Lysosomal Disorders Associated With Leukoencephalopathy
Metachromatic leukodystrophy is an autosomal recessive disorder associated with deficiency of arylsulfatase A and accumulation of 3-O-sulfogalactosylceramide (sulfatide) in oligodendrocytes, Schwann cells, and some neurons. Greater than 100 mutations in the arylsulfatase A gene have been described, mostly missense mutations. Genotype-phenotype correlation is difficult due to clinical variability, particularly in the juvenile and adult forms, and the large number of mutations. However, some prediction is possible based on the types of mutations. Patients homozygous for null alleles usually present with late-infantile disease. A null allele in combination with an allele with residual activity is usually seen in juvenile-onset patients, whereas two alleles with residual activity can be seen in either adult- or juvenile-onset patients. Arylsulfatase A pseudodeficiency, due to polymorphisms in the arylsulfatase A gene, is present in 0.2 to 0.5% of Caucasians resulting in decreased activity in vitro, but no clinical symptoms. Deficiency of the activator protein, saposin B, is a rare variant of metachromatic leukodystrophy. Arylsulfatase A deficiency can also be seen as a component of multiple sulfatase deficiency, a complex condition with symptoms of metachromatic leukodystrophy, mucopolysaccharidosis, and ichthyosis.
The most common clinical phenotype is the late-infantile form. Children present between 1 and 2 years of age, following a period of apparently normal early development, with hypotonia, weakness, and decreased deep tendon reflexes affecting gait. Spasticity then evolves followed by cognitive regression and decline in fine motor skills, due to a combination of spasticity and peripheral neuropathy. Optic atrophy and seizures occur late in the disease course. Death usually results from a respiratory or other infection. Patients with the juvenile form present with decreased school performance, change in behavior, and psychiatric symptoms between 3 and 16 years of age. Gross motor impairment and signs of peripheral neuropathy precede progressive spasticity and neurologic decline. Adult-onset patients usually show a slow decline in intellectual abilities over years accompanied by behavioral or psychiatric changes, memory difficulties, and signs of gait disturbance due to spasticity and peripheral neuropathy. Patients with all forms may have demyelination of the central nervous system, peripheral nervous system, or both at the time of presentation. Cholecystitis can be seen as a nonneurologic complication of metachromatic leukodystrophy.
MRI scans reveal confluent, symmetrical T2 hyperintensity in the periventricular white matter with sparing of the subcortical U fibers. The white matter changes tend to progress from the parietooccipital to the frontal regions in late-infantile cases ([Fig. 1]) and are frontally dominant in juvenile and adult-onset cases. Tigroid stripes, consisting of spared perivascular white matter, extend radially. In severe disease projection fibers, corpus callosum and cerebellum may show white matter changes. Atrophy is present late in the course due to white matter volume loss.
(Enlarge Image)
Figure 1.
Magnetic resonance images of a patient with late-infantile metachromatic leukodystrophy. (A) T1-weighted sagittal image, and (B) T2-weighted fast spin echo image demonstrating confluent, symmetrical abnormalities in the periventricular white matter with sparing of the subcortical U fibers, more prominent in the parietooccipital regions with tigroid stripes extending radially, consisting of spared perivascular white matter.
Diagnosis of arylsulfatase A is confirmed by the presence of low arylsulfatase A activity in leukocytes or skin fibroblasts in conjunction with increased sulfatide excretion in the urine. Patients with saposin B deficiency have normal arylsulfatase A activity (in vitro), but have increased sulfatide excretion in the urine. Patients with pseudodeficiency have decreased arylsulfatase A activity, but no excretion of sulfatide in the urine and can be confirmed by molecular analysis.
Treatment of metachromatic leukodystrophy is primarily symptomatic and supportive. Medications and physical therapy may be helpful for spasticity. Antiepileptic medications should be provided for seizures. Burning paresthesias from peripheral neuropathy may respond to medications for neuropathic pain. Hematopoietic cell transplantation can stabilize the central nervous system demyelination in patients with juvenile- and adult-onset forms of metachromatic leukodystrophy when performed early in the disease course, but is not beneficial in late-infantile-onset patients. Hematopoietic stem cell gene therapy trials for late-onset metachromatic leukodystrophy are currently underway.
Metachromatic Leukodystrophy
Metachromatic leukodystrophy is an autosomal recessive disorder associated with deficiency of arylsulfatase A and accumulation of 3-O-sulfogalactosylceramide (sulfatide) in oligodendrocytes, Schwann cells, and some neurons. Greater than 100 mutations in the arylsulfatase A gene have been described, mostly missense mutations. Genotype-phenotype correlation is difficult due to clinical variability, particularly in the juvenile and adult forms, and the large number of mutations. However, some prediction is possible based on the types of mutations. Patients homozygous for null alleles usually present with late-infantile disease. A null allele in combination with an allele with residual activity is usually seen in juvenile-onset patients, whereas two alleles with residual activity can be seen in either adult- or juvenile-onset patients. Arylsulfatase A pseudodeficiency, due to polymorphisms in the arylsulfatase A gene, is present in 0.2 to 0.5% of Caucasians resulting in decreased activity in vitro, but no clinical symptoms. Deficiency of the activator protein, saposin B, is a rare variant of metachromatic leukodystrophy. Arylsulfatase A deficiency can also be seen as a component of multiple sulfatase deficiency, a complex condition with symptoms of metachromatic leukodystrophy, mucopolysaccharidosis, and ichthyosis.
The most common clinical phenotype is the late-infantile form. Children present between 1 and 2 years of age, following a period of apparently normal early development, with hypotonia, weakness, and decreased deep tendon reflexes affecting gait. Spasticity then evolves followed by cognitive regression and decline in fine motor skills, due to a combination of spasticity and peripheral neuropathy. Optic atrophy and seizures occur late in the disease course. Death usually results from a respiratory or other infection. Patients with the juvenile form present with decreased school performance, change in behavior, and psychiatric symptoms between 3 and 16 years of age. Gross motor impairment and signs of peripheral neuropathy precede progressive spasticity and neurologic decline. Adult-onset patients usually show a slow decline in intellectual abilities over years accompanied by behavioral or psychiatric changes, memory difficulties, and signs of gait disturbance due to spasticity and peripheral neuropathy. Patients with all forms may have demyelination of the central nervous system, peripheral nervous system, or both at the time of presentation. Cholecystitis can be seen as a nonneurologic complication of metachromatic leukodystrophy.
MRI scans reveal confluent, symmetrical T2 hyperintensity in the periventricular white matter with sparing of the subcortical U fibers. The white matter changes tend to progress from the parietooccipital to the frontal regions in late-infantile cases ([Fig. 1]) and are frontally dominant in juvenile and adult-onset cases. Tigroid stripes, consisting of spared perivascular white matter, extend radially. In severe disease projection fibers, corpus callosum and cerebellum may show white matter changes. Atrophy is present late in the course due to white matter volume loss.
(Enlarge Image)
Figure 1.
Magnetic resonance images of a patient with late-infantile metachromatic leukodystrophy. (A) T1-weighted sagittal image, and (B) T2-weighted fast spin echo image demonstrating confluent, symmetrical abnormalities in the periventricular white matter with sparing of the subcortical U fibers, more prominent in the parietooccipital regions with tigroid stripes extending radially, consisting of spared perivascular white matter.
Diagnosis of arylsulfatase A is confirmed by the presence of low arylsulfatase A activity in leukocytes or skin fibroblasts in conjunction with increased sulfatide excretion in the urine. Patients with saposin B deficiency have normal arylsulfatase A activity (in vitro), but have increased sulfatide excretion in the urine. Patients with pseudodeficiency have decreased arylsulfatase A activity, but no excretion of sulfatide in the urine and can be confirmed by molecular analysis.
Treatment of metachromatic leukodystrophy is primarily symptomatic and supportive. Medications and physical therapy may be helpful for spasticity. Antiepileptic medications should be provided for seizures. Burning paresthesias from peripheral neuropathy may respond to medications for neuropathic pain. Hematopoietic cell transplantation can stabilize the central nervous system demyelination in patients with juvenile- and adult-onset forms of metachromatic leukodystrophy when performed early in the disease course, but is not beneficial in late-infantile-onset patients. Hematopoietic stem cell gene therapy trials for late-onset metachromatic leukodystrophy are currently underway.