Metachromatic Leukodystrophies

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The metachromatic leukodystrophies (see TabJe.,.30-6 ), also known as sulfatide lipidoses, are a group of lysosomal storage disorders recognized by the accumulation of excessive amounts of sulfatide. The term metachromatic, as a description of the diseases, derives from the staining properties of the stored lipid sulfatides, which develop a brown or gold hue with toluidine blue rather than the usual blue of myelin. The enzymatic defect involves arylsulfatase-A or cerebroside sulfatase-A. A heat-stable nonenzymatic protein activator is also necessary for the hydrolysis of the sulfatide. The sulfatide is stored in lysosomes of neuronal white matter as well as in other somatic tissues, giving rise not only to signs of the disease in the central and peripheral nervous systems but also to disease in other organs and tissues such as the kidneys, pancreas, adrenal glands, liver, and gallbladder. y

In the classic form of metachromatic leukodystrophy, sulfatide content in the white matter is four to eight times that found in normal controls. [8 There are three isoenzymes for arylsulfatase, A, B, and C. Decreased arylsulfatase-A activity is present in the late infantile, juvenile, and adult forms of the syndrome. y In another condition, multiple sulfatase deficiency, which is often considered a mucopolysaccharidosis, activity of both arylsulfatase-A and -B is markedly reduced.

Epidemiology and Risk Factors. All forms of meta- chromatic leukodystrophy are inherited as autosomal recessive traits. Carriers are identified by white cell or fibroblast arylsulfatase determinations using either natural or artificial substrates. They have levels of arylsulfatase that vary from 25 to 50 percent of normal. Heterozygotes have approximately ten times more enzyme activity than patients. According to these assays, the disorders are apparently universal in geographical distribution and have no gender, racial, or ethnic preferences.

Clinical Features and Associated Findings. The late infantile form of metachromatic leukodystrophy usually begins between the ages of 18 and 24 months of age, although onset may occasionally be delayed until as late as age 4 years. y , y These children develop a gait disturbance that may appear as ataxia or weakness. y Hypotonia is very prominent during this time. At times, abnormalities in the macula resembling the cherry-red spot may be present. y Thereafter, a rather rapid decline continues over a period of 6 months or more until steady regression persists and bulbar signs become apparent. The hypotonia becomes much worse as the disease continues, and weakness dominates during these phases. Intellectual deterioration occurs reasonably rapidly over a 6- to 12-month period. By the terminal stage, hypotonia has reverted to hypertonia and frank spasticity. Involuntary movements are obvious. Another characteristic of the classic form that distinguishes it from other forms of metachromatic leukodystrophy is the presence of megalencephaly, although this finding is not as striking as it is in the gangliosidoses or in Alexander's and Canavan's syndromes.

A peripheral neuropathy may exist even in the early stages of this disease when absence of reflexes or hyporeflexia is evident. This is a result of peripheral segmental demyelination and the deposition of sulfatide within the nerve fibers. As the CNS sulfatide deposits increase with disease progression, one can account for the turn-around in muscle tone. The hypotonia is first accentuated because of suprasegmental shock influences. These in turn are altered when suprasegmental release occurs. This is the switching point of the change from clinical hypotonia to clinical hypertonia and its associated phenomena. Patients with the classic form often die by 8 to 10 years of age. Yet other patients reach a vegetative trough and live well into their teens. By this time, such patients are indistinguishable from those with the later-onset forms of the disease.

Onset in the juvenile form occurs between 4 and 10 years of age. The majority of patients show the first symptoms during their early years at school. The first observed symptoms are usually bradykinesia and poor school performance. In the very early periods, daydreaming, confusion, and emotional lability are frequently reported. Unsteadiness of gait, usually because of pyramidal tract involvement, may be noted. Extrapyramidal dysfunction such as postural abnormalities and tremor may develop. Myotactic reflexes are usually increased even in the early stages. The rate of deterioration is usually slow and is much more variable than that of the late infantile form of the syndrome. Patients often are not bedridden even 5 to 10 years after the initial symptoms appear.

In this form usually early motor findings such as spastic gait and ataxia may be the most prominent symptoms; they are secondary to intellectual impairment. There is little tendency for hypotonia to appear. When it is manifest, a greater degree of peripheral neuropathy is evident, although even then brisk reflexes and extensor toe signs are frequently present. In spite of this, nerve conduction times are decreased. Dementia occurs but is slower to develop than in the late infantile form. Decerebrate posturing and generalized convulsions occur, perhaps more frequently than in the late infantile syndrome. When the late infantile form is subacute, the juvenile form is chronic, and patients usually live for 20 years or longer.

Onset of the adult form occurs at any time after puberty. Initial symptoms consist of the personality and mental changes that signal impending dementia. Such symptoms are often misdiagnosed as schizophrenia or manic depressive illness. There are usually no clinical signs of peripheral neuropathy. Disorders of movement and posture appear later. Frank dementia becomes the central feature, occurring most frequently by the third or fourth decade of life. Often these mental symptoms in the adult are accompanied by progressive corticobulbar, corticospinal, and cerebellar changes. Visual and somatosensory evoked

potentials are delayed. Even in this form, nerve conduction velocities are markedly lowered.

Differential Diagnosis. Many variants of metachromatic leukodystrophy as well as other conditions should be considered in the differential diagnosis. Among these are multiple sulfatase deficiency that is not associated with striking leukodystrophy. Also, several subtypes in which there is no clear demonstration of a deficiency in the enzyme but in which there is a defect in the activator protein should be considered. Additionally, all leukodystrophies should be entered in the differential diagnosis. Consideration of other leukodystrophies depends on their phenotypic expression as well as a variety of peripheral neuropathies without prominent central nervous system symptoms. Since manifestations include seizures, dementia, and motor failure, any disorder showing these abnormalities must be considered.

Evaluation. Spinal fluid protein concentration is usually moderately elevated, with concentrations in the 150 to 300 mg/100 ml range. There are no qualitative abnormalities in the protein profile. Demonstration of a deficiency of arylsulfatase-A activity either in urine or in leukocytes confirms the diagnosis in the majority of cases. Decreased gallbladder function may be detected by a simple cholecystogram or ultrasonography examination and may be a useful adjunct in the workup. The presence of metachromatic granules in the urine is of some help and gross inspection of an office urine sample can be suggestive of the diagnosis. Brain stem, auditory, visual, and somatosensory evoked responses show some abnormalities, but the results are variable. The most consistent finding is the characteristic decreased nerve conduction velocities found in almost all forms of metachromatic leukodystrophy.

Management. Promotion of enzymatic activity in the nervous system in patients with metachromatic leukodystrophy has been attempted by means of intravenous infusion of beef brain arylsulfatase-A. This has not produced any obvious benefits. Bone marrow transplantation in patients with late infantile metachromatic leukodystrophy has reportedly arrested the motor and intellectual deterioration. The effectiveness and safety of this therapy need further evaluation.

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