Arch Dis Child: first published as 10.1136/adc.47.252.163 on 1 April 1972. Downloaded from Review Article Archives of Disease 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 diseases 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 spinal muscular atrophy 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