Dysmyelinating diseases, or leukodystrophies, encompass a wide spectrum of inherited neuro-degenerative disorders affecting the integrity of myelin in the brain and peripheral nerves.
Most of these disorders fall into one of three categories – lysosomal storage diseases, peroxisomal disorders and disease caused by unknown metabolic defect. Each leukodystrophy has distinctive clinical, biochemical, pathologic and radiological features.
Leukodystrophies result from inherited enzyme deficiency that causes abnormal formation, destruction or turnover of myelin.
LYSOSOMAL STORAGE DISEASES
Metachromatic Leukodystrphy (MLD)
Metachromatic Leukodystrphy is the most common of all the familial leukodystrophies. It is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme arylsulfatase A. The accumulation of sulfatides within glial cells and neurons causes the characteristic metachromatic reaction. The name metachromatic is derived from the neuro-pathologic description of metachromatic staining which consists of a brownish or reddish colour compared with the blue colour of cell nuclei when stained with cresyl violet or toluidine blue.
Clinical Features:
According to the patient age three patterns of MLD are recognized – the late infantile, juvenile and adult forms. The most common type is the late infantile variety, which usually manifests in children between 12 and 18 months of age and is characterized by motor signs of peripheral neuropathy followed by deterioration in intellect, speech and co-ordination. The disease progresses quickly and within 2 years of onset, gait disturbance, quadriplegia, blindness and decerebrate posturing may be seen. Disease progression is continuous and death occurs 6 months to 4 years of age. The clinical picture is similar to the late infantile form except that the child is old enough to manifest behavioural disturbances as well. There is impaired school performance and emotional liability. The neurological examination reveals cerebellar incoordination, pyramidal tract signs and decreased reflexes as in the lower extremities. In the uncommon adult form, patients tend to present with dementia and progress to develop motor signs.
Imaging Features:
CT appearance of MLD is a symmetrical lucency of the white matter, especially prominent in the centrum semiovale and in corpus callosum. There is no evidence of inflammation or contrast enhancement and the cortical grey matter is spared.
CT appearance of MLD is a symmetrical lucency of the white matter especially prominent in the centrum semiovale and in corpus callosum. There is no evidence of inflammation or contrast enhancement and the cortical grey matter is spared.
MR features of MLD include symmetric confluent areas of high signal within the periventricular and cerebellar white matter on T2W images. There is sparing of the subcortical U fibres until late in the disease, In the late onset (juvenile and adult forms) there is predominant involvement of the frontal white matter. In the late infantile form of MLD, the most common type, a posterior (occipital) predominance of signal abnormality has been reported with dorsofrontal progression of disease. Involvement of the corticospinal tracts may also be seen in the late infantile form of MLD. High signal intensity is seen on the long TR images along the path of corticospinal tracts in the posterior limbs of the internal capsules and brainstem. The corpus callosum is invariably affected and hypointensity may be seen within the thalami on T2W images.
Krabbe Disease/Globoid Cell Leukodystrophy (GLD)
Krabbe disease is an autosomal recessive disorder caused by a deficiency of lysosomal enzyme b-galactocerebrosidase, an enzyme that degrades cerebroside, a normal constituent of myelin.
Clinical Features
The clinical presentation of the disease varies with the age of onset. In the early onset form, presentation is either before or at the age of 2 years while the late onset form presents after the age of 2 years. The early infantile form of the disease is the most common clinical form and has three phases. By 6 months of age the infant is irritable and hypertonic with spasticity and fever. Development fails to progress and the infant regresses neurologically. The second phase is characterized by rapid deterioration in motor function with chronic opisthotonous and myoclonic jerking accompanied by heperpyrexia. In the third phase the child appears decerebrate and has flaccid paralysis that culminates in death by 2 years of age. The late onset forms have a variable clinical presentation with a slower progression of disease.
Imaging Features
The CT findings in GLD range from white matter lucency to diffuse cerebral atrophy. The CT findings of hyperdense thalami, caudate nucleus and corona radiate are characteristic but not specific for the disease and have been shown to correspond to fine calcifications at autopsy. The most characteristic MR finding in both early and late onset forms of GLD is high signal intensity on T2W images found along the lengths of the corticospinal tracts. Additional findings in the early onset form include abnormal signal intensity within the cerebellar white matter and deep grey nuclei (dentate, basal ganglia, thalamus) with progressive involvement of the parieto-occipital white matter and posterior portion of the corpus callosum.
The CT findings of hyperdense thalami, caudate nucleus and corona radiate are characteristic but not specific for the disease and have been shown to correspond to fine calcifications at autopsy.
PEROXISOMAL DISORDERS
Peroxisomes are small intracellular organelles that are involved in the oxidation of very long chain and monounsaturated fatty acids. Peroxisomal enzymes are also involved in gluconeogenesis, lysine metabolism and glutaric acid metabolism.
The first group is characterized by defects in the formation and maintenance of white matter and X-linked adrenoleukodystrophy is the prototype.
Clinical Features
The clinical features of X-linked type ALD include the onset of neurological symptoms between the ages of 5 and 9 years with behaviour problems, decreasing mental function, visual and hearing disorders progressing to motor signs and ataxia. The disease progresses to include seizures, spastic quadriplegia with death ensuring within the first few years of onset.
Imaging Features
The CT and MR appearance of adrenoleukodystrophy is somewhat specific with symmetric areas of white matter abnormality in the peritrigonal regions and extending across the splenium of the corpus callosum. Demyelination then spreads outward and cephalad as a confluent lesion until most of the cerebral white matter is affected. The subcortical white matter is relatively spared in the early stage but often becomes involved in the later stages.
The central or inner zone which corresponds to irreversible gliosis and scarring is moderately hypointense on T1W MR imaging and markedly hyperintense at T2W imaging. The intermediate zone corresponding to active inflammation is isointense or slightly hypo-intense and rapidly enhances after administration of contrast. The peripheral or outer zone representing the leading edge of active demyelination appears moderately hyperintense on T2W MR imaging and demonstrates no contrast enhancement. Pontomedullary corticospinal tract involvement is a common finding in adreno-leukodystrophy and is uncommon in other leukodystrophies. Atypical case of ALD with unilateral or predominantly frontal lobe involvement may occur.
Proton MR spectroscopy typically shows a decrease in NAA peak and an increase in the choline peak. The spectra may be abnormal before the conventional MR findings and studies have shown the potential of MRS for prognostic assessment of ALD.
Proton MR spectroscopy typically shows a decrease in NAA peak and an increase in the choline peak. The spectra may be abnormal before the conventional MR findings and studies have shown the potential of MRS for prognostic assessment of ALD
AMINO ACID DISORDER
Canavan Disease
Canavan disease (Canavan- van Bogaert- Bertrand disease) or spongy degeneration of the brain is an autosomal recessive disorder caused by deficiency in activity of the enzyme N-acetylaspartylase, which result in accumulation of N-acetylaspartic acid in the urine, plasma and brain. This is the only known disease with a defect in NAA metabolism.
Clinical Features
It usually manifests in early infancy as hypotonia followed by spasticity, cortical blindness and macrocephaly. Macrocephaly may not be apparent in the first few months of life but the head enlarges above the ninetieth percentile within 6 months to 1 year of age. Canavan disease is a rapidly progressive illness with a mean survival time of 3 years, although protracted cases do occur. Definite diagnosis usually requires biopsy or autopsy.
Imaging Features
The CT shows diffusely decreased attenuation of the cerebral and cerebellar white matter. The MR imaging findings demonstrate diffusely decreased T1W signal and increased T2W signal within the white matter that corresponds to the CT abnormalities. Typically, there is diffuse symmetric increase signal on T2W images throughout the white matter. Unlike metachromatic leukodystrophy or Krabbe disease the subcortical U fibres also are usually involved. Occasionally there is sparing of the internal capsule, corpus callosum and putamen. Cerebral and cerebellar atrophy is a late finding.
MR spectroscopy – There is a characteristic increase in NAA peak.
WHITE MATTER DISORDERS WITH UNKNOWN METABOLIC DEFECT
Pelizaeus- Merzbacher disease, a sudanophilic leukodystrophy, is the best example of a hypo-myelinating leukoencephalopathy.. PMD has been linked to a severe deficiency of myelin specific lipids caused by a lack of proteolipid protein (PLP). This myelin specific proteolipid is responsible for oligodendrocyte differentiation and survival.
Clinical Features
PMD has traditionally been divided into classic and connatal forms. Classic PMD begins during late infancy with X-linked recessive inheritance. Connatal PMD is a rarer and more severe variant that begins at birth or in early infancy. This form has either X-linked or autosomal recessive inheritance. Patients with all forms of PMD present with clinical signs and symptoms including abnormal eye movements, nystagmus, extrapyramidal hyperkinesias, spasticity and slow psychomotor development.
Imaging Features
CT may demonstrate only atrophy. T2W MR findings reveal a nearly total lack of normal myelination with diffuse high signal intensity that extends peripherally to involve the sub-cortical U fibres along with early involvement of the internal capsule. Sometimes, the white matter demonstrates high signal intensity with small scattered foci of more normal signal intensity – a finding that may reflect the tigroid pattern of myelination seen on histology.
T2W MR findings reveal a nearly total lack of normal myelination with diffuse high signal intensity that extends peripherally to involve the sub-cortical U fibres along with early involvement of the internal capsule.
MR Spectroscopy
Proton MR spectroscopy may reveal no abnormal peak consistent with the absence of sclerosis and well-preserved axons. Diffuse or focal reduction in NAA consistent with axonal damage may be seen in more severe cases.
Alexander Disease
Alexander disease or fibrinoid leukodystrophy is a rare disorder that occurs sporadically with no known pattern of inheritance.
Clinical Features
Three clinical subgroups are recognized. The infantile subgroup is characterized by early onset of macrocephaly, psychomotor retardation with seizures and death occurring within 2-3 years. The diagnosis is made on the basis of a combination of macrocephaly, early onset of clinical findings and imaging findings but definite diagnosis usually requires brain biopsy or autopsy. In the juvenile subgroup, onset of symptoms occurs between 7 and 14 years of age. Progressive bulbar symptoms with spasticity are common. In the adult subgroup, onset of symptoms and disease course can be indistinguishable from those of classic multiple sclerosis in the adult subgroup.
Imaging Features
Alexander disease has a predilection for the frontal lobe white matter early in its course. CT demonstrates low attenuation in the deep frontal lobe white matter. Enhancement is often seen near the tips of the frontal horns early in the disease course. The characteristic frontal lobe areas of hyperintensity are seen on T2W MR imaging. The hyperintense areas progress posteriorly to the parietal white matter and internal and external capsules. The subcortical white matter is affected early in the disease course. In the late stages of the disease, cysts may develop in the affected regions of the brain.
Childhood Ataxia with Diffuse CNS Hypomyelination (Vanishing White Matter Disease)
This entity has been characterized in the last few years by a number of investigators. MRI demonstrates a diffuse confluent abnormality in white matter that was noted early in the course of the disease. Histopathology demonstrates a cavitating leukoencephalopathy with replacement of white matter between ependyma and U fibres that was replaced by CSF.
- Normal or mildly delayed initial psychomotor development.
- Neurologic deterioration with a chronic progressive and episodic course
- Presence of cerebellar ataxia and spasticity with relative preservation of mental function. Optic atrophy and epilepsy may occur.
- Diffuse symmetric white matter involvement on MRI with all or part of white matter exhibiting a signal intensity similar to CSF.
