Arch Dis Child: first published as 10.1136/adc.47.252.163 on 1 April 1972. Downloaded from Review Article

Archives of in Childhood, 1972, 47, 163.

Investigation of Degenerative Disease of the Central Nervous System

JOHN WILSON From The Hospitalfor Sick Children, Great Ormond Street, London

Degenerative of the nervous system in TABLE I children are acknowledged to be chronic (usually) Neuropathological Classification of Heredodegenera- and destructive (invariably), and for the biochemi- tive Neurological Diseases cally oriented clinician they provide a challenging interest because most are genetically, and probably, I: Diseases of intracellular storage-the sphingolipidoses therefore, chemically determined. Individually e.g. GM2 gangliosidosis relatively rare, most of them are inherited as auto- (Tay-Sachs disease) II: Generalized metabolic disorders, with secondary effects on

somal recessive conditions, and by implication may neural function copyright. represent the clinical effects of inborn metabolic e.g. Hartnup disease Leigh's infantile necrotizing encephalomyelopathy errors. Nevertheless only a minority at present III: Abiotrophies are thus identified because, except where there is an e.g. Friedreich's ataxia Chronic easily recognizable storage product such as ganglio- IV: Neurocutaneous syndromes side, or abnormal metabolic cumulation readily e.g. Neurofibromatosis identifiable in body fluids such as amino acid, it is Tuberous sclerosis usually very difficult to guide biochemical research on purely clinical and pathological indications. http://adc.bmj.com/ It is still necessary and possible, however, to Abiotrophy is the term suggested by Gowers to give an accurate prognosis and genetic analysis represent conditions in which, after apparently without any biochemical information, but biochemi- normal differentiation and function, tissues degener- cal refinements offer the opportunity of delineating ate and die. Recent usage by some workers has syndromes which at a given point in time are implied that tissues are prematurely effete, perhaps clinically indistinguishable, e.g. Tay-Sachs variants, because of faulty differentiation or structure, but such a view is speculative. and this may be important in genetic counselling. purely on September 26, 2021 by guest. Protected In a few conditions biochemical identification of Though the suggested classification is intended to fetal tissues enables a more constructive opportunity be helpful in orienting investigations, the groups for eugenic measures. are not mutually exclusive. For example, though At the present stage of our knowledge, and with intracellular metabolic derangement in Group I perennial economic limitations on screening mea- may be primarily responsible for most of the sures, a discriminating use of elaborate biochemical symptoms, there may also be secondary generalized techniques is desirable and it is proposed to review metabolic derangement, as has been suggested in, a scheme of investigation which depends for its for example, Niemann-Pick disease. Moreover, usefulness upon a careful clinical appraisal, and the abiotrophic disorders may represent the effects therefore is applicable to conditions which are not of either intracellular or generalized accumulation identifiable chemically as well as those that are. of as yet unrecognized metabolites. Abroad neuropathological classification ofheredo- The diseases of intraneuronal storage have been degenerative neurological diseases is presented in intensively studied and the biochemical basis of Table I. many of them is now known and they are listed in 163 2 Arch Dis Child: first published as 10.1136/adc.47.252.163 on 1 April 1972. Downloaded from

164 John Wilson Table II, with their 'chemical' as well as 'familiar' history. Unless it is then possible on examination names. and utilizing suitable laboratory investigations to establish a diagnosis,it may be necessary to wait until Clinical Appraisal the evolving character of the condition declares itself Perhaps the most difficult clinical problem is to on prospective review. The clinician's case notes decide whether or not a condition is progressive, (no matter how assiduously maintained) and and yet this is usually the most important step in memory (faithful-and failing) are most valuably the diagnosis of a degenerative disease. In those supplemented by cine-film of gait or co-ordination, situations where a previous child is affected by a which may be the best way of disclosing the chang- recognized heredodegenerative disease it may be ing character of very slowly progressive diseases. possible to obtain discriminatorily valuable findings from special laboratory studies some time before Dementia. Dementia is a characteristic early clinical abnormalities appear in a sib. For example, clinical feature of all the diseases of intraneuronal a rectal biopsy may show significant abnormalities storage, and a common but later feature of other and white cell hexosaminidase may be deficient in a degenerative diseases, but is conspicuously absent, homozygous newborn sib of a child with Tay-Sachs even preterminally, in conditions such as chronic disease several months before its development spinal muscular atrophy. Dementia in infancy becomes abnormal. and early childhood manifests itselffirst as a slowing, At the first meeting with a patient, without a then arrest, of acquisition of skills (linguistic or prospective personal longitudinal analysis of a physical) before there is obvious regression. It is condition, one is entirely dependent on an evaluation important to distinguish dementia from both of a retrospective narrative and, because of this, primary mental subnormality and from psychotic time is well spent on listening to a carefully elicited regression (e.g. autism), but from a careful history TABLE II

Nature of Biochemical Abnormalities in Some Sphingolipidoses copyright.

Chemical Name or Class Other Names Stored Material Enzyme Deficiency GM1 gangliosidosis Type 1 (infantile) Neurovisceral lipidosis GM] ganglioside plus ,-galactosidase A, B, and C Tay-Sachs disease with mucopolysaccharide visceral involvement Psuedo-Hurler Type 2 infantile) GM1 ganglioside plus ,3-galactosidase B and C (late http://adc.bmj.com/ mucopolysaccharide GM2 gangliosidosis Infantile Tay-Sachs Type I GM2 ganglioside Hexosaminidase A Hexosaminidase B/high Tay-Sachs Type II GM2 ganglioside with globo- Hexosaminidase A and B side in viscera Tay-Sachs Type III ? (Hexosaminidase A and B slightly raised) Late infantile GM2 ganglioside Hexosaminidase A slightly reduced Juvenile GM2 ganglioside Hexosaminidase A on September 26, 2021 by guest. Protected Sphingomyelinosis Acute infantile Niemann-Pick Sphingomyelin Sphingomyelinase Acute infantile Gaucher with Glucocerebroside Glucocerebrosidase cerebral involvement Sulphatide neurolipidosis Metachromatic leucodystrophy Cerebroside sulphate Cerebroside sulphatase (arylsulphatase A) Krabbe's globoid cell Galactocerebroside in Galactocerebroside ,3- leucodystrophy globoid bodies galactosidase Lipofuscinosis Late infantile AFI* Lipofuscin ? (Bielschowsky) Juvenile AFI (Batten- Lipofuscin ? Spielmeyer-Vogt) Adolescent (Kufs) AFI Lipofuscin ?

*Amaurotic family idiocy. Arch Dis Child: first published as 10.1136/adc.47.252.163 on 1 April 1972. Downloaded from

Investigation of Degenerative Disease of the Central Nervous System 165 supplemented by incidental documentation (baby Dementia may be a presenting finding, but fits books or photographs) it is usually possible to usually occur early in the course of the disease. distinguish nonprogressive subnormality from more Not only are there major seizures often with focal dynamic loss even in very young children in whom features, but also there are 'hung-up' movements, the tempo of degenerative disease tends to be more too slow for myoclonus, inhibitory rather than rapid than in older children. In older children excitatory in some respects, and undeniably of deteriorating school performance, often associated central dysrhythmic origin as shown by correspond- with behaviour problems due to organic dementia ing EEG abnormalities. These attacks may be (which is comparatively rare), may be exceedingly sufficiently distinctive to make a bedside diagnosis. difficult to distinguish from the much more com- Neurological abnormalities include a mixed pyra- mon psychosocial causes of failing academic midal and striatal clinical picture. performance and misbehaviour. Only longitudinal If the diagnosis is uncertain clinically, the cis- comparison over a few months will allow the tinctively periodic complexes in the EEG, a paratic distinction clinically, supplemented by serial psycho- Lange, and very high levels of measles antibody in logical and usually EEG assessment. both blood and CSF are usually enough to establish Though in the more diffuse diseases no part of the diagnosis adequately without recourse to brain the neuraxis is spared, increasing weakness, ataxia, biopsy. and clumsiness are the commonest manifestations of changing physical status, and these features 3. Cerebral palsy. It is well known that are best recorded by cine-film. during the first year or two years of life certain forms of cerebral palsy, notably the diplegic and Seizures. Seizures may be an early feature of athetoid forms, have an evolving character. The a large number of degenerative diseases. They are circumstances in which these conditions occur particularly common in diseases primarily of grey normally help in differentiation: athetoid cerebral matter, whereas in the leucodystrophies, if they palsy usually follows either kernicterus (with or occur at all, they develop relatively late in the without prematurity) or birth asphyxia or shock, natural history. Myoclonic attacks and 'minor while diplegic cerebral palsy is usually seen as a copyright. status epilepticus' may be a distinctive feature of, consequence of prematurity in infants weighing for example, Tay-Sachs disease and late infantile less than 1-5 kg. In their absence the clinician (Bielschowsky) amaurotic family idiocy. must be especially wary since a substantial propor- Before discussing the relevance of laboratory tion of the remainder include heredodegenerative studies in evaluation of degenerative diseases, it is syndromes. well to consider the differential diagnosis and the clinical pitfalls. 4. Psychiatric problems. From time to time http://adc.bmj.com/ regression of an exceptionally severe degree proves Differential Diagnosis very baffling to both psychiatrist and paediatrician. 1. Tumour. The principal potentially sinister In the context of gross disturbance in the psycho- alternative cause of an evolving illness is a tumour, social environment-separation, deprivation, mal- particularly of brainstem and posterior fossa. treatment, marital disharmony, psychopathy or Posterior fossa tumours are especially frequent in psychosis in parents-and in the absence of

childhood and their very early diagnosis may be evolving neurological abnormalities, it is most on September 26, 2021 by guest. Protected very difficult when invasive rather than space- likely that psychological factors are pre-eminent, occupying characteristics present. A mixed picture though it is virtually impossible to exclude an of cerebellar and pyramidal dysfunction can be organic substrate at a given instant. Sensitive very misleading. If coexisting clinical abnormali- management of a grossly disturbed social situation ties (such as cranial nerve palsies) do not give more usually allows reasonably confident clarification of positive clues, then air studies usually resolve the the issues on clinical grounds alone, but the initial doubt. Exceptionally they may be normal. evaluation in the conventional setting of an anam- nestic interview may be limited or misleading, and 2. Subacute sclerosing panencephalitis observation in the home by a trained observer may (SSPE). Although evidence from the United be much more illuminating. Mistakes will never- States and Canada suggests that the incidence of this theless be made occasionally, but perhaps it is condition is declining, perhaps as a result of wide- better to manage overtly psychiatric problems spread inoculation with attenuated measles , which are relatively common, unfettered by fears cases are still occurring in the United Kingdom. of missing a progressive organic disease, than to be Arch Dis Child: first published as 10.1136/adc.47.252.163 on 1 April 1972. Downloaded from

166 John Wilson preoccupied about missing a rare (incurable) cytes as seen, for example, in Niemann-Pick disease. disease, though it must be remembered that small In so-called 'hysterical' illness in childhood, it is numbers of abnormal-looking cells may be found usually possible to identify reasonably easily the in apparently normal individuals. factors which either potentiate what may have Marrow examination provides an extension of originally begun as a trivial organic illness, or haematological studies especially valuable where determine the form and content of the physical there is a reticuloendothelial involvement. It may symptomatology. provide diagnostically significant material in, for During the ingravescent phase of autism, usually example, Gaucher's disease, generalized GM1 in the second year of life, there may be regression gangliosidosis, and in 'sea blue histiocyte' disease in speech and behaviour, without any physical (Lake, Stephens, and Neville, 1970). As a manifestations of disease, but with behavioural source of culture material for histochemical study changes characteristic of autism. It is unlikely it is rivalled by skin biopsy (see later). to be a source of confusion more than very temporarily. Radiology. Diagnostically helpful radiological abnormalities of long bones and/or spine are seen 5. Epilepsy. Intellectual and neurological deter- in a variety of conditions where both marrow and ioration sometimes occurs in patients with idiopathic matrix as well as epiphysial plate may be involved, epilepsy. Both are not infrequently seen after e.g. the mucopolysaccharidoses, Gaucher's disease, status epilepticus and some patients may have, for mucolipidoses (Spranger and Wiedemann, 1970), example, evidence of a cerebellar deficit, transiently homocystinuria, and the gangliosidoses. or permanently. Skull radiology can be most informative. Parti- In some schoolchildren with epilepsy who may cularly helpful is the thickening and increase in have neither particularly severe nor frequent fits diploic pattern with loss of 'digital' markings seen there is reputedly a progressive lowering of IQ. where there is cortical atrophy. Though this On closer scrutiny of test results one usually finds sign is seen after a single cerebral insult in childhood, that the child manages to complete more or less after which the brain stops growing and there is copyright. exactly what he achieved at his previous test, critical shrinkage (as in reaction to pertussis antigen), perhaps a year earlier. When this is related to age, it is often most prominent in the amaurotic family of course it appears as a fall in IQ. One possible idiocies, particularly in some cases of longer dura- interpretation of this finding is that he has either tion, and represents in them progressive cortical stopped learning or is learning more slowly, and atrophy. one suspects that this may be due as much to the Progressive calcification of Sturge-Weber disease depressant effects of anticonvulsant drugs, especially beginning posteriorly and spreading forwards is http://adc.bmj.com/ barbiturate and primidone, as to dysrhythmia. often mistakenly thought to represent calcification There is very rarely evidence of 'hard' neurological in arterial walls because of its parallel and linear signs or degenerative disease. characteristics. The calcification seen on x-ray In minor status epilepticus, by contrast, not only occurs in the gyri, and is in the substance of the may there appear to be gross intellectual regression cortex. for periods lasting several months, but also recovery Contrast studies are not themselves diagnostic may be almost as dramatic once the dysrhythmia but may show localized, for example, cerebellar, or is controlled. generalized, for example cortical, atrophy. The on September 26, 2021 by guest. Protected presence of the latter can, of course, be surmised if Investigations thickening of skull bones is seen on plain films Haematology. Haematological abnormalities of the skull. Air studies will serve to delineate are sometimes sufficiently distinctive to suggest a aqueduct stenosis, posterior fossa, or brainstem diagnosis. For example, a macrocytic anaemia tumours, or aneurysm of the great vein of Galen, may suggest an inborn abnormality of vitamin B12 conditions which, because of their progressive metabolism, acquired abnormalities being very nature, may mimic heredodegenerative syndromes. rare in childhood, while the presence of acantho- cytes as evidence of a-3-lipoproteinaemia may give Electroencephalogram (EEG). At the same a simple and direct clue to the diagnosis of an time as being most valuable in the diagnosis of obscure cerebellar syndrome. certain progressive neurological diseases such as Examination of the peripheral white cells may subacute sclerosing panencephalitis, late infantile disclose significant numbers of vacuolated lympho- (Bielschowsky) amaurotic idiocy, and giving other Arch Dis Child: first published as 10.1136/adc.47.252.163 on 1 April 1972. Downloaded from

Investigation of Degenerative Disease of the Central Nervous System 167 valuable nonspecific evidence of an evolving disease, of selection of patients, the yield is quite low. the EEG may be most misleading, especially when Depending on the laboratory, certain tests can now seizure control is variable, showing wide and be considered to be routine, e.g. urinary chroma- unsustained fluctuations in dysrhythmic pattem. tography for amino acids and sugars; nitroprusside The persisting lack of statistically controlled and test on fresh urine (homocystinuria); urinary standardized evaluation of EEG changes must still mucopolysaccharide screening tests; fasting blood limit their value in this respect. sugar; uric acid; serum calcium; phosphate, Of outstanding positive diagnostic value is the alkaline, and acid phosphatases; and plasma phenomenon described by Pampiglione (1961) and cholesterol. Protein-bound iodine, magnesium, now validated in over a score of histologically serum immunoglobulins (ataxia telangiectasia, dys- proven cases of one of the late infantile forms of trophia myotonica), pyruvate and lactate concentra- amaurotic family idiocy. It comprises an abnormal tions (Leigh's acute necrotizing infantile encephalo- response to photic stimulation at low rates of flicker, myelopathy), blood ammonia, are worth while con- with repetitive discharges at an idiosyncratic sidering as screening procedures; their expense can frequency independent of the higher flicker rates. be justified by the fact that in several cases they can This pathognomonic 'sign' has recently been detect diseases which, however rare, may be amen- 'rediscovered' (Green, 1971). able to treatment sooner or later, if not already. For departments with appropriate apparatus Their greater complexity requires first-class there is a computerized averaging technique for laboratory facilities with an acknowledged readiness measuring cortically evoked responses to both to deal with paediatric problems, and where possible, auditory and visual stimuli. In the case of the with fingerprick samples of blood. latter the study of visually evoked responses in the Other biochemical studies are deservedly restric- occipital cortex is of special value in some of the ted for conditions where clinical studies and pre- degenerative diseases which specially affect optic liminary screening have provided some selection radiations or occipital cortex, e.g. diffuse scleroses. of patients, in particular separating off cases of can The study of visual pathways be further primary mental subnormality and cerebral palsy. copyright. clarified by measurement of the electroretinogram Likewise, assay of sphingomyelinase and - potentials, with an electrode placed on the bridge of glucocerebrosidase in white blood cells may estab- the nose or on the corneal conjunctiva (Harden lish, respectively,the biochemical basisof a diagnosis and Pampiglione, 1970). The electroretinogram of Niemann-Pick (Kampine et al., 1967) or response is diminished or absent in the tapeto- Gaucher's disease (Patrick, 1965). In GM1 gan- retinal degenerations, and can be of particular help gliosidosis the various forms can be differentiated in investigation of the amaurotic family idiocies. by white cell assays of the g-galactosidase iso- In these conditions the response is lost at an early enzymes (R. Ellis, personal communication). http://adc.bmj.com/ stage when ophthalmic signs may not be particularly Similarly isoenzyme assay of white cell and serum obvious (Harcourt, 1970). hexosaminidase is of value in differentiating the various forms of Tay-Sachs disease and the other Electromyogram (EMG) and nerve conduc- GM2 gangliosidoses. tion studies. The combination of EMG and Although essential for a diagnosis of hepato- nerve conduction studies has now achieved a lenticular degeneration, blood copper and copper

degree of refinement and elaboration in young child- oxidase are needlessly included in some neurological on September 26, 2021 by guest. Protected ren as well as in adults to enable a reliable distinc- screening programmes since it is almost unknown tion not only between myopathic and neuropathic for this condition to manifest itself as a neurological weakness but also valuable differentiation between condition before the age of 10 years, though it may segmental demyelination (e.g. metachromatic leuco- present as a haemolytic-hepatitic episode earlier. dystrophy, globoid cell leucodystrophy) and axonal The demonstration of an increased phytanic degeneration (e.g. spinal muscular atrophy). acid concentration in the blood is sufficient to establish a diagnosis of Refsum's disease, while Biochemical studies. Certain biochemical in- plasma lipoprotein assay is necessary unequivocally vestigations (especially those amenable to automatic to identify a-,B-lipoproteinaemia (Bassen-Komz- analysis) are sufficiently cheap and reliable to be weig disease) or an a-lipoproteinaemia (Tangier used extensively in screening studies of patients disease), both of which have important neurological with fits or other neurological or mental handicaps. components. Nevertheless, in terms of the proportion of abnormal Among the heterogeneous leucodystrophies, two results found in this way, even allowing for a degree main conditions have been separately identified: Arch Dis Child: first published as 10.1136/adc.47.252.163 on 1 April 1972. Downloaded from

168 John Wilson metachromatic leucodystrophy (late infantile, juve- At parents' request, histological examination of nile, and adult forms) and globoid cell leucody- ganglion cells has been used at The Hospital for strophy (Krabbe, or infantile form, and later forms). Sick Children on several occasions in clinically Aryl sulphatase determinations in white blood unaffected sibs of patients with either Tay-Sachs cells and urine may clinch a diagnosis of meta- disease or late infantile amaurotic idiocy to make chromatic leucodystrophy, already strongly sug- either a premorbid diagnosis of the same condition gested by the clinical picture with evidence of slow- or to establish the normality of the child. ing of nerve conduction, and by the demonstration of distinctive intracellular metachromatic material Brain biopsy. The amounts of neural tissue in fresh spun urinary sediment (Lake, 1965). obtained by rectal biopsy or appendicectomy are In Krabbe's leucodystrophy the enzyme galacto- insufficient for even semiquantitative chemical cerebroside /-galactosidase is lacking (Austin et al., analysis, and allow only limited histochemical and 1970), and this deficiency can be shown by an ultrastructural study. To obtain sufficient grey isotopic technique in white blood corpuscles. and white matter for these purposes and for enzyme Less well-defined biochemically among the studies, a brain biopsy is essential if there is strong diffuse scleroses is a sex-linked recessive form evidence to suppose that there is diffuse cortical associated with suprarenal insufficiency (Siemerling involvement. and Creutzfeldt, 1923). Though the literature The drawbacks are obvious: there is a significant suggests that clinical adrenal insufficiency antedates morbidity, if not mortality, even in the most skilled the (Forsyth, Forbes, and hands; the amount of tissue removed is relatively Cumings, 1971), in my experience in a series of small; it is difficult to be sure in advance that cases selected by their presentation as neurological cortical involvement is sufficiently diffuse to yield a syndromes (mimicking acute encephalopathies, or specifically abnormal abnormality in the few 'silent' acute demyelinating diseases) the only evidence of sites available for brain biopsy. If it is concluded suprarenal dysfunction has been reduced or absent on clinical grounds that the degenerative process is cortisol production after ACTH stimulation.

predominantly striatal or brainstem in situation, copyright. such as in Hallevorden-Spatz disease and olivo- Biopsy pontocerebellar degeneration, or if it is likely that Rectal mucosa and appendix. The purpose neuropathological characterization depends on of a rectal biopsy is to obtain a full-thickness sample appraisal of the total distribution of cerebral containing sufficient ganglion cells to allow histo- lesions, cortical biopsy is useless. chemical study (Bodian and Lake, 1963). The The main clinical prerequisites for selection of staining may show intraneuronal lipid inclusions patients are dementia, and clinical and preferably as in Tay-Sachs disease and the other ganglio- EEG evidence of a diffuse cortical process. http://adc.bmj.com/ sidoses, or lipofuscin inclusions in the amaurotic The number of occasions on which a diagnosis family idiocies. In sulphatide lipidosis (metachro- can be achieved in life by brain biopsy alone are matic leucodystrophy) metachromatically-staining very rare and dwindling since the commonest material is seen either lying apparently free, or degenerative 'storage' diseases seen in the U.K., phagocytosed in the ganglion-cell layer. i.e. Tay-Sachs, amaurotic family idiocy, and Though the histochemical demonstration of metachromatic leucodystrophy, can be diagnosed

increased lysosomal acid phosphatase activity in on other evidence. The only current example of on September 26, 2021 by guest. Protected the ganglion cells is nonspecific, its occurrence in brain biopsy which can be justified for potential an infant with a suggestive clinical picture makes a therapeutic reasons is herpetic encephalitis; the diagnosis of Krabbe's leucodystrophy very probable. justification in the degenerative diseases is Ifthe technique ofwhite cell assay of ,B-galactosidase prognostic and genetic. mentioned above is not available, the diagnosis can It is appropriate here to acknowledge the need for only be established with certainty by brain biopsy. careful morbid anatomical studies in all children A full-thickness biopsy carries with it a higher dying of obscure neurological disease. Not only risk of haemorrhage, sepsis, and technical failure is this required as a sobering corrective for supposed in inexperienced hands than removal of the appen- clinical expertise, but also especially for accurate dix, and for these reasons the latter is often preferred. genetic counselling. Since this is of tremendous Ganglion cells are, however, smaller and abnormal importance to parents who are usually still in their staining correspondingly less impressive in the procreative years, and, having recently lost a child, appendix than in the rectum (Brett and Berry, may be especially anxious to extend their family, 1967). the need for detailed neuropathological studies Arch Dis Child: first published as 10.1136/adc.47.252.163 on 1 April 1972. Downloaded from

Investigation of Degenerative Disease of the Central Nervous System 169 assumes an urgency which many pathologists are even as a group they represent a small minority of slow to realize. the neurological and neuropsychiatric problems in paediatric practice. But since they often present Tissue culture. A number of specialized and masquerade as more benign conditions such as laboratories are concentrating efforts on developing cerebral palsy or epilepsy, the paediatrician's tissue culture techniques by which both the abnor- perturbation about not missing a sinister disease mally stored material and the enzymic defect can may tempt him into the indiscriminate use of pro- be identified in fibroblast culture (Sloan, 1970). cedures that are unnecessary. From the array of This is because the metabolic abnormalities under- biochemical abnormalities now identified and the lying many of the neurolipidoses are not restricted welter of laboratory studies available, the clinician only to neuraxial tissue. may be forgiven some bewilderment. It is sug- Such studies are of interest at present mainly for gested that the use of both potentially harmful as research purposes, for example in the mucopoly- well as complex and expensive investigations must saccharidoses (Wiesmann and Neufeld, 1970), the be concentrated in appropriately equipped and mucolipidoses (Spranger and Wiedemann, 1970; specialized units. Leroy et al., 1971; Tondeur et al., 1971), Tay- Sachs disease (Schneck et al., 1970), GM1 ganglio- REFERENCES sidosis (Sloan et al., 1969), and metachromatic Austin, J., Suzuki, K., Armstrong, D., Brady, R., Bachhawat, B. K., leucodystrophy (Porter et al., 1970), but the Schlenker, J., and Stumpf, D. (1970). Studies in globoid technique will undoubtedly be of great practical (Krabbe) (GLD). V. Controlled enzymic studies in ten human cases. Archives of Neurology, 23, 502. importance. Bodian, M., and Lake, B. D. (1963). The rectal approach to neuro- Enzymological and histochemical studies in pathology. British Jfournal of Surgery, 50, 702. in those conditions Brett, E. M., and Berry, C. L. (1967). Value of rectal biopsy in cultured tissue is of special value paediatric neurology: report of 165 biopsies. British Medical in which amniotic cells either normally contain a Journal, 3, 400. particular enzyme or accumulate an identifiable Dunn, H. G., Lake, B. D., Dolman, C. L., and Wilson, J. (1969). The neuropathy of Krabbe's infantile cerebral sclerosis storage compound when abnormal. This tech- (globoid cell leucodystrophy). Brain, 92, 329. copyright. nique has obvious application in prenatal diagnosis Forsyth, C. C., Forbes, M., and Cumings, J. N. (1971). Adreno- cortical atrophy and diffuse cerebral sclerosis. Archives of and allows 'positive' genetic counselling in a Disease in Childhood, 46, 273. steadily increasing number of conditions, of which Fullerton, P. M. (1964). Peripheral nerve conduction in metachro- matic leucodystrophy (sulphatide lipidosis). Journal of one might quote Tay-Sachs disease (Schneck et al., Neurology, Neurosurgery and Psychiatry, 27, 100. 1970) and metachromatic leucodystrophy (Porter Green, J. B. (1971). Neurophysiological studies in Batten's disease. et al., 1970). Developmental Medicine and Child Neurology, 13, 477. Harcourt, B. (1970). Electroretinography and the diagnosis of

tapeto-retinal degeneration in childhood. Developmental http://adc.bmj.com/ Medicine and Child Neurology, 12, 775. Peripheral nerve biopsy. Segmental demye- Harden, A., and Pampiglione, G. (1970). Neurophysiological lination of peripheral nerves is well recognized in approach to disorders of vision. Lancet, 1, 805. Kampine, J. P., Brady, R. O., Kanfer, J. N., Feld, M., and Shapiro, metachromatic leucodystrophy (Fullerton, 1964) and D. (1967). Diagnosis of Gaucher's disease and Niemann-Pick in globoid cell leucodystrophy (Lake, 1968; Dunn disease with small samples of venous blood. Science, 155, 86. Lake, B. D. (1965). A reliable, rapid screening test for sulphatide et al., 1969). This may be suspected not only lipidosis. Archives of Disease in Childhood, 40, 284. from the clinical picture but also from the slowing Lake, B. D. (1968). Segmental demyelination of peripheral nerves of nerve conduction, and a specimen suitable for in Krabbe's disease. Nature (London), 217, 171.

Lake, B. D., Stephens, R., and Neville, B. G. R. (1970). Syndrome on September 26, 2021 by guest. Protected both histochemical and ultrastructural study can of the 'sea-blue histiocyte'. Lancet, 2, 309. be obtained just behind the lateral malleolus. In Leroy, J. G., Spranger, J. W., Feingold, M., Opitz, J. M., and Crocker, A. C. (1971). I-cell disease: a clinical picture. metachromatic leucodystrophy the characteristic Journal of Pediatrics, 79, 360. staining reaction can usually be shown easily if there Pampiglione, G. (1961). E.E.G. in some inborn errors ofmetabolism. VIIth International Congress of Neurology, Rome, September is evidence of electrical abnormality. 1961, Vol. 1, p. 53. Soc. Graf. Romana, Rome. Also abst. In hypertrophic interstitial neuritis, the distinc- in Excerpta med. int. Congr. Ser., 39, 2. will the disease Patrick, A. D. (1965). A deficiency of glucocerebrosidase in tive onion-skin appearance identify Gaucher's disease. Biochemical Jrournal, 97, 17c. before clinical evidence of nerve hypertrophy is Porter, M. T., Fluharty, A. L., Harris, S. E., and Kihara, H. (1970). discovered, but the condition can be surmised The accumulation of cerebroside sulfates by fibroblasts in culture from patients with late infantile metachromatic leuko- without biopsy in Refsum's disease, if increased dystrophy. Archives of Biochemistry and Biophysics, 138, 646. phytanic acid concentration is shown in plasma. Schneck, L., Friedland, J., Valenti, C., Adachi, M., Amsterdam, D., and Volk, B. W. (1970). Prenatal diagnosis of Tay-Sachs disease. Lancet, 1, 582. Siemerling, E., and Creutzfeldt, H. G. (1923). Bronzekrankheit In summing up it is acknowledged that, indivi- und sklerosierende Encephalomyelitis. Archiv fur Psychiatrie dually, the conditions mentioned here are rare, and und Nervenkrankheiten, 68, 217. Arch Dis Child: first published as 10.1136/adc.47.252.163 on 1 April 1972. Downloaded from

170 John Wilson Sloan, H. R. (1970). Tissue culture studies in the lipid storage Tondeur, M., Vamos-Hurwitz, E., Mockel-Pohl, S., Dereume, disorders. Chemistry and Physics of Lipids, 5, 250. J. P., Cremer, N., and Loeb, H. (1971). Clinical, biochemical, Sloan, H. R., Uhlendorf, B. W., Jacobson, C. B., and Fredrickson, and ultrastructural studies in a case of chondrodystrophy D. S. (1969). 3-galactosidase in tissue culture derived from presenting the I-cell phenotype in tissue culture. Journal of human skin and bone marrow: enzyme defect in GM1 ganglio- Pediatrics, 79, 366. sidosis. Pediatric Research, 3, 532. Wiesmann, U., and Neufeld, E. F. (1970). Scheie and Hurler Spranger, J. W., and Wiedemann, H. R. (1970). The genetic syndromes: apparent identity of the biochemical defect. mucolipidoses. Neuropddiatrie, 2, 3. Science, 169, 72. copyright. http://adc.bmj.com/ on September 26, 2021 by guest. Protected