The leucodystrophies are a group of disorders, originally described on the basis of their non-inflammatory demyelinating neuropathology and including an heterogeneous collection of conditions, many of which are now known to result from specific defects affecting genes that determine the synthesis, maintenance, and structure of myelin. Other disorders originally classified as leucodystrophies have specifically different aetiologies and are no longer included in the group. These are rare conditions even in paediatric practice, but need to be considered in young adults with atypical syndromes combining physical and intellectual deficits, with or without peripheral nerve involvement, in whom imaging shows more confluent lesions confined to white matter.
No attempt is made comprehensively to cover this miscellaneous group of predominantly paediatric developmental and neurodegenerative disorders, but readers are referred to the full clinical, biochemical, and beautifully illustrated imaging descriptions given by van der Knaap and Valk (1995) and other definitive accounts (Moser 1997). Here, the emphasis is mainly on those disorders that may be seen in adult neurological practice and their childhood forms.
Diffuse sclerosis (Schilder's disease)
Earlier editions of this book described, as diffuse sclerosis or Schilder's disease (Schilder 1912), a condition in which a previously healthy child between the ages of 5 and 12 years developed intellectual impairment and a gait disorder. The onset was occasionally rapid but usually insidious. Headache and giddiness occurred, but fever was exceptional. Visual impairment was often an early symptom and sometimes preceded by mental deterioration, epileptic attacks, aphasia, or weakness and incoordination of the limbs. Visual failure was usually due to destruction of the optic radiations. Homonymous hemianopia occurred when one occipital lobe was first involved, but the remaining visual field was gradually lost as the pathological process spread, and the end result was blindness in most cases. Visual impairment was less often due to bilateral retrobulbar neuritis causing central scotomas. In these cases, disc swelling in the acute stage was followed by optic atrophy. Acute widespread demyelination sometimes caused cerebral oedema, raised intracranial pressure, and papilloedema. Diplopia was usually due to lateral rectus paralysis and accompanied by nystagmus more often than third nerve palsy. Loss of smell and taste, deafness, and tinnitus were described.
The children then developed progressive spastic weakness of the extremities, leading eventually to spastic tetraplegia. Sensory loss of cortical type was common, with loss of postural sensibility, appreciation of passive movement, and tactile discrimination, but cutaneous sensation could also be involved, producing hemi-analgesia. Aphasia was noticeable in the early stages; later, this was masked by spastic dysarthria, and dysphagia due to pseudobulbar palsy eventually supervened. The mental changes were those of progressive dementia. Generalized or focal motor seizures were seen at any stage.
The early onset of blindness with progressive dementia and spastic paralysis was considered to constitute a distinctive clinical picture. This could be confused with intracranial tumour when the symptoms and signs were predominantly unilateral and especially if there was papilloedema. The disease was almost invariably progressive and usually fatal, although temporary remissions and, very rarely, arrest or recovery did occur. It ran an acute course, leading to death within 1 or 2 months. Few patients survived more than 3 years from onset but life occasionally was prolonged for several years.
In describing this condition, we use the past tense because it has since become clear that the term ‘diffuse cerebral sclerosis’ has been used to identify a heterogeneous group of diseases affecting cerebral white matter. Not all have turned out to be genetically determined disorders of myelin formation and metabolism. Thus, of the diseases originally classified under this heading, familial sudanophilic diffuse sclerosis, Pelizaeus - Merzbacher disease, Krabbe's diffuse sclerosis (globoid cell leucodystrophy), Canavan's diffuse sclerosis (spongy degeneration of the white matter), Alexander's disease, and metachromatic leucodystrophy are all dysmyelinating leucodystrophies. Conversely, Binswager's subcortical encephalopathy is a consequence of diffuse cerebral arteriosclerosis—although the provocative suggestion has since been made that this was an early example of CADASIL (Dichgans et al. 1998); and Balo's concentric sclerosis is considered within the spectrum of multiple sclerosis. Many male cases previously classified as having diffuse sclerosis were probably suffering from adrenoleucodystrophy. Some of the relapsing disorders were almost certainly examples of Leigh's disease associated with mutations of mitochondrial DNA. An extreme interpretation is that diffuse sclerosis was never anything more than an exceptionally severe and generalized variety of childhood multiple sclerosis.
Relatively simple investigations have proved useful in distinguishing some of these childhood encephalomyelopathies. Electroencephalography is of considerable value in making the distinction from subacute sclerosing panencephalitis and the lipidoses; it usually shows diffuse slow activity which is unlike the recurrent bizarre complexes of subacute sclerosing panencephalitis or the irregular spike and wave discharges that characterize Tay–Sachs disease. Imaging demonstrates extensive areas of low attenuation in the white matter of both cerebral hemispheres but these are not specific. Even after separating these specifically different conditions, the nosological status of diffuse sclerosis remains uncertain and some experts consider that, between them, acute multiple sclerosis and adrenoleucodystrophy account for all the cases (Lassmann 1998).
Globoid cell leucodystrophy usually presents during early infancy, and late onset is uncommon—almost all cases present before the age of 5 years and so are almost never confused with (childhood) multiple sclerosis. Grewel et al. (1991) describe the onset in a boy of 14, not finally diagnosed until the age of 24 years. The clinical picture is dominated by behavioural changes with light and noise startle, progressive intellectual and motor decline, with pyramidal, extrapyramidal, and cerebellar involvement, and epilepsy, visual failure, and peripheral neuropathy leading to severe disabilities with pyrexia and other autonomic features prior to the onset of a vegetative state. Visual evoked potentials are delayed and the spinal fluid has a raised protein but does not contain oligoclonal bands. Magnetic resonance imaging shows periventricular lesions and subsequently extensive white matter changes.
Examination of peripheral blood leucocytes or skin fibroblasts shows a deficiency of α-galactocerebrosidase which leads to the accumulation of cerebroside in phagocytes, resulting in the diagnostic feature of globoid cells; these represent the end stage of oligodendrocyte and myelin degradation triggered by psychosine accumulation. Although myelinating cells in the central and peripheral nervous systems are each affected, there seems to be differential susceptibility of oligodendrocytes and Schwann cells.
The biochemical characterization of a peroxisomal defect separated adrenoleucodystrophy from the other dysmyelinating disorders, although the X-linked pattern of inheritance had always been a distinctive feature. There are several types, each characterized by the accumulation of very-long-chain saturated fatty acids (VLCFAs) in all lipid-containing tissues and body fluids (Moser et al. 1981). The various disorders arise from defective very-long-chain fatty acyl coenzyme-A synthetase activity in peroxisomes (Wanders et al. 1988) and lead to the accumulation of membrane-like cytoplasmic inclusions in brain tissue. One hypothesis is that the protein product of the adrenoleucodystrophy gene normally anchors very-long-chain fatty acids into the peroxisomal membrane or translocates these into peroxisomes. The diagnosis may also be made by ultrastructural examination of nerve biopsied from the skin or conjunctiva which show typical curved clefts and leaflets in Schwann cells. Four related syndromes share this biochemical abnormality: childhood adrenoleucodystrophy and adult-onset adrenomyeloneuropathy are sex linked, whereas neonatal adrenoleucodystrophy and Zellweger's syndrome are autosomal recessive disorders (Moser 1997). About 25 per cent of cases are of adult onset with a progressive myelopathy developing in the third or fourth decade.
X-linked adrenoleucodystrophy may present in childhood with behavioural disturbance, dementia, and epilepsy, followed by involvement of the special senses and motor systems and leading to total disability within the first decade. Even though this is a dysmyelinating leucodystrophy, the aggressive childhood cases may show inflammatory demyelination with confluent symmetrical magnetic resonance imaging and spectroscopic (N-acetyl aspartate reduced and choline increased) abnormalities. The proposal is that VLCFAs trigger the inflammatory response which is mediated by TNF-α produced by activated microglia. Although a significant proportion of children later develop adrenal insufficiency, Addison's disease may precede the neurological manifestations by several years. Treatment has been proposed with a dietary supplement containing a 4 : 1 mixture of glyceryl trioleate and trieructate, popularly known as Lorenzo's oil. This lowers the plasma levels of VLCFA but appears not to influence the phenotype in individuals with established neurological disease, although there may yet be role in prophylaxis. Bone-marrow transplantation is successful in early symptomatic cases and, in view of the inflammatory reaction, trials of immunosuppression are in progress (reviewed by Moser 1997).
X-linked adrenomyeloneuropathy presents in adult men with spastic paraparesis and sensory loss in the legs; although clinicians may be alerted to unusual causes for this otherwise common neurological problem by the presence of peripheral nerve involvement, the diagnosis may be overlooked if adrenal insufficiency is not clinically or biochemically apparent at the time of presentation and unless VLCFAs are assayed. Some patients show a progressive cerebellar phenotype and intellectual function may be impaired with a subcortical pattern of dementia. The clinical phenotypes of childhood and adult adrenoleucodystrophy, which are usually quite distinct, may both be seen in the same family (Elrington et al. 1989). The availability of a biochemical assay that reliably identifies the peroxisomal defect in easily sampled body tissues or fluids, has inevitably led to the demonstration of cases with obscure clinical manifestations; these include focal cerebral lesions with imaging abnormalities, the Kluver–Bucy syndrome, dementia, spinocerebellar degeneration, and olivopontocerebellar atrophy. About 20 per cent of female heterozygotes develop relatively mild, and occasionally remitting, spastic limb weakness and sensory loss, but cerebellar involvement is rare, as is cerebral or adrenal involvement; the age of onset is usually in the fourth or fifth decade. A higher proportion of manifesting carriers have neurological signs without clinical disabilities. Although adrenal disease is almost never present in carriers, VLCFAs are usually elevated and brain imaging or measurement of the auditory-evoked brainstem responses may help in diagnosis of the carrier state (O'Neill et al. 1983). The spinal fluid is usually normal, although oligoclonal bands have been described, and white matter lesions are occasionally seen on magnetic resonance imaging (Ménage et al. 1994). Such cases may first be diagnosed as having multiple sclerosis, but the symmetry of the lesions and their diffuseness (even if predominantly placed posteriorly in the early stages) differ from the usual findings in multiple sclerosis. The correct diagnosis can be established on the family history and by finding an excess of VLCFAs in plasma or fibroblasts. Adrenal failure may precede neurological involvement or present as X-linked Addison's disease without nervous system involvement (Josien et al. 1993). Biochemical abnormalities include reduced urinary excretion of 17-hydroxycorticosteroids and 17-oxysteroids, with impaired response to corticotrophin but high basal levels; there may be associated androgen deficiency. All racial groups are affected by the sex-linked adrenoleucodystrophies and the gene has been mapped to the region of Xq28, close to that for glucose 6-phosphate dehydrogenase deficiency and colour blindness (Aubourg et al. 1990). It encodes a peroxisomal membrane protein (now known as ALD protein) belonging to the ATP-binding cassette protein family.
Autosomal recessive adrenoleucodystrophy
Autosomal recessive adrenoleucodystrophy presents in infancy with seizures, hypotonia, retardation, retinal degeneration, and hepatic involvement; females are more commonly affected than males. The pattern of organ involvement and mode of inheritance are similar in neonatal adrenoleucodystrophy and Zellweger's syndrome but these are thought to be separate disorders. These X-linked recessive disorders can produce a clinical picture which mimics multiple sclerosis; the distinction is most reliably made on the basis that affected patients have or subsequently develop the clinical and biochemical manifestations of
The sensitivity and specificity of routine assaying of VLCFAs has been reviewed (Moser et al. 1999): together, the level of hexacosanoic acid and its ratios to tetrasanoic and docosanoic acids are fully discriminating in homozygote males, irrespective of the clinical phenotype, from the day of birth, if dietary supplements have not been given, providing an opportunity for mass screening; there is a false negative rate of 15 per cent for heterozygotes.
The separation of metachromatic leucodystrophy from the heterogeneous group of diffuse sclerosis was first made when metachromatic material was detected in urinary deposits (Austin 1957). It subsequently became clear that the diagnosis can be confirmed by demonstrating increased urinary sulphatide excretion with a deficiency of arylsulphatase A in urine, peripheral blood leucocytes, and skin fibroblasts, or by the demonstration of metachromatic material in peripheral nerve biopsies which show segmental demyelination and remyelination. There is diffuse white matter involvement due to non-inflammatory demyelination with loss of oligodendrocytes, axon preservation, and reactive astrocytes which, together with macrophages, contain the metachromatic material, especially in the most extensively demyelinated areas.
The gene for arylsulphatase A is encoded on chromosome 22 and the clinical phenotype varies with the amount of surviving enzyme, depending on heterozygosity of the mutant allele; pseudo-deficiency refers to those individuals with low but sufficient levels of arylsulfatase A who do not have a clinical phenotype. Some affected individuals have a genetic defect of the arylsulphatase A activator (encoded on chromosome 10) and this is associated with a more complex pattern of sphingomyelin storage, biochemically and in terms of the tissue distribution. The most common form of metachromatic leucodystrophy develops in late infancy, with delayed walking and other motor milestones, due to the neuropathy which may be painful. There are also features of brainstem involvement and the emergence of diffuse upper motor neuron signs with reduced intellectual development, optic atrophy, and death within about 5 years from presentation. In older-onset childhood cases, after several years of normal development, there are behavioural changes with poor school performance, ushering a cerebellar and upper motor neuron pattern of disability which then follows much the same course as in the younger cases, although with less evidence for neuropathy. The early adult form of metachromatic leucodystrophy is rare, or perhaps seldom diagnosed, and tends to present with intellectual or emotional abnormalities; as with many other inherited disorders, onset after the age of 60 years has been described. Onset with dementia and behavioural disorders is usual, with ataxia, paralysis, and optic atrophy only developing at late stages, although the presentation is occasionally with paraparesis or cerebellar ataxia (Hageman et al. 1995) and the condition can then more easily be mistaken for multiple sclerosis. Clinical evidence for peripheral neuropathy may be revealed by slowed nerve conduction. The full range of clinical manifestations has probably not yet been fully explored. For example, Sadeh et al. (1992) describe an apparently unique case with a relapsing - remitting course; more usually, the disorder is progressive with steady decline into dementia or persistent vegetative state. Treatments have included dietary manipulation with reduced vitamin A and sulphur-containing substances, and bone-marrow transplantation, but the successes are limited.
Multiple sulphatase deficiency combines the features of metachromatic leucodystrophy with mucopolysaccharidosis. It, too, has neonatal, early childhood, and juvenile forms. The pattern of combined motor and mental regression or lack of development reflecting widespread dysmyelination with peripheral neuropathy is associated with dysmorphic features and organomegaly. The more severe phenotype also reflects extensive neuronal loss due to the combination of stored sulphatide, sulphated steroids, and mucopolysaccharides. The enzyme defects are complex, involving many sulphatases other than arylsulphatase A.
The three phenotypes of X-linked Pelizaeus–Merzbacher disease usually present in childhood. The clinical features which may distinguish the otherwise ubiquitous motor and developmental delay with epilepsy are abnormal eye movements, dystonia and choreoathetosis, and laryngeal paralysis. Affected individuals often stabilize with severe disabilities and live into early adult life. In the earlier-onset group (connatal), either sex may be affected, with X-linked and autosomal pedigrees; the phenotype has many of the same features but the course is more accelerated. There are also transitional cases of intermediate prognosis. Some cases do not manifest until early adult life but here the blur with specifically different disorders becomes more apparent. Magnetic resonance imaging either fails to show myelin or depicts myelin which is immature with an atrophic brain.
The molecular defect is a mutation of the gene for proteolipid protein (PLP: encoded on X-q21.2) and, in severe cases, this leads to extensive loss of myelin in the central nervous system, with patchy depletion of oligodendrocytes and axons. Proteolipid protein is normally involved in stabilizing the lamellar structure of central myelin. Biochemically, there is a reduction in sulphatide and cerebroside. Over 30 mutations have been described, and novel ones are still being identified, resulting in expression of truncated forms of PLP sufficient to cause extensive oligodendrocyte loss and failure of myelination (Aoyagi et al. 1999), but no one can be detected in most patients. Osaka et al. (1999) found causative mutations in 6 members of 27 families, and correlated severity of the phenotype and closely related X-linked hereditary spastic paraplegia (in which the closely related myelin protein DM20 may substitute for PLP) with these defects. Because more severe genetic mutations of PLP and DM20 are sometimes associated with a relatively mild phenotype, one mechanism for the dysmyelination is an increase in toxicity of mutant PLP through metabolic exertion of the compromised myelinating oligodendrocyte. Almost certainly, another genetic defect explains the non-X-linked families.
Adult-onset dominant leucodystrophies
Forms of dominantly inherited leucodystrophy also occur exclusively in adults and may closely resemble chronic progressive multiple sclerosis (Eldridge et al. 1984; Schwankhaus et al. 1994). Magnetic resonance imaging shows diffuse, non-discrete, white matter disease and there are no oligoclonal bands in the spinal fluid. It remains uncertain whether all the adult-onset dominant leucodystrophies are one and the same disorder, and many are difficult to distinguish from the complicated hereditary spastic paraplegias and CADASIL. The various phenotypes are gradually being classified as their biochemical and genetic defects are characterized. Fukazawa et al. (1997b) described a family with spastic paraparesis, ataxia, and mild dementia, presenting in adulthood but with onset in childhood; diffuse white matter abnormalities were present on cerebral magnetic resonance, whereas pathognomonic features of the other leucodystrophies were absent. The most recent addition to this group involves two siblings with behavioural abnormalities progressing to dementia, with extensive white matter magnetic resonance abnormalities, in whom brain biopsy showed glycolipid inclusions in macrophages unlike any other lysosomal storage disease (Simon et al. 1998).