DISORDERS OF MYELINATION
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This document discusses disorders of myelination. It begins by defining myelin and its functions, describing normal myelination milestones. It then covers various white matter disorders including dysmyelination, hypomyelination, and delayed myelination. Specific leukodystrophies are discussed in more detail such as Canavan's disease, Alexander disease, Van der Knapp disease, and glutaric aciduria type 1. Clinical features, imaging findings, and pathology are described for each condition. The document provides an overview of disorders of myelination.
![Classical X linked ALD:
Onset usually between 4 - 8 yrs of age.
Progressive gait difficulty with spasticity, ataxia and
Cognitive / emotional disturbance.
Adrenal impairment with severe vomiting and episodes of
circulatory collapse.
Increased pigmentation of the oral mucosa and the skin
around nipples and over elbows, knees, and scrotum.
Adrenomyeloneuropathy [AMN]:
Adrenal insufficiency had been present since early childhood,
progressive spastic paraparesis with relatively mild
polyneuropathy develops in 2nd -5th decade.
Gait may have an ataxic component.
Female carriers: Similar clinical picture but in mild form and
without adrenal insufficiency.](https://image.slidesharecdn.com/disordersofmyelination1-190628030604/85/DISORDERS-OF-MYELINATION-61-320.jpg)
DISORDERS OF MYELINATION
- 2. What is myelin ? Myelin is an electrically insulating phospholipid layer that surrounds the axons of many neurons. Myelin is produced by specialized cells: Oligodendrocytes in the central nervous system Schwann cells in the peripheral nervous system.
- 3. Cholesterol, galactocerebrosidase, spingomyelin & phospholipids are found in fully formed white matter and account for stability & strength of the myelin membrane. Myelin sheaths wrap themselves around axons. Each oligodendrocyte can myelinate several axons (up to 40). Hence the destruction of even only a few oligodendrocytes can have an extensive demyelination effect.
- 4. Function of myelin layer : The main function of a myelin layer is an increase in the speed at which impulses propagate along the myelinated fiber. Myelination also helps prevent the electrical current from leaving the axon.
- 5. Normal myelination After normal myelination in utero, myelination of the neonatal brain is far from complete. The first myelination is seen as early as the 16th week of gestation, in the column of Burdach, but only really takes off from the 24th week. • Evolves in predictable sequential fashion over the first 2 years of life. • It correlates very closely to developmental milestones.
- 6. The progression of myelination occurs in predictable fashion. Myelination progresses from: Central to peripheral Caudal to rostral Dorsal to ventral Sensory then motor.
- 7. Imaging approach CT brain: At birth the cerebral cortex is mature with distinctly defined gyri & sulci. The frontal sub arachnoid space and basal cisterns often prominent upto I year of age. WM is unmyleinated hence it appears quite hypodense. MRI brain: Imaging modality of choice to assess myelination.
- 8. Basic principles of myelination on MRI: Unmyelinated WM: Hypointense on T1 W Hyper intense on T2 W. Myelinated WM : Hyper intense on T1 W Hypointense on T2 W. ( signal intesity in relation to grey Matter.) Increase in signal intensity on T1W images precede the decrease in signal intensity on T2W images.
- 9. T1W images: Most sensitive sequence in children < 1 year of age. T2W images Most sensitive in children between 1- 2 years of age. FLAIR: Follows the same pattern as T2 but somewhat lags behind. MR Spectroscopy: Increased Myo Inositol and Choline in neonates. NAA increases with myelination.
- 10. At Birth (full term): Myelinated areas were: Dorsal brainstem Posterior limb of internal capsule Prerolandic area.
- 11. Myelination milestones 1 month : Deep cerebellar WM 3 months : Anterior limb of the IC, splenium of the CC 6 months : Genu of the CC 8 months: Centrum semiovale 12 months: Peripheral extension into the subcortical WM 18-24 months: Like adult
- 12. Terminal zones of myelination: These are areas of slow myelination within the brain Should not be mistaken for areas of ischemia. Seen from 16 months to 10 years of age. These include: Areas lateral, superior, and posterior to the lateral ventricles, particularly in the region of trigones. Peri vascular spaces
- 13. Normal myelination At birth At 6months At 1 year At 2 years
- 14. Disorders of myelination White matter disorders De- myelination Destruction of normal myelin Dys- myelination formation of abnormal myelin Hypo- myelination Reduction of the amount of myelin Delayed myelination
- 15. Demyelination Vs Dysmyelination De-myelination: Multifocal & asymmetrical. Dysmyelination: Confluent & symmetrical.
- 16. Dys myelination Vs hypo myelination Dysmyelination: Prominent T2 hyper intensity and T1 hypo intensity. Hypomyelination: Mild T2 hyper intensity. Variable T1 signal (hypo, iso or hyper intense). Delayed myelination Vs hypo myelination Repeat MRI after 6 months. Delayed myelination myelination progression. Hypomyelination no myelination progression.
- 18. Lysosomal storage diseases MLD GLD (Krabbe’s) Fabry disease Gangliosidosis Muco-poly- saccharidosis Peroxisomal disorders X linked adreno- leukodystrophy Zellweger syndrome Refsum disease Mitochondral disorders Leigh disease MELAS MERRF Kearns Sayer Classification of IMD ‘s on the Basis of Organelle Disorder
- 19. Amino-acidopathies and organic acidopathies Canavan disease Glutaric aciduria Urea cycle disorders Defects of myelin proteins Pelizaeus Merzbacher syndrome 18 q syndrome Unknown etiology Alxander disease Van Der Knapp disease
- 20. Classification based on imaging Dys myelinating disorders Diffuse white matter Canavan Alexander Van Der Knapp Organic acidurias Subcortical white matter Hydroxy glutaric aciduria Kerns sayer syndrome Deep white matter Krabbe’s MLD Vanishing WM disease Peroxisomal Gangliosidosis Phenyl ketonuria
- 21. Disorders of hypo myelination Most common Pelizaeus merzbacher disease Pelizaeus merzbacher like disease POL III leuko dystrophies ( including 4 H syndrome) Hypo myelination of unknown cause Less common Hypo myelination with congenital cataracts Hypomyelination with atrophy of cerebellum and BG Salla disease Fucosidosis Cockayne syndrome GM1 & GM 2 gangliosidosis. Rare: 18 q syndrome Tay syndrome
- 22. Clinical Presentation of Leukodystrophy Developmental delay and regression of milestones Gait , visual and auditory disturbances Pyramidal involvement with spasticity, brisk reflexes and extensor planter's. Ataxia d/t cerebellar involvement Failure to thrive (less common) Seizures +/- Dysmorphisms.
- 23. Leuko dystrophies with diffuse white matter involvement Canavan’s disease Alexander Disease Van Der Knapp Glutaric Aciduria Type 1 & 2 Other Organic acidurias
- 24. Canavan’s disease : Also called as spongiform leukodystrophy. AR inheritance Deficiency of asparto-acylase leading to impairs NAA metabolism. Clinical features: Presents by the age of 3 - 5 months Developmental delay with regression of milestones. Visual and auditory distubance Hypotonia eventually changes to spasticity with pyramidal signs Macrocelphaly & blond hair Life expectancy is usually into the teens.
- 25. Diagnosis: Urinary N-acetyl aspartic acid (NAA) - ↑↑ NECT: shows a large head with diffuse WM hypodensity. MRI: Abnormal myelination with confluent T2/FLAIR hyper intensity throughout the white matter and globus pallidi. MRS: Shows markedly elevated NAA peaks (diagnostic). Leuko dystrophy Macrocephaly canavan’s disease Diffuse WM involvement ↑↑ Urinary NAA levels
- 27. Alexander Disease: Also called as fibrinoid leuko dystrophy (but involves both white and grey matter). AD inheritance. Mutation in the glial fibrillary acidic protein (GFAP). Clinical features: Infantile form: Most common. Present with megalencephaly, progressive psycho motor retardation ,pyramidal signs and seizures. Juvenile & adult forms: constipation, sleep disturbance’s since childhood. Other features develop at 3rd-4th decade Bulbar signs, ataxia, and pyramidal signs.
- 28. Diagnosis: MRI: T1 hypo intensity and T2/FLAIR hyper intensity in the frontal WM, caudate nuclei, and anterior putamina. Subcortical U-fibers are involved early in the disease course. Classic finding : T1 hyper intense, T2 hypo intense rim around the frontal horns. Another unique finding: Enlargement of the caudate heads and fornices, which appear swollen and hyperintense. On T1 C+ : striking enhancement in peri ventricular WM. MRS: ↓ NAA, ↑ myoinositol peaks and variably increased choline and lactate. In the adult form MRI shows medullary atrophy without signal changes.
- 29. Pathology: Rosenthal fibers: Distinctive eosinophilic hyaline bodies, most prominent just below the pia and around blood vessels. are seen throughout the cerebral cortex, brainstem, and spinal cord. Leuko dystrophy Macrocephaly Predominant frontal WM involvement Frontal rim sign Alexander’s Contrast enhancement disease ↑ GFAP levels in CSF
- 31. Vander Knapp disease: Also called as Megaloencephalic Leukodystrophy with Subcortical Cysts. AR inheritance. 75% cases: MLC 1 gene mutation. HEPACAM gene mutation in remaining cases. Both the lead to abnormal cell junction trafficking. Clinical features: Age at symptom onset: Birth to 25 years Infantile onset macrocephaly f/b developmental delay, seizures and mental retardation. Slow course of neurological deterioration.
- 32. Diagnosis: MRI: A large head with diffuse confluent WM T2/FLAIR hyper intensity with subcortical WM involvement is typical. The basal ganglia are spared. Characteristic CSF-like subcortical cysts develop in the anterior temporal lobes and then appear in the frontoparietal lobes. MRS: shows ↓ NAA and NAA:Cr ratio. Leuko dystrophy Macrocephaly Slow course Vander Knapp Diffuse sub cortical WM involvement disease CSF like Sub cortical cysts
- 34. Glutaric Aciduria Type 1( GA 1): AR inheritance with deficiency of glutaryl co enzyme A dehydrogenase. Leads to accumulation of glutaric acid. Clinical features: Most present in the 1st year of life with acute striatal necrosis triggered by febrile illness or vaccination. Chronic: Seizures, mental retardation and movement disorders are common. MRI: The three "signature" imaging findings of classic GA1 are 1. Macrocephaly 2. Bilateral widened ("open") sylvian fissures, 3. Bilaterally symmetric basal ganglia lesions.
- 35. In Acute crisis : Bilateral diffusely swollen basal ganglia that are T2/FLAIR hyper intense and that restrict on DWI are typical. In Chronic GA1: volume loss can produce recurrent sub dural hematomas.
- 36. Other organic aciduria’s: In Western countries phenylketonuria is the most common IMD. However organic aciduria’s common in India but are comparatively rare Western countries. Important organic aciduria’s include Propionic aciduria (PA), Methyl malonic aciduria (MMA), Branched chain organic acidurias (which includes isovaleric aciduria), Glutaric aciduria Type 1 & 2 Maple syrup urine disease (MSUD) Multiple carboxylase deficiency.
- 37. Major clinical features : Developmental delay/mental retardation, Vomiting, failure to thrive, Seizures, coma, hypotonia, Respiratory distress and cardiac dysfunction. MRI : Usually shows diffuse WM hyper intensities with or with out involvement of basal ganglia. Blood investigations reveal hyper ammonemia and high anion gap metabolic acidosis. Additional biochemical features include hypoglycemia, ketonuria. Diagnosis is confirmed by analysis of organic acids in urine.
- 38. Leuko dystrophies with subcortical white matter involvement Hydroxy glutaric aciduria Kerns sayer syndrome
- 39. Hydroxy glutaric aciduria: Autosomal recessive inheritance. Deficiency of L-2-hydroxyglutarate dehydrogenase. Clinical presentation: Affected children are often initially normal. Diagnosis is commonly in late childhood to early adolescence. Initially developmental delay and learning difficulties, and in later years cerebellar signs becomes prominent. Seizures are common usually precipitated by fever.
- 40. Diagnosis: MRI: T2/FLAIR hyper intensities affecting the subcortical U- fibers which progressing to a deeper confluent pattern. Even in the advanced stages, periventricular WM, corpus callosum and internal capsule remain preserved. Hyper intensities also seen in basal ganglia and dentate nuclei. Vermis becomes highly atrophic. Definitive diagnosis: ↑↑ L-2-Hydroxyglutaric acid in urine.
- 41. Kerns sayer syndrome: Mitochondrial DNA disorder. Number gene deletions are identified in KSS patients. Most typical pathological feature is spongiform WM vacuolation. Clinical features: Typically presents in older children or young adults. Characterized by Short stature, Progressive external ophthalmoplegia, Retinitis pigmentosa, Sensorineural hearing loss, Ataxia.
- 42. Imaging: CT scan: Show variable symmetric basal ganglia calcifications. Mild cortical and cerebellar volume loss is common. MRI: T2/FLAIR hyper intensity in the WM, basal ganglia and cerebellum. The subcortical U fibers, cerebellum, and posterior brainstem are involved early in the disease course. Periventricular WM remains relatively spared in early stages. MRS : demonstrates elevated lactate.
- 44. Leuko dystrophies with deep white matter involvement Metachromatic Leuko dystrophy Krabbe’s Disease Vanishing White Matter Disease Peroxisomal disorders Adreno leukodystrophy (ALD) Zellweger spectrum Disorders
- 45. Metachromatic Leuko dystrophy : Lysosomal storage disorder, AR inheritance Deficiency of enzyme Arylsulfatase A (ARSA gene) ARSA mutations – type O and type R Type OO – Late infantile form ( 1 – 4 years) → common Type OR– Juvenile form Type RR – Adult form
- 46. Clinical features: Loss of acquired motor milestones Gait disturbances ( spasticity with brisk DTR) Cognitive decline and Speech disturbances Visual impairment and cerebellar involvement Optic atrophy (1/3 patients), sometimes with grayish degeneration around the maculae. DTR may diminish as the peripheral nerves are involved. Seizures (rare) Progression to a bedridden quadriplegic state over a period of 1- 3 years.(Late onset forms – slow progression). Pathology: Widespread degeneration of myelinated fibers in the CNS and PNS. The stored material, sulfatides, stains brown-orange with aniline dyes and PAS-positive.
- 47. Diagnosis: CSF – moderately elevated protein (75 -250 mg/dL ) Urine: ↑↑ sulfatides in urine Peripheral nerve biopsy: Metachromatic granules. Deficiency in aryl sulfatase A activity in leucocytes / cultured fibroblasts. MRI: Confluent, symmetric, butterfly-shaped T2/FLAIR hyper intensity in the periventricular and deep WM. Starts in parieto occipital periventricular WM later extends into the frontal & temporal WM. Subcortical U-fibers and cerebellum are spared until late stages. Islands of normal myelin around medullary veins in the WM produce a striking "tigroid " or "leopard" pattern. Restricted diffusion is common. MRS shows ↑ choline & myo inositol peaks.
- 49. Leuko dystrophy Peripheral neuropathy Metachromatic granules on nerve biopsy Meta chromatic Peri ventricular & deep WM involvement Leuko dystrophy (Butter fly pattern & tigroid appearance) ↑ sulfatides in urine Treatment: • Enzyme replacement or bone marrow transplantation. • Marrow transplant is less beneficial once the patient becomes symptomatic • May be useful early in the disease and in the treatment of an asymptomatic sibling.
- 50. Krabbe’s Disease: Also called as Globoid Cell Leukodystrophy . Lysosomal storage disorder, Females ( 80 %) Deficiency of enzyme Galactocerebroside β- galactosidase. Forms: Early onset – In infancy (onset at 3-8 months ) Late onset – Extremely uncommon, in childhood to adulthood.
- 51. Clinical features: Generalized rigidity, loss of head control, Poor feeding, irritability Heightened startle reflex ( Spasms induced by stimulation). Develop seizures, opisthotonus Deafness and blindness by 9 months DTR may diminish as the peripheral nerves are involved. Survival beyond 2 years is unusual. Late onset forms: progressive Corticospinal, corticoblubar & cerebellar involvement with mental regression. Pathology: Early destruction of oligo dendrocytes with unique "globoid" cells on histology.
- 52. Diagnosis: CSF – moderately elevated protein (70 -450 mg/dL) ENMG - Demyelinating polyneuropathy. CT brain: Bilaterally symmetric hyper densties in the thalami, basal ganglia, dentate nuclei. MRI: Confluent, symmetric, T2/FLAIR hyper intensity in the peri ventricular and deep WM. Subcortical U-fibers are spared . B/L thalamic hypo intensity on T2WI is common. Characteristic “Halo” or ring like hyper intensities around dentate nuclei. enlargement of the pre chiasmatic optic nerves. MRS shows ↑ choline & ↓ NAA peaks.
- 53. Krabbe’s disease
- 54. Leuko dystrophy Demyelinating neuropathy B/L BG & thalamic calcifications on CT Peri ventricular & deep WM involvement Krabbe’s T2 B/L thalamic hypo intensities Disease Ring hyper intensities around dentate nuclei Enlargement of optic nerves Treatment: BMT with umbilical cord hematopoietic cells was successful in asymptomatic babies with Krabbe disease. Not useful after becoming symptomatic. The donors were partially HLA matched and substantial anti rejection medication was required.
- 55. Vanishing White Matter Disease: AR inheritance, mutations in the elF2B gene Defective function of m RNA leads to deficient protein recycling. Clinical features: Variable age of onset is most commonly between 2 -5 years. Progressive cognitive impairment with cortico spinal & cerebellar involvement. Episodic rapid deterioration. Usually precipitated by infection or fever. Cree leuko encephalopathy: Rapidly progressive form of VWM that effects the infants.
- 56. MRI: Extensive, confluent, WM T1 hypo intensity with T2/FLAIR hyper intensity. Initially involves periventricular & deep WM. Subcortical U fibers involves later. Over time, the WM undergoes rarefaction with development of cavitation. ( “ melting away” or “vanishing” of WM). DD’s of WM rarefaction and cystic degeneration are 1. Vanishing WM disease 2. Mitochondrial encephalopathies 3. Alexander’s disease
- 57. Leuko dystrophy Episodic rapid deterioration Precipitated by fever Vanishing WM Peri ventricular & deep WM involvement disease WM rarefaction with cavitation
- 59. Adreno leukodystrophy (ALD): X-linked disorder ABCD1 gene mutation on X chromosome. Impaired oxidation of very-long-chain fatty acids (VLCFAs). Accumulation of VLCFA’s In adrenals – Addison’s disease In white matter – leuko dystrophy. In testes - infertility Only males are affected with the entire syndrome 50 % female carriers exhibit AMN like clinical picture.
- 60. Multiple phenotypes of X-ALD 1. Childhood cerebral form ~35% Classical X linked ALD Onset - 4 - 8 yrs (survival: several years) 90% with adrenal insufficiency 2. Adreno myeloneuropathy (AMN) ~50% Spastic paraparesis and sphincter dysfunction Onset - 2nd-5th decade (survival: decades) 2/3 with adrenal insufficiency 3. Other phenotypes ~15% Addison disease only Adult-onset cerebral involvement - dementia
- 61. Classical X linked ALD: Onset usually between 4 - 8 yrs of age. Progressive gait difficulty with spasticity, ataxia and Cognitive / emotional disturbance. Adrenal impairment with severe vomiting and episodes of circulatory collapse. Increased pigmentation of the oral mucosa and the skin around nipples and over elbows, knees, and scrotum. Adrenomyeloneuropathy [AMN]: Adrenal insufficiency had been present since early childhood, progressive spastic paraparesis with relatively mild polyneuropathy develops in 2nd -5th decade. Gait may have an ataxic component. Female carriers: Similar clinical picture but in mild form and without adrenal insufficiency.
- 62. Diagnosis: specific laboratory marker - excess of VLCFAs. 3 measurements are of value ( plasma, erythrocytes, leukocytes, or cultured fibroblasts): Absolute level of hexa cosanoic acid (C26), Ratio of C26 to C22 (docosahexanoic acid) (C26:C22), Ratio of C24 (tetra cosanoic acid) to C22 (C24:C22). 93 % of female carriers will show the abnormal VLCFA – when skin fibroblasts & plasma both are tested. Features of adrenal insufficiency: Low serum Na+ and ↑ K+ levels Low serum cortisol levels, Lack of rise in 17-hydroxyketosteroids after ACTH stimulation.
- 63. MRI: A posterior-predominant pattern is seen in 80%. The earliest finding is T2/FLAIR hyper intensity in the middle of the corpus callosum splenium. As the disease progresses, hyper intensity spreads from posterior to anterior and from the center to the periphery. The leading edge of demyelination appears hyper intense on T1WI but does not enhance. The intermediate zone of active inflammatory demyelination often enhances on T1 C+. Intermediate zone may also show diffusion restriction. MRS: Shows ↓ NAA even in normal-appearing WM & ↑choline, myoinositol.
- 64. Leuko dystrophy Adrenal insufficiency ↑ VLCFA’s (plasma, skin fibroblasts) Adreno Peri ventricular & deep WM involvement Leuko dystrophy Posterior predominant Contrast enhancement
- 65. Zellweger spectrum Disorders: Prototype of peroxisomal disorders. Spectrum includes: 1.Classical Zellweger disease 2.Infantile refsum’s disease 3.Neonatal adreno leuko dystrophy Classical Zellweger disease : Also called as cerebro hepato renal disease. mutation in PEX1 gene , AR inheritance. Basic biochemical abnormality: Lack of liver peroxisomes which leads to impaired oxidation of VLCFA’s. VLCFA’s particularly hexacosanoic acid were ↑↑ in the plasma and cultured skin fibroblasts.
- 66. Clinical features: Onset in the neonatal period or early infancy & leads to death 1st year of life. Facial dysmorphism, Seizures, hypotonia Global developmental delay , failure to thrive Deafness and ocular abnormalities Liver disease. Stippled, irregular calcifications of the patellae and greater trochanters are highly characteristic. MRI: Confluent T2/FLAIR hyper intensity in deep and Peri ventricular WM. Microgyria and pachygyria, often with bilaterally symmetric para sylvian lesions.
- 67. Disorders of hypo myelination Most common Pelizaeus merzbacher disease Pelizaeus merzbacher like disease POL III leuko dystrophies ( including 4 H syndrome) Hypo myelination of unknown cause Less common Hypo myelination with congenital cataracts Hypomyelination with atrophy of cerebellum and BG Salla disease Fucosidosis Cockayne syndrome GM1 & GM 2 gangliosidosis. Rare: 18 q syndrome Tay syndrome
- 68. Pelizaeus merz bacher disease: X-linked disorder. Proteo lipid protein (PLP) gene mutation. Another set of PLP mutations causes an infantile spastic paraplegia. Classic PMD – occur in males (100%). Pelizaeus merz bacher like disease( PMLD): mutations in the GJC2 gene, encoding the gap junction protein connexin47. Clinical features: Onset of symptoms is most often in the first months of life. The first signs are abnormal movements of the eyes (nystagmus, hypo metric saccades) psychomotor developmental delay with spastic qudri paresis, cerebellar and extra pyramidal involvement. Optic atrophy (with preserved pupillary reflex) Seizures (rare)
- 69. MRI: Entire cerebral WM homogeneously hyper intense on T2WI (indicates nearly complete lack of myelination). Preserved myelin around perivascular spaces - "tigroid " pattern. Hyper intensity of the pyramidal tracts or entire pons is typically present in PMLD. Leuko dystrophy Males (100%) Abnormal eye movements Pelizaeus merzbacher Diffuse WM involvement disease (New born like pattern) Tigriod appearance ↑
- 70. Pol III-related leuko dystrophies: Group of Hypomyelinating leuko dystrophies classic clinical findings & MRI features. AR inheritance Mutations in the POLR3A or POLR3B genes. Three major clinical findings: Progressive gait abnormalities with pyramidal & cerebellar involvement Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth) Hypogonadotropic hypogonadism. MRIs obtained at least six months apart after age one year reveal no significant improvement in myelination.
- 71. Five overlapping clinical phenotypes : These described as distinct entities before their molecular basis was known. These include: 4H syndrome: Hypomyelination, hypodontia, hypogonadotropic hypogonadism. ADDH: Ataxia, delayed dentition, and hypomyelination. TACH: Tremor-ataxia with central hypomyelination. LO: Leuko dystrophy with oligodontia HCAHC :Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum.
- 72. Hypomyelination and congenital cataract (HCC): AR inheritance, FAM126A gene mutation. Clinical features: Normal development in the 1st year of life. F/b slowly progressive, spastic quadriparsis with Cerebellar involvement. Mild to moderate cognitive impairment. B/L congenital cataracts peripheral neuropathy present in the many patients. MRI: features s/o hypomyelintion.
- 73. Salla disease: Also called Sialic acid storage disease or Finnish type Sialuria. AR inheritance, mutations of the SLC17A5 gene. This gene codes for sialin, a lysosomal membrane protein. Clinical features: Affected individuals normal at birth. Hypotonia presents in 1st year of life Later progressive spasticity, cerebellar signs and cognitive impairment develops. MRI: Shows features of hypo myelination. Urine free sialic acid levels – elevated.
- 74. Fucosidosis: AR disorder due to a deficiency of α-L-fucosidase Results in intra cellular accumulation of fucose containing glycolipids and glycoproteins in various organs. Clinical features: Progressive cognitive and motor deterioration, seizures, Coarse facial features, recurrent infections, organomegaly, Angiokeratoma corporis and dysostosis multiplex. MRI: T2 W images shows diffuse symmetric hyper intensity of bilateral subcortical and deep white matter along with hypo intensities in the Globus pallidus.
- 75. Cockayne syndrome: AR inheritance. The underlying disorder is a defect in a DNA repair mechanism. Diagnosis: Essential criteria: Failure to thrive & developmental delay. 2 of the 3 following criteria: Cutaneous photosensitivity, Pigmentary retinopathy, Sensory neural hearing loss, Dental caries. CT: Basal ganglia calcifications. MRI: There is atrophy which predominantly involves the supra tentorial white matter, the cerebellum, the corpus callosum, and the brain stem.
- 76. GM 1 gangliosidosis: Lysosomal storage disorder, AR inheritance. Caused by deficiency of the β –galactosidase. 3 clinical subtypes: Infantile (type 1): Features of a Neuro lipidosis (i.e, neuro degeneration, macular cherry-red spots) Muco polysaccharidosis (i.e, organomegaly, dysostosis multiplex, coarse facial features). Juvenile (type 2): slightly later age of onset. Adult (type 3): Normal early neurologic development with no physical stigmata. slowly progressive dementia with extra pyramidal features.
- 77. GM 2 gangliosidosis: Lysosomal storage disorder, AR inheritance. deficiency of the enzyme β-hexosaminidase. 3 variants: Tay–Sachs disease: HEXA gene on Ch 15, β-hexosaminidase A deficiency, Sandhoff disease: HEXB gene on Ch 5, β-hexosaminidase A & B deficiency. GM2-gangliosidosis, AB variant: GM2A gene, deficiency of co factor for β-hexosaminidase A.
- 78. Clinical features: Onset by by 4 to 6 months of age progressive delay in psychomotor development and regression of mile stones. corticospinal tract signs and visual failure. Abnormal startle to acoustic stimuli Fundus: cherry-red spot with optic atrophy. Additional findings in Sand hoff’s: Hepatosplenomegaly, Coarse granulations in bone marrow histiocytes. MRI: hypomyelination with hyper intensities in basal ganglia and thalami.
- 79. Approach to dysmyelinating diseases Deep white matter Thalami abnormal Krabbe’s disease GM2 gangliosidosis Thalami normal Brain stem specific tract involvement Zellweger spectrum disorders Brain stem normal Vanishing white matter MLD ALD Phenylketonuria
- 80. Approach to dysmyelinating diseases Subcortical white matter Hydroxy glutaric aciduria Kearns Sayer syndrome
- 81. Approach to dysmyelinating diseases Diffuse white matter With macro-cephaly Canavan disease Alexander disease Vander Knapp disease Without macro-cephaly Organic acidurias (MMA,PA,MSUD)
- 82. Approach to hypo myelinating diseases