Dysmyelinating diseases,
or leukodystrophies,
encompass a wide spectrum of inherited neurodegenerative disorders affecting the integrity of myelin in the brain and peripheral nerves.
Most of these disorders fall into one of three categories:
o Lysosomal storage diseases
o Peroxisomal disorders
o Diseases caused by mitochondrial dysfunction
Each leukodystrophy has distinctive clinical,
biochemical,
pathologic,
and radiologic features.
Magnetic resonance (MR) imaging has be-come the primary imaging modality in patients with leukodystrophy and plays an important role in the identification,
localization,
and characterization of underlying white matter abnormalities in affected patients.
1. Lysosomal Storage Diseases :
Lysosomes are cellular organelles that contain various enzymes,the deficiencies of which lead to impaired break down and subsequently abnormal accumulation of specific macromolecules (proteins,
nucleic acids,
lipids,
lipoproteins and polysaccharides).
Involvement of the neural cells by the disease causes disintegration of the neuro-axonal units,
whereas dysfunction of the oligodendrocytes adversely affects myelin build-up and maintenance.
The most common diseases include:
- Metachromatic leukodystrophy
- Krabbe’s disease
- Mucopolysaccharidoses
- Gangliosidoses
A / Metachromatic Leukodystrophy
Metachromatic leukodystrophy is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme arylsulfatase A .
Imaging: fig 1
T2-weighted MR imaging: show symmetric confluent areas of high signal intensity in the periventricular white matter with sparing of the subcortical U fibers.
A peculiar “tigroid” white matter lesion pattern may be seen within the centrum semiovale, which is due to the relative sparing of myelin around the transmedullary vessels.
During the disease course,
progressive and eventually severe diffuse brain atrophy develops and cerebellar white matter involvement may also be seen.
Diffusion-weighted images: in the active stage of the disease usually show moderate hypersignal in the presumed progression zones of the disease process.
T1 C+ (GAD): no contrast enhancement in these areas.
B/Krabbe Disease
Krabbe disease,
or globoid cell leukodystrophy,
is an autosomal recessive disorder caused by a deficiency of galactocerebroside _galactosidase.
Imaging:
CT: performed during the initial stage of the disease may demonstrate symmetric high-attenuation foci in the thalami,
caudate nuclei,
corona radiata,
posterior limbs of the internal capsule,
and brainstem.
MRI (fig 2):
T2-weighted MR imaging: demonstrate high signal intensity in the centrum semiovale,periventricular white matter,
and deep gray matter.
The subcortical U fibers are spared until late in the disease course.
Abnormalareas of hyperintensity may be seen in the cerebellum and pyramidal tract early in the disease course.
Diffusion-weighted images: may show hypersignal along the rogression line of the active demyelinating process in the early stage of the disease.
This is most probably due to myelin edema.
T1 C+ (GAD): Mild enhancement has been described at MR imaging at the junction of the subcortical U fibers with the underlying abnormal white matter despite the absence of an inflammatory reaction in the pathologic specimen.
C/ Mucopolysaccharidosis
Mucopolysaccharidosis is caused by a deficiency of the various lysosomal enzymes involved in the degradation of glycosaminoglycans.
Imaging:
CT: Show diffuse low-attenuation areas within the cerebral hemispheric white matter.
MRI:
T2-weighted MR imaging: show focal and diffuse areas of high signal intensity and low signal intensity on T1-weighted MR images.
The sharply defined foci are commonly present in the corpus callosum,
basal ganglia,
and cerebral white matter.
They are isointense relative to cerebrospinal fluid with all imaging sequences and probably represent mucopolysaccharide-filled perivascular spaces.
Severe progressive atrophy and varying degrees of hydrocephalus occurs as the disease advances.
Diffusion-weighted imaging: findings are quite unremarkable in mucopolysaccharidoses.
Usually iso- or faint hyposignal is seen within the white matter lesion areas,suggestive of dysmyelination and low-grade demyelination without significant myelin edema
2. Peroxisomal Disorders:
Peroxisomes are cellular organelles that have both anabolic and catabolic functions.
Since peroxisomes are involved in lipid metabolism,
their functional integrity is indispensable in normal myelination and myelin
maintenance.
Schematically,
two types of peroxisomal disorders are known:
«Peroxisome assembly deficiencies include
- Zellweger syndrome
- neonatal adrenoleukodystrophy,
- infantile Refsum disease and its variants.
« The other group of peroxisomal disorders comprises single enzyme deficiencies.
The best-known diseases are :
- pseudoneonatal adrenoleukodystrophy,
- X-linked adrenoleukodystrophy,
adrenomyeloneuropathy,
- classical Refsum disease and pseudo-Zellweger syndrome.
A/ Zellweger Syndrome
Is an autosomal recessive disorder caused by multiple enzyme defects and characterized by liver dysfunction with jaundice,
marked mental retardation,
weakness,
hypotonia,
and craniofacial dysmorphism.
Imaging:
MRI:
MR imaging: reveals diffuse demyelination with abnormal gyration that is most severe in the perisylvian and perirolandic regions.
The pattern of gyral abnormality is similar to that seen in polymicrogyria or pachygyria.
Diffusion tensor imaging findings in patients with Zellweger syndrome show reduced fractional anisotropy and elevated apparent diffusion coefficient values compared to age-matched controls .
B/ X-linked adrenoleukodystrophy
This is a true leukodystrophy,
with no lesions within the grey matter structures.
Imaging:
MRI:
symmetric white matter demyelination occurs in the peritrigonal regions and extends across the corpus callosum splenium.
The progression pattern of the disease is centrifugal and postero-anterior.
The affected cerebral white matter typically has three different zones:
- The central zone appears moderately hypointense at T1-weighted MR imaging and markedly hyperintense at T2-weighted imaging( irreversible gliosis and scarring).
- The intermediate zone appears isointense or slightly hypointense at T2-weighted MR imaging this zone may and readily enhances after intravenous administration of contrast materi are presents (active inflammation)
- The peripheral zone: appears moderately hyperintense at T2-weighted MR imaging and demonstrates no enhancement (represents the leading edge of active demyelination).
3. Diseases Caused by Mitochondrial Dysfunction :
Well-defined disorders include MELAS syndrome,
Kearn-Sayre syndrome,
Leigh disease,
and MERRFsyndrome.
A/Melas Syndrome:
Typical changes in brain imaging include stroke-like areas,
basal ganglia calcifications and brain atrophy .
MR imaging: demonstrates multiple cortical and subcortical infarct-like lesions that cross vascular boundaries,
along with varying degrees of generalized cerebral and cerebellar atrophy.
Diffusion tensor imaging: shows that ADC map is usually not reduced at all or less reduced.
MR spectroscopy: shows large lactate peak at 1.3 ppm.
B/ Leigh disease:
Leigh syndrome is the most common clinical phenotype of mitochondrial disorders in childhood.
Imaging:
MRI:
T2-weighted MR imaging: show bilateral,
symmetric focal hyperintensities in the basal ganglia,
thalamus,
substantia nigra,
and brainstem nuclei.
The cerebral white matter is rarely affected.
T1 C+ (GAD): Enhancement may be seen at MR imaging and may correspond to the onset of acute necrosis.
4. Unknown metabolic defect :
A/ Canavan disease :is a rare form of leukodystrophy,
inherited as an autosomal-recessive disease,
caused by a deficiency of N-acetylaspartylase,
which results in an accumulation of N-acetylaspartic acid in the urine,
plasma,
and brain.
Imaging:
MRI:
T2-weighted MR imaging :shows symmetric white matter hyper intensities ,particular involvement of subcortical U fibers is characteristic.
Thalamus,
basal ganglia,
periventricular region,
brainstem and cerebellum may be affected variably.
MR spectroscopy: shows markedly elevated NAA peak accompanying increased NAA to choline ratio and NAA to creatinine ratio.
B/ Pelizaeus-Merzbacher disease
is a rare leukodystrophy characterized by global delayed myelination resulting from an inherited mutation in the proteolipid protein gene and abnormal formation of proteolipid.
Patients with all forms of PMD present with nystagmus,
hypotonia,
extrapyramidal hyperkinesias,
spasticity,
and slow psychomotor development.
Imaging:
MRI
The typical MR imaging finding in Pelizaeus-Merzbacher disease is an almost total absence of myelin within brain
T2-weighted MR imaging :shows either diffuse or patchy (tigroid) hyperintensity in the cerebellar, brain stem,
and supratentorial white matter.
This appearance is believed to be the result of the lack of formation of myelin (hypomyelination or dysmyelination).
MR spectroscopy: Shows the greatest reduction in NAA levels in regions of white matter.
C/ Alexander disease: is a rare,
progressive non familial leukodystrophy affecting the central nervous system white matter with frontal lobe preponderance. The infantile form usually presents within first 2 years of life and is characterized clinically by megalencephaly,
developmental delay,
psychomotor retardation,
seizures,
and a lethal progressive course.
Imaging:
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.
MRI
T2-weighted MR imaging: shows the characteristic frontal lobe areas of hyperintensity. These 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 affected regions of the brain.
Diffusion-weighted imaging :shows prominent hyposignal within subcortical cysts and decreased signal within affected white matter.
The ADC is increased and diffusion tensor imaging data show reduced fractional anisotropy.
5. Metabolic disease:
Amino acidopathies typically present with white matter abnormalities on conventional MR imaging.
A/ Maple syrup urine disease
Maple syrup urine disease (MSUD) is related to a deficiency of the metabolism of branched-chain amino acids (L-leucine,
L-isoleucine and L-valine).
The most severe,
classical neonatal form of MSUD is characterized by early postnatal onset and rapidly progressive neurological de terioration.
Imaging:
CT: showed bilateral symmetrical white matter hypodensities in the posterior limb of internal capsule,
thalami,
midbrain,
and cerebellar white matter.
MRI (Fig 3)
T2-weighted MR imaging: showed bilateral symmetric white matter hyperintensites in the posterior limb of internal capsule,
thalami,
midbrain,
corticospinal tracts,
and cerebellar white matter .
Diffusion-weighted imaging (DWI): (Fig 4) showed characteristic pattern of bilateral symmetrical restricted diffusion within the myelinated areas in the posterior limb of the internal capsule,
centrum semiovale,
corona radiata,
corticospinal tract,
thalami,
posterior aspect of the mid brain,
pons,
middle cerebellar peduncle,
medulla,
and cerebellar white matter,
attributed to intramyelinic edema.
MR spectroscopy :showed the presence of branched-chain amino acids BCAAs (leucine,
isoleucine,
and valine) and branched-chain α-keto acids resonating at 0.9-1.0 ppm,
which are seen especially during a metabolic crisis.(Fig 5)
B/Non-ketotic hyperglycinemia
Nonketotic hyperglycinemia (NKH) is an auto-somal recessive disorder of glycine metabolism characterized by elevated concentrations of glycine in plasma,
cerebrospinal fluid (CSF),
and urine .
Imaging:
MRI
T2-weighted MR imaging:revealed thinning of the corpus callosum.
Abnormally increased signal intensities were noted symmetrically in the centra semiovales,
coronae radiatae,
genua,
posterior limbs of the internal capsules,
cerebellar peduncles,
and pyramid tracts.
Diffusion-weighted imaging (DWI): Showed Symmetric distribution of restricted diffusion in the cerebellar peduncles,
coronae radiatae,
genua,
anterior and posterior limbs of internal capsules was depicted on apparent diffusion coefficient (ADC)
MR spectroscopy: a prominent peak at 3.55ppm detected,
which is assigned to glycine