Metachromatic Leukodystrophy
This child presented to medical attention because of recurrent prolonged seizures; the two times he was seen in our institution were for management of status epilepticus. His parents reported several previous seizures, the first occurring at age three. They also indicated that he had psychomotor regression that became evident around the age of five or six. The differential diagnosis of progressive encephalopathies with onset after the age of two covers a variety of disorders including disorders of lysosomal enzymes (juvenile Tay-Sachs disease, Gaucher disease type III, late-onset Krabbe disease, aspartylglycosaminuria, mannosidosis type II, metachromatic leukodystrophy, mucopolysaccharidosis types II and VII, and Niemann-Pick type C), infectious diseases (AIDS encephalopathy, congenital syphilis, subacute sclerosing panencephalitis), other disorders of gray matter (ceroid lipofuscinosis, Heller syndrome, Huntington disease, mitochondrial disorders, and xeroderma pigmentosa), and other disorders of white matter (adrenoleukodystrophy, Alexander disease, cerebrotendinous xanthomatosis).
Several of the disorders that may be considered in the differential usually involve hepatomegaly, which was not evident in this case. These disorders include mucopolysaccharidosis types II and VII (Hunter syndrome and Sly disease), glycoprotein degradation disorders (aspartlyglycosaminuria and mannosidosis type II), Wilson disease, Niemann-Pick disease type C, and Gaucher disease type III. In addition, this child does not have the Hurler phenotype typical of Hunter syndrome or Sly disease, nor does his urine show mucopolysacchariduria. The glycoprotein degradation disorders would lead to oligosacchariduria, which was not found in this patient. This child showed no evidence of the cerebellar ataxia or dystonia that are initial features of Niemann-Pick disease type C. In Gaucher disease type III, hepatomegaly usually precedes neurologic deterioration. The most common neurologic manifestations are seizures and mental regression.
Neuroimaging is very important in the evaluation of progressive encephalopathies in children. This child underwent both a CT and MRI that demonstrated diffuse leukoencephalopathy. This appearance significantly limits the differential diagnosis. If the child had evidence of adrenal failure, the diagnosis would most likely be adrenoleukodystrophy. This disease is transmitted via X-linked inheritance. Affected children have an impaired ability to oxidize very long chain fatty acids because of a deficiency of peroxisomal acyl coenzyme A synthetase. Very long chain fatty acids accumulate in tissue and plasma, and are easily detected by routine screening of serum. Such testing was normal in this patient. Another leukodystrophy that must be considered is globoid cell leukodystrophy (late-onset Krabbe disease). This is caused by deficiency of the enzyme galactosylceramide beta-galactosidase. The defect is transmitted by autosomal recessive inheritance. Neurologic deterioration usually begins between the ages of two and six, including mental regression, cortical blindness, and spasticity. Of note, peripheral neuropathy is a feature of the infantile form, but is not typical of the juvenile form. Krabbe disease was not tested for in this patient, but the peripheral neuropathy evident in this patient, as well as the late presentation, makes this disease unlikely. Other primary leukodystrophies with a known metabolic defect include multiple sulfatase deficiency, Zellweger syndrome, Canavan-Van Bogaert disease, and Pelizaeus-Merzbacher disease. Primary leukodystrophies without a known enzymatic defect include sudanophilic leukodystrophies and Alexander disease. The very low leukocyte arylsulfatase A activity in this case strengthens the diagnosis of metachromatic leukodystrophy.
Nerve conduction velocities are low in three particular leukodystrophies because of marked demyelination involving peripheral nerves. These include metachromatic leukodystrophy, Krabbe disease (infantile form), and Cockayne disease. The latter is a disease in which progeric features, failure to thrive, and slowly progressive neurodevelopmental deficit become apparent from the second year of life. Ventricular dilatation and intracranial calcification are prominent features of Cockayne disease, but were absent in this patient.
Several other disorders in the differential diagnosis were unlikely for various reasons. The patient showed no retinal degeneration, a feature of subacute sclerosing panencephalitis (SSPE) and ceroid lipofuscinosis. Furthermore, his EEG did not demonstrate the characteristic pattern of periodic bursts of spike-wave complexes seen in SSPE. He did not have lactic acidemia or elevated pyruvate, a feature of the mitochondrial disorders. These levels may vary somewhat with diet, so normal levels in our patient would not entirely rule out a mitochondrial disorder, if there had been high clinical suspicion. A muscle biopsy or DNA testing could assist with the diagnosis of a mitochondrial disorder, if concern for such a process was raised.
Other diseases included in the differential of progressive encephalopathies with onset after age two include Heller disease and Huntington disease, but neither of these would be expected show changes of diffuse demyelination on MRI.
Metachromatic leukodystrophy (sulfatide lipidosis) is a lysosomal storage disease caused by the deficiency of the enzyme arylsulfatase A. The inheritance is autosomal recessive, and the incidence is estimated to be 1:40,000. Arylsulfatase A is involved in the degradation of sulfated glycolipids and one of its major substrates is cerebroside-3-sulfate. This lipid is mainly found in the myelin membranes, where it accounts for 3-4% of total membrane lipids. Arylsulfatase A initiates the degradation of this lipid by desulfation of a sulfated galactose residue. In this reaction, arylsulfatase A needs the assistance of a small acidic protein, which has been called sphingolipid activator protein, or saponin B. This protein solubilizes the hydrophobic lipid, so that it becomes accessible to catalytic action by arylsulfatase A. Deficiencies of the activator protein can cause a rare disease that is indistinguishable from metachromatic leukodystrophy.
Cerebroside sulfate accumulates in lysosomes and in the plasma membrane when arylsulfatase A is deficient. In affected patients, cerebroside sulfate may constitute up to 30% of total myelin membrane lipids. Although the storage occurs in all tissues, it only clinically affects the nervous system. It leads to progressive demyelination, which causes a variety of neurologic symptoms. In histological preparations, the accumulated sulfatides form spherical granules that stain metachromatically.
The disease is clinically heterogeneous. Three different forms can be distinguished depending on the age of onset: a severe late-infantile form starting between the ages of 1-3 years, a juvenile form with an age of onset of 3-16 years, and an adult form that may not become apparent before the third decade of life. The progression is slower in the late-onset forms and patients may survive for as much as 20 years after the disease has started. The late infantile form is the most common, accounting for about 2/3 of cases. After a period of normal development, gait disturbances develop, usually by two years of age. Initial examination shows distal weakness of the feet with loss of ankle reflexes. Progressive weakness of all limbs results in generalized hypotonia and hyporeflexia. Cerebral demyelination follows, causing dementia, spasticity, and blindness. CSF typically shows elevated protein in the infantile-onset MLD.
Juvenile- and adult-onset cases affect primarily the brain and are difficult to distinguish from each other. In juvenile MLD, the onset of symptoms is usually between 5-10 years, but may be delayed until adolescence or occur as early as late infancy. Despite this overlap with the infantile form, they differ in terms of clinical manifestations. In the juvenile form, no symptoms of peripheral neuropathy occur, progression is slow, and the protein content of the CSF may be normal. Mental regression, speech disturbances, and clumsiness of gait are the prominent initial features. Dementia usually progresses slowly over a period of 3-5 years, but may sometimes progress rapidly to a vegetative state. A delay of several years may separate the onset of dementia from the appearance of other neurologic disturbances. Ataxia may be an early and prominent manifestation. A spastic quadriplegia eventually develops in all affected children, and more than half experience seizures. A recent review suggested that generalized seizures are more frequent in patients with late-infantile onset, whereas partial seizures are more common in those with juvenile-onset disease. Death usually occurs in the second decade in those with juvenile-onset disease.
Adult MLD may begin at almost any age beyond puberty and has been reported in patients as old as 62. Survival from onset of disease is usually 5-10 years, but extended survival has been reported. Changes in personality and poor school or job performance herald the onset of the disease. The individual becomes anxious, apathetic, and emotionally labile. Defective visual-spatial discrimination, poor memory, disorganized thinking, and decreased mental alertness are common. Psychiatric care is frequently sought because of depression and psychosis.
Arylsulfatase A deficiency can also be observed in individuals who are clinically healthy, a phenomenon that has been termed pseudodeficiency. These individuals have only about 10-20% of normal enzyme activity, a level that appears to be adequate to prevent the manifestations of MLD. Pseudodeficiency is caused by homozygosity for an arylsulfatase A allele that owing to certain mutations supports the synthesis of reduced amounts of enzyme. An additional distinguishing feature is that pseudodeficient individuals do not have sulfatiduria. The frequency of this pseudodeficiency allele is estimated to be between 7-15%, which predicts that 0.5-2% of the population would be homozygous for this allele and thus pseudodeficient.
Cerebrospinal fluid protein may be elevated to about 100 mg/dL in late-infantile and juvenile MLD. In most patients with adult onset MLD, the CSF protein has been normal. The EEG findings may be normal early in the course of the disease. As the disease advances, the EEG becomes diffusely slow and increases in amplitude, exhibiting mainly 4-7 Hz activity. In a few cases, occasional bursts of spikes or of asymmetric slow wave activity have been recorded. In most patients, motor nerve conduction velocity is decreased and sensory nerve action potentials are diminished in amplitude with prolonged latency to peak. These nerve conduction abnormalities may be present before clinical symptoms appear and thus provide evidence of MLD in a presymptomatic stage. The most marked nerve conduction slowing is in late-infantile MLD.
CT of patients with MLD reveals a symmetric decrease in the attenuation of the cerebral white matter that does not enhance with contrast. MRI reveals a diffuse hyperintense signal in both the periventricular and subcortical white matter on T2-weighted images. The white matter lesions are slightly hypointense on the T1-weighted images. In the early stages, the arcuate fibers are spared.
The arylsulfatase A gene maps to chromosome 22 q13.31-qter, covers 3.2 kb of genomic DNA, and includes eight exons. It codes for a 507 amino acid protein, 18 of these representing a leading peptide, so that the mature enzyme consists of 489 amino acids. By now, at least 60 MLD-related arylsulfatase A mutations have been described. Occurrence and frequency of mutations differ within different ethnic groups. Two of the affected alleles (459+1G>A and P426L) have frequencies of about 25% each among MLD patients and thus account for about half of all MLD alleles, whereas all other mutations have only been found in a few or single patients.
Prenatal diagnosis has been repeatedly and successfully accomplished for the late-infantile and juvenile forms of MLD. The usual procedure is to determine the activity of arylsulfatase A in cultured amniotic fluid cells or cells grown from a chorionic villus sample. In any prenatal diagnosis it is important to establish whether the pseudodeficiency allele is also present in either parent.
Currently, there is no specific treatment that will halt the progression of MLD. The objectives in management of a patient with MLD are to maintain useful function and interaction as long as possible. Attempts have been made to reduce sulfatide synthesis by a diet low in vitamin A or low in sulfur. Unfortunately, neither of these approaches has had a favorable long-lasting effect. Drug therapy may include antiepileptics, or agents to help control spasticity. Attempts at enzyme replacement therapy have thus far been unsuccessful.
Bone marrow transplantation has been used to treat several dozen patients with MLD. Presymptomatic infants and children diagnosed on a biochemical basis (because of a diagnosis of MLD in a sibling) are likely to have the best outcome following BMT. The transplant process takes about a year to produce beneficial changes in the central nervous system. Thus, ideally a presymptomatic child should be transplanted at least one year before the age at which his sibling developed symptoms. The results of BMT in infantile MLD are conflicting, but in one case clinical stabilization occurred, and it was demonstrated that donor cells penetrated the central nervous system. Transplantation is indicated in juvenile forms of the disease. A recent report detailed the case of a child who had been symptomatic since age nine and was transplanted at age 16. During eight years of follow-up, he remained stable, with no further deterioration. Favorable results have also been reported for several patients with adult-onset disease who have undergone BMT. It is unclear how BMT may work. Transplant-derived lymphoid cells may enter the brain and liberate enough arylsulfatase A extracellularly to stop further neuronal death. Alternatively, other factors, including the medications used for maintenance of transplants, could also contribute to modification of the disease process.
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