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.

1. 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.

17. Disorders of myelination

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

26. Canavan’s disease

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

30. Alexander’s disease

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

33. Vander Knapp disease

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.

43. Kerns sayer syndrome

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.

48. Metachromatic Leuko dystrophy

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

58. Peroxisomal disorders

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