAA (which sug-gests an impairment in serotonin metabolism)may be used to predict the efficacy of serotoninprecursors and that this criterion could be usedto detect an L 5HTP sensitive population amongpatients with myoclonic syndromes.13 This wouldnot hold true for our patient or for some otherpatients with myoclonic syndromes we havestudied. According to the preliminary results ofour study the only common characteristic sharedby all patients responding to L 5HTP was theprominence of action and intention-myoclonus.

It should be noted, however, that such myo-clonus also was present in the three patients witha cherry-red spot reported by Rapin et a!2 to beunresponsive to L 5HTP plus carbidopa.

a-neuraminidase deficiency in cultured fibro-blasts from patients with mucolipidoses II andIIIJ15 16 has been reported. In these patients, a-neuraminidase deficiency accompanied markeddeficiencies in several lysosomal hydrolases incultured cells, with increases in the correspond-ing activities in the cell culture media orserum.'7 18 In cultured fibroblasts from patientswith mucolipidosis I, a disease characterised bybone dysplasia, Hurler-life face, macular cherry-red spot, myoclonic jerks, progressive dementiaand no inclusion bodies in cultured cells, themarked deficiency in a-neuraminidase is not asso-ciated with other known enzyme deficiencies.'7Neuraminidase deficiency has been regarded as aprimary defect in this condition and thedisease named "Sialidosis."20 21The spectrum of a-neuram.inidase deficiency

was broadened by the reports of Rapin et a!2and O'Brien,' when they described their threepatients with progressive incapacitating myo-clonus, macular cherry-red spots and a-neur-aminidase deficiency in their cultured cells. Thesepatients differed from those with ML I in theadult onset of the signs and symptoms, the lackof bone dysplasia and the normal intelligence.They share with the ML I patient macularcherry-red spots, myoclonus and a-neuraminidasedeficiency.2 Moreover, additional patients withclinical features distinct from those of thepatients with mucolipidoses I, II, III and thecherry-red spot myoclonus syndrome, but witha-neuraminidase deficiency, have been reported:an eight-month-old girl with normal mental de-velopment and dysostosis multiplex'0 and anadult patient with skeletal dysplasia, cerebellarataxia, cherry-red spot and myoclonus22: con-versely, patients with a phenotypic conditionsimilar to mucolipidosis I and to the CRS-MShave been described in whom the biochemical de-fect was however 1-galactosidase deficiency23-25:in some patients 8-galactosidase deficiency wasassociated and probably secondary to a-neur-aminidase deficiency.26-28 It is clear, therefore,that similar phenotypic conditions can be associ-ated with different biochemical abnormalities andthat a given enzyme deficiency (for example, a-neuraminidase deficiency) can be associated withdifferent clinical phenotypes.Our patient was clinically and biochemically

closely similar to the patients described byRapin et a!2 and falls into the type I Sialidosis.4

938

Cherry-red spot myoclonus syndrome

The degree of a-neuraminidase deficiency incultured cells from our patient, as measured witha-2-3 neuraminylactose, was not distinguishablefrom that found in cultured cells of a patientwith ML III (table 2). The two patients couldnot be distinguished on the basis of a-neur-aminidase activity in their cultured cells.However, the two diseases are clinically and bio-chemically different; cultured cells from theCRS-MS patient showed both intracellular andextracellular activities of lysosomal enzymescomparable to those of controls, while cells fromML III patient showed the known"8 decrease inintracellular and increase in extracellular lyso-somal enzyme activities (table 2).

a-neuraminidase deficiency is a secondarydefect in I-cell disease,23 29 but it is considered aprimary defect in both mucolipidosis I and thecherry-red spot myoclonus syndrome. We believe,however, that a more detailed characterisationof a-neuraminidase activity using natural sub-strates8 is needed in order to link well-definedclinical conditions with biochemical abnormalities.

We thank Marisa Andreasi and MarilenaScarpina for technical assistance. L 5HTP wassupplied by Roche Company and Carbidopa byMerck Sharpe and Dohme.

References

I O'Brien JS. Neuraminidase deficiency in thecherry-red spot myoclonus syndrome. BiochemBiophys Res Commun 1977; 79:1136-41.

2 Rapin I, Goldfisher S, Ketzman R, Engel J,O'Brien JS. The cherry-red spot myoclonus syn-drome. Ann Neurol 1978; 3:234-42.

3 Thomas PK, Abrams JD, Dallas Swallow, StewartG. Sialidosis type I: cherry-red spot myoclonussyndrome with sialidose deficiency and alteredelectrophoretic mobilities of some enzymesknown to be glycoproteins. I. Clinical findings.J Neuro! Neurosurg Psychiatry 1979; 42:873-80.

4 Lowden JA, O'Brien JS. Sialidosis: a review ofhuman neuraminidase deficiency. A m J HumGenet 1979; 31:1-18.

5 Avanzini G, Bossi L, Caraceni T et al. Effect ofL-SHTP and drugs acting on serotonin meta-bolism in various myoclonic syndromes. In:Majkowski J, ed. Epilepsy-Clinical and experi-mental research. Warsaw: Pol Chapt InternatLeague against Epilepsy, 1979: in press.

6 Di Donato S, Wiesmann UN, Herschkowitz N.Membrane absorption and internalisation of(C1 4) chloroquine by cultured human fibroblastsBiochem Pharmacol 1977; 26:7-10.

7 Tettamanti G, Lombardo A, Marchesini S et al.Lipid storage diseases: biochemical diagnosis.Biochem Exp Biol 1977; 13:45-60.

939

8 Caimi L, Lombardo A, Preti A, Wiesmann UN,Tettamanti G. Optimal conditions for the assayof fibroblast neuraminidase with different naturalsubstrates. Biochim Biophys Acta 1979; 571:137-46.

9 Engel J, Rapin L, Giblin DR. Electrophysio-logical studies in two patients with cherry-redspot myoclonus syndrome. Epilepsia 1977; 18:73-87.

10 Kelly JJ Jr, Sharbrough FW, Westmoreland BF.Movement-activated central fast rhythms: anEEG finding in action myoclonus. Neurology1978; 28:1037-40.

11 Shibasaki H, Yamashita Y, Kuroiwa Y. Electro-encephalographic studies of myoclonus. Brain1978; 101:447-60.

12 Lhermitte F, Peterfalvi M, Mareau R, GazengelJ, Serdaru M. Analyse pharmacologique d'un casde myoclonies d'intention et d'action post-anoxiques. Rev Neurol (Paris) 1971; 124:21-31.

13 Chadwick D, Hallett M, Harris R, Jenner P,Reynolds EH, Marsden CD. Clinical, biochemicaland physiological features distinguishing myo-clonus responsive to 5-hydroxytryptophan with amonoamine oxidase inhibitor and clonazepam.Brain 1977; 100:455-78.

14 Van Woert MH, Rosenbaum D, Howieson J.,Bowers MB. Long-term therapy of myoclonusand other neurologic disorders with L-5-Hydroxy-tryptophan and Carbidopa. N Engl J Med 1977;296:70-5.

15 Stretcher G, Michalski JC, Montrenil J, TarriauxJP. Deficit in neuraminidase associated withmucolipidosis II (I-cell disease). Biomedicine1976; 25:238-40.

16 Thomas GH, Tiller GE, Reynolds LW, MillerCS, Bace JW. Increased levels of sialic acid asso-ciated with a sialidase deficiency in I-cell diseasemucolipidosis II) fibroblasts. Biochem BiophysRes Commun 1976; 71:188-95.

17 Hickman S. Neufeld EF. A hypothesis for I-celldisease: Defective hydrolases that do not enterlysosomes. Biochem Biophys Res Commun 1972;49:992-9.

18 Wiesmann UN, Herschkowitz NN. Studies onpathogenetic mechanism of I-cell disease in cul-tured fibroblasts. Pediatr Res 1974; 8:865-70.

19 Cantz M. Gehler J5 Spranger J. Mucolipidosis I1Increased sialic acid content and deficiency ofan a-N-acetylneuraminidase in cultured fibro-blasts. Biochem Biophys Res Commun 1977; 74:732-8.

20 Spranger J, Gehler J, Cantz M. Mucolipidosis 1.a Sialicidosis. Am J Med Genet 1977; 1:21-9.

21 Durand P, Gatti R, Cavalieri S et al. SialidosisMucolipidosis I). Helv Paediatr Acta 1977; 32:391-400.

22 Kelly TE, Graetz G. Isolated acid neuraminidasedeficiency: a distinct lysosomal storage disease.Am J Med Genet 1977; 1:31-46.

23 Miyatrake T, Yamada T, Serzuki M et al. Siali-dase deficiency in adult type neuronal storage

S Franceschetti, G Uziel, S Di Donato, L Caimi, and G Avanzini

disease. FEBS Letters 1979; 97:257-9.24 Suzuki Y, Nakamura N, Shimade Y, Yotsuinoto

H, Endo H, Nagashima K. Macular cherry-redspot and ,-galactosidase deficiency in an adult.Arch Neurol 1977; 34:157-61.

25 Orii T, Minami R, Sukegawa K et al. A new

type of mucolipidosis with fB-galactosidase de-ficiency and glycopeptiduria. Tohoku J Exp Med1972; 107:303-15.

26 Yamamoto A, Adachi S, Kawamura S et al.Localised B-galactosidase deficiency. Occurrencein cerebellar ataxia with myoclonus epilepsy andmacular cherry-red spot-a new variant ofGM,-gangliosidosis? Arch Intern Med 1974; 134:627-34.

27 Thomas GH, Goldberg ME, Miller CS, ReynoldsLW. Neuraminidase deficiency in the original

patient with the Goldberg syndrome. Clin Genet1979; 16:323-30.

28 Okada S, Yutaka T, Tomochika K et al. A caseneuraminidase deficiency associated with a

partial /8-galactosidase defect. Eur J Pediatr 1979;130:239-49.

29 Wenger DA, Tarby TJ, Wharton C. Macularcherry-read spot and myoclonus with dementia:coexistent neuraminidase and fl-galactosidasedeficiencies. Biochem Biophys Res Commun 1978;82:589-95.

30 Di Donato S. Biochemistry of mucolipidosis ll,or I-cell disease. In: Berra B, Balduini B,Di Donato S, Tettamanti G, eds. Perspectives inInherited Metabolic Disease, vol 2, Glycoproteinsand Glycosaminoglycans in Health and Disease.1979: 129-39.

940