Develop. Med. Child Nrurol. 1974, 16, 228-241
Revision Article M. J . Noronha
Cerebral Degenerative Disorders of - Infancy and Childhood
Introduction The classification and terminology of the
progressive cerebral degenerative disorders present certain problems. It had been traditional to divide them into the neuro- lipidoses and the leucodystrophies, this having had the deceptive virtue of sim- plicity. However, recent advances conse- quent on newer histological and bio- chemical techniques have made the distinc- tion between the two groups and other associated disorders less certain. Two leucodystrophies. metachromatic and Krabbes globoid cell, are now known to be disorders of sphingolipid metabolism and are accordingly classified with the neurolipidoses. On the other hand, in Battens disease-which was previously classified with the amaurotic family idiocies -no abnormality of sphingolipid meta- bolism has so far been demonstrated. there- fore it cannot be included with the sphingolipidoses. Further, it is now known that some of the mucopolysaccharide disorders, e.g, Hunters and Hurlers disease, also show an excess of sphingo- lipid in the stored neuronal material as we11 as the accumulated mucopolysaccharide.
OBrien (1970) has suggested that there are four levels of sophistication to be distinguished in the elucidation of inborn errors of metabolism.
( I ) The phenotypical delineation of the disorder from the clinical, pathological and genetic points of view. (2) The identification of the compounds of which metabolism is deranged. ( 3 ) The determination of the enzymic or structual protein defect which is the pathogenetic key-stone. (4) The determination of the nature of the enzymatic or structural protein abnorm- ality, e.g. reduced hydrolytic activity, in- creased rate of degradation or depressed synthesis either because of operator gene mutation or because of activity change in a repressor gene.
From the clinicians point of view, OBrien suggests that the diagnosis should extend to levels 1 and 2, as the clinician is neither trained nor required to become fully conversant with the chemical and molecular biological complexities, i.e. levels 3 and 4.
Accordingly, on clinical and patho- logical grounds it is possible to divide cerebral degenerative disorders into two broad groups : those affecting primarily the neurone (grey matter), resulting in the accumulation within it of enlarged or numerically increased lysosomes--the neuronal storage diseases: and those in which the metabolic defect affects predom- inantly the myelin sheath (white matter).
Royal Manchester Childrens Hospital and Booth Hall Childrens Hospital, Manchester.
M. J. NORONHA
Grey-matter disease is usually character- ised early on by impairment of neuronal function. This may manifest itself clinically in infancy and early childhood as a slowing and then arrest of the acquisition of skills, linguistic and physical, before there is obvious regression. In older children, deteriorating school performance-often associated with behaviour problems and dementia-is a common presenting feature. Epileptic seizures are almost invariable, but less common is progressive visual failure due to retinal involvement. Pyramidal tract signs usually occur as a late feature.
White-matter disease, on the other hand, is characterised by a different course, since the tracts are initially involved. Early symptoms are motor rather than intellectual deterioration, and they are characterised by spasticity, ataxia, hyper- reffexia and a positive Babinski sign. Epileptic seizures and dementia occur as a late feature, whilst visual disturbance is due to optic nerve or optic tract involve- ment.
Grey Matter or Neuronal Storage Diseases The vast majority of the recognised de-
generative diseases of grey matter involve the accumulation of material within neurones. In some, the material is a sphingolipid (gangliosides are highly com- plex sphingolipids), mucopolysaccharide, glycogen or other substance (Table I). The neuronal storage or abnormal material sooner or later results in many neurones perishing, and their loss is accompanied by atrophy and gliosis of the tissue. The intensity and extent of the involvement vary widely, but as a general rule, the earlier the onset, the more widespread the neuronal involvement and the more rapid the course of the disease.
GM, Gaizgliosidoses (Generalised Gangliosidosis)
In this disease there is a generalised storage of ganglioside GM, consequent on an enzyme deficiency of GM, J-galactosi- dase. Two clinical types are described. Type I, or Znfantile-generalised ganglio-
TABLE I Classification of neuronal storage diseases
Accumulation of ganglioside
Accumulation of other sphingo- lipids
Accumulation of other substances
Chemical name or eponym
Generalised Tay-Sachs Neurovisceral
Gaucher (acute infantile)
leucodystrophy Krabbes globoid
Pompe Ceroid lipofuscinosis :
Kufs Mucopolysaccharidoses :
Hunter Hurler Sanfillipo
GM, ganglioside GM, ganglioside GM, ganglioside
Sphingomy elin Cerebroside sulphate
Glycogen Ceroid and lipofuscin
MPS and ganglioside
Mucopolysaccharides and glycolipids
P-galactosidase A, B, C Hexosaminidase A, B P-galactosidase
Sphingomy elinase Cerebroside sulphatase
(arylsulphatase A) Galactocerebroside
Lysosomal acid hydro- lases, P-galactosidase
m-fucosidase a-mannosidase a-lysosomal hydrolases
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1974, 16
sidosis in which there is a total deficiency of J-galactosidase isoenzymes A, B and C. Onset is at birth or early infancy and con- sists of hypotonia and hypoactivity, with facial and peripheral oedema. Facial features and skeletal changes resemble those seen in Hurlers syndrome. The corneas are clear and a cherry-red spot at the macula region occurs in 50 per cent of patients. Hepatosplenomegaly is usual Mental and motor retardation occur and death is usual between six months and two years. Tiyc I I , or Lare Il!fantilc-generalised gangliosidosis in which there is a total deficiency of J-galactosidase B and C. Onset is usually in the second or third year of life and is characterised by mental and motor retardation. Cerebellar and striatal signs may be present and seizures may develop. After the second year of the ill- ness, deterioration is rapid and leads to a severe decorticate state. Hepatospleno- megaly is absent and skeletal changes usually do not occur. Survival beyond five years of age is rare.
G M , Gangliosidoses (Tay-Sachs Disease) In this disease there is storage of
ganglioside GM, in neurones and in viscera, due usually to a total or partial deficiency of hexosaminadase A and/or B. Three clinical types have been described. I/?fatitile. Onset usually is within the first six months of life and the first sign is an abnormal and excessive startle reaction to sound. Retardation of growth and develop- ment occur first, followed later by motor regression and dementia. Seizures of various types occur. Muscle weakness and hypotonia are present initially but are later replaced by spasticity. hyperreflexia and contractures. A cherry-red spot at the macula is usual and optic atrophy leads to blindness. Megalencephaly is common. Death usually occurs by the fourth year. Lrrtc, I/$mti/e. Onset is between one and
two years of life. Epileptic seizures occur early and are associated with an excessive startle reaction, progressive motor loss and dementia. A cherry-red spot and optic atrophy may be seen. Death usually occurs between the ages of four and 10 years. Juvenile. Onset is between four and five years and is characterised by dementia, speech loss and fits of various types. There may also be pyramidal, cerebellar and striatal signs and optic atrophy is usual later. Death occurs in the mid-teens.
G M , Gangliosidosis This condition is extremely rare and very
few of the patients described have been studied in detail. Clinically, the patients have developed mental retardation and hepatosplenomegaly and examination of the cortex has shown an excess of GA,, GM, and GM, gangliosides (Pilz et al. 1966). The defect appears to be a deficiency of J-galactosidase (Raine 1970).
Gaudiers Disease Cerebral involvement only occurs in the
acute or infantile variety, and is character- ised by the storage of glucocerebroside in neurones and the reticulo-endothelial system. The enzyme deficiency is gluco- cerebrosidase.
Onset usually occurs by the fourth month and is characterised by failure to thrive, hepatosplenomegaly and anaemia. There is regression of development and the infant becomes apathetic and fretful. Pyramidal signs result in a spastic quadri- paresis and in progressive bulbar palsy with swallowing difficulties. Fits are un- common. Death usually occurs in the second year of life.
Sphirigoni~eliiiosis (Niemann-Pick Disease) This group is characterised by the accu-
mulation of sphingomyelin intracellularly and this may occur in most cells throughout
M. J. NORONHA
the body. At least four types have been described and they can be distinguished into cases with and without cerebral in- volvement (visceral and cerebral forms).
The infantile form, with cerebral in- volvement, is the most common and typical expression of Niemann-Pick diseas