Imaging in inherited metabolic disorders
- 2. Normal Myelination of the Brain At birth, as seen on T1W images, myelination is present in the medulla, dorsal midbrain, cerebellar peduncles, posterior limb of internal capsule and ventrolateral thalamus. Maturation proceeds from: 1. Central to peripheral 2. Inferior to superior 3. Posterior to anterior
- 4. Presenting symptoms Usually non-specific such as seizures, Spasticity, ataxia, movement disorder or delay in achieving the developmental milestones. Biochemical tests and genetic analyses are often negative. As a result, at least 60% of children with the inborn errors of metabolism never receive a specific diagnosis despite extensive investigations.
- 5. Classification According to Cellular Organelle Dysfunction The cellular organelles have distinctly different functions in the metabolism: mitochondria are involved mainly in energymetabolism, lysosomes in the degradation of macromolecules(lipids, lipoproteins, mucopolysaccharides) and Peroxisomes in both anabolic and catabolic functions.
- 6. Classification of Metabolic Disorders on the Basis of Organelle Disorder Lysosomal Storage Diseases with White Matter Involvement • Metachromatic leukodystrophy • Krabbe disease • Niemann-Pick disease • Fabry disease • GM1 gangliosidosis • GM2 gangliosidosis • Mucopolysaccharidosis • Fucosidosis • Wolman disease and cholesterol ester storage disease • Ceroid lipofuscinosis
- 7. Peroxisomal Disorders • Zellweger syndrome • X-linked adrenoleukodystrophy (ALD) • Neonatal ALD • Pseudoneonatal ALD • Classic Refsum disease • Hyperpipecolic acidemia • Cerebrotendinous xanthomatosis • Abetalipoproteinemia • Rhizomatic chondrodysplasia calcificans punctata.
- 8. Mitochondrial Dysfunction with Leukoencephalopathy • Leigh disease • MELAS syndrome • MERRF syndrome • Kearns-Sayre syndrome Disorders of Amino Acid and Organic Acid Metabolism • Canavan disease
- 9. White Matter Disorders with Unknown Metabolic Defect • Pelizaeus-Merzbacher disease (PMD) • Alexander disease • Congenital muscular dystrophy (Fukuyama type)
- 10. LYSOSOMAL STORAGE DISORDERS Metachromatic Leukodystrophy (MLD) most common of all the familial leukodystrophies. autosomal recessive disorder caused by a deficiency of the lysosomal enzyme aryl.sulfatase. This enzyme is necessary for the normal metabolism of sulfatides, which are important constituents of myelin sheath.Cerebroside sulfate (galactosyl sulfatide) abnormally accumulates within the white matter resulting in breakdown of the membrane of the myelin sheath, kidneys, gallbladder and other viscera.
- 11. Metachromatic Leukodystrophy (MLD) The late infantile, juvenile and adult forms. 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 coordination. 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 after the onset of symptoms.
- 12. Imaging Features The typical CT appearance of MLD is a symmetrical lucency of the white matter, especially prominent in the centrum semiovale and in corpus callosum. No evidence of inflammation or contrast enhancement and the cortical gray 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 fibers until late in the disease Thus, MLD is a progressive centrifugal white matter disease. Metachromatic Leukodystrophy (MLD)
- 14. 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 Metachromatic Leukodystrophy (MLD)
- 15. As the disease progresses the signal abnormality becomes more extensive and confluent with associated atrophy The corpus callosum (first the splenium then the anterior portions), the internal capsule and the deep hemispheric white matter are always involved Metachromatic Leukodystrophy (MLD)
- 17. In later stages, considerable atrophic dilatation of the lateral ventricles is seen. Atrophy may be the only finding in late adult onset cases Metachromatic Leukodystrophy (MLD)
- 18. Proton MR spectroscopy frequently demonstrates abnormality in the metabolic peaks before conventional MR imaging. The spectrum includes decrease NAA, abnormal elevation of choline, myoinositol and lactate peak. The elevation of myoinositol is highly suggestive of MLD. Metachromatic Leukodystrophy (MLD)
- 19. Lysosomal Storage Diseases with White Matter Involvement Krabbe Disease/Globoid Cell Leukodystrophy (GLD) Deficiency of lysosomal enzyme beta galactocerebrosidase, an enzyme that degrades cerebroside, a normal con The diagnosis is made by demonstrating a deficiency of the enzyme in peripheral blood. Clinical Features 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. In early onset GLD, CSF analysis always demonstrates an abnormally high protein level with a normal cell count. In the late onset form the protein level is not consistently high in CSF. Bone marrow transplantation has been shown to halt/reverse the neurologic manifestation of disease.
- 20. Krabbe Disease/Globoid Cell Leukodystrophy (GLD) CT findings Hyperdense thalami, caudate nucleus and corona radiata are characteristic but not specific for the disease. MR findings 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 gray nuclei (dentate, basal ganglia, thalamus) with progressive involvement of the parieto- occipital white matter and posterior portion of the corpus callosuml.
- 22. Late onset cases of GLD with primary involvement of the parietal periventricular white matter,splenium of the corpus callosum and corticospinal tracts may appear similar on imaging to adrenoleukodystrophy (ALD) However, auditory pathway involvement is characteristic of ALD and is not seen in GLD. Krabbe Disease/Globoid Cell Leukodystrophy (GLD)
- 23. Diffusion weighted images, like MLD, may show prominent hypersignal along the presumed progression zone of the demyelinating process Krabbe Disease/Globoid Cell Leukodystrophy (GLD)
- 24. Sphingolipidosis The sphingolipidoses involve abnormal metabolism and accumulation of sphingolipids. Deficiency of hexosaminidase. A alone results in GM2 gangliosidosis, the classic form of which is Tay-Sachs disease. Sandhoff’s disease is caused by a deficiency in both hexosaminidase A and B. Clinical findings are identical to that of Tay-Sachs with additional findings of hepatosplenomegaly and bony deformities
- 25. Sphingolipidosis Clinical Features Between 3 and 6 months of age. The initial sign is an excessive startle reflex. A macular cherry red spot is almost always present at this stage and psychomotor regression then begins. Imaging Features CT examination : Shows hyperdensities within the basal ganglia and or thalami due to calcifications. MR imaging : All the white matter structures are involved except for the corpus callosum, the anterior commissure and the posterior limbs of the internal capsules.
- 27. Mucopolysaccharidoses (MPS) variable combinations of coarse facies, short stature, bony defects, stiff joints, mental retardation, hepatosplenomegaly and corneal clouding. All forms of MPS are autosomal recessive except MPS type-II (Hunter syndrome) which is X-linked recessive. The spines in MPS are usually imaged to determine the site and cause of cord compression which occurs frequently in MPS types IV and VI. The most common location for the cord compression is at the atlantoaxial joint. Atlantoaxial subluxation may occur in these patients as a result of laxity of the transverse ligament in conjunction with hypoplasia of the odontoid.
- 28. Magnetic resonance shows a shortened odontoid with a soft tissue mass of variable size with intermediate signal on T1 and low signal on T2 W images. The low signal on T2W images is a combination of unossified fibrocartilage and reactive changes. Another cause of cord compression at the C1 – C2 level is dural thickening resulting from intradural deposition of collagen and mucopolysaccharides. This is seen as a thickening of the soft tissue proterior to the dens with consequent cord compression. Mucopolysaccharidoses (MPS)
- 29. PEROXISOMAL DISORDERS X-linked Adrenoleukodystrophy (ALD) X-linked ALD is caused by a deficiency of a single enzyme, acyl CoA synthetase. True leukodystrophy with no involvement of the gray matter structures. Imaging Features CT and MR appearance somewhat specific with symmetric areas of white matter abnormality in the peritrigonal regions and extending across the splenium of the corpus callosum.
- 31. The progression pattern is thus centrifugal and posteroanterior PEROXISOMAL DISORDERS
- 32. 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 hypointense 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. PEROXISOMAL DISORDERS
- 34. Diffusion weighted MR images The burned out zone is hypointense, the intermediate inflammatory zone is Moderately hyperintense and The most peripheral demyelinating zone is very faintly hyperintense PEROXISOMAL DISORDERS
- 37. UNCLASSIFIED LEUKODYSTROPHIES Canavan Disease deficient activity of the enzyme. Nacetylaspartylase, which results in accumulation of N-acetylaspartic acid in the urine, plasma and brain. Only known disease with a defect in NAA metabolism. Imaging Features The subcortical U fibers also are usually involved. Centripetal progression. Typically, there is diffuse, symmetric increased signal intensity on the T2-weighted images throughout the white matter with relative sparing of the internal and external capsules and corpus callosum.
- 38. Canavan Disease
- 39. On MR spectroscopy there is a characteristic increase in NAA peak Canavan Disease
- 40. Alexander Disease Imaging Features Alexander disease has a predilection for the frontal lobe white matter early in its course.
- 41. Contrast enhancement may also be seen along the ependymal linings of the lateral ventricles, within the basal ganglia or even the dentate nuclei Alexander Disease
- 43. MITOCHONDRIAL DISORDERS/DEFECTS OF THE RESPIRATORY CHAIN Mitochondrial Encephalomyopathy—Lactic Acidosis and Stroke-like Symptoms (MELAS) Imaging Features Basal ganglia calcifications. bilateral symmetric or asymmetric cortical and subcortical distribution. The finding of multiple migrating infarct like lesions not limited to a specific vascular territory especially in the basal ganglia and the posterior part of the cerebral hemisphere in children suggest MELAS syndrome Muscle biopsy isimportant to confirm the diagnosis.
- 44. MELAS
- 45. Subacute Necrotizing Encephalomyopathy (Leigh Disease) Typical MR finding in Leigh disease is the remarkably symmetrical involvement, most frequently in the putamen.
- 48. Thank you