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Control# 591
Title: “It’s not a Rorschach test” Imaging
pattern recognition of pediatric metabolic
disorders of the brain
eEdE# eEdE-162
Nothing To Disclose
“It’s not a Rorschach test”
Imaging pattern recognition of pediatric
metabolic disorders of the brain
Nucharin Supakul, MD1
Chang Y Ho, MD2
1 Ramathibodi Hospital, Mahidol University
Bangkok, Thailand
2 Riley Hospital for Children
Indiana University School of Medicine
Indianapolis, Indiana, USA
Purpose
• To review the characteristic imaging
findings of inherited metabolic disorders
involving the brain categorized primarily by
location
Gray matter
White matter
Both Gray and White matter
• To recognize imaging patterns for the most
common disorders in each group
Introduction
• Metabolic brain disorder
 Genetic condition  enzyme deficiency and metabolism problem
• Overall incidence: 1: 1,000 – 2,500 newborns
• Higher incidence in certain ethnic population: Ashkenazi Jews
• Imaging is typically bilateral and symmetric, with progressive
functional deterioration without treatment.
• Type
 Hypomyelination (Pelizaeus – Merzbacher disease, 18q deletion syndrome, 4H syndrome)
 Lysosomal storage disorder (Hurler syndrome, Neimann-Pick disease, metachromatic
leukodystrophy, Tay-Sachs disease, Gaucher disease, Fabry disease, Krabbe disease)
 Mitochondrial disorders (Leigh syndrome, myoclonic epilepsy with Ragged red fiber (MERRF),
MELAS)
 Peroxisomal disorder (Zellweger syndrome, X-linked adrenoleukdystrophy)
 Glycogen storage disease (von Gierke disease (type I), Pompe disease (type II), type III-VII)
 Metal metabolism disorders (Wilson disease, hemochromatosis)
 Others: Alexander disease, Canavan disease, Galactosemia, Maple syrup urine disease,
Phenylketouria (PKU), Friedreich ataxia, Organic academia, Urea cycle disorder
http://www.webmd.com/a-to-z-guides/inherited-metabolic-disorder-types-and-treatments
Case list
Predominantly White Matter
Predominantly Gray Matter
• Pelizaeus - Merzbacher
disease
• Leigh syndrome
• MELAS
• X-linked
adrenoleukodystrophy (ALD)
• Metachromatic
leukodystrophy
• Alexander disease
Both Gray and White Matter
• Canavan disease
• Krabbe disease
• Tay-sachs disease
Predominantly White Matter
Hypomyelination
Demyelination
(Myelination never matures)
(Loss of myelination)
Pelizaeus-Merzbacher disease
Deep WM
Subcortical WM
(Early subcortical U-fiber involvement)
Look at thalami
T1hyper/T2hypo
- Krabbe disease
- GM2 gangliosidosis
(Tay Sachs)
Involvement
X-linked ALD
Normal thalami
Look at brainstem/
corticospinal tract
No involvement
- Metachromatic leukodystrophy
- Phenylketouria
Macrocephaly
Normocephaly
- Galactosemia
- Salla disease
- Alexander disease
- Megalencephalic
leukoencephalopathy with
subcortical cysts (MLC)
Predominantly Gray Matter
Deep GM
Cortical GM
Striatum (caudate + putamen)
Globus pallidus
T2 hypointense
T2 hyperintense
- Pantothenate kinaseassociated degeneration
- Leigh syndrome
- MELAS
- Organic acidurias
- Wilson’s disease
- Juvenile Huntington’s disease
- Hypoglycemia
- Urea cycle disorder
- Organic acidurias
- Kernicterus
- CO, cyanide toxicity
Normal T2/
T1 hyperintense
- Chronic liver disease
- Mineralizing angiopathy
Both Gray and White Matter
Cerebral cortex
Deep GM
Look at long bones and spinal column
Normal
+ Cortical migrational
anomalies
- Congenital CMV
- Congenital muscular
dystrophy (type II
lissencephalies)
- Cortical migrational
anomalies
- Alpers disease
- Menkes disease
Abnormal
- Lipid storage disorder
- Peroxisomal disorders
Thalami
- Krabbe disease
- GM1/ GM2 gangliosidoses
Striatal
(putamen + caudate)
- Leigh syndrome
- MELAS
- Organic acidurias
- Wilson’s disease
Globus pallidus
- Canavan disease
- Late phase Kearns-Sayre syndrome
- Maple syrup urine
- CO/ cyanide toxicity
PELIZAEUS-MERZBACHER
DISEASE
Pelizaeus - Merzbacher disease
• X-linked disorder
• Mutation of proteolipid protein 1
(PLP1) gene
• Chromosome X (Xq22)
• Defective central nervous
system myelination
• 1: 500,000 in USA
• 1: 100,000 – 1,000,000
internationally
• Clinical presentation
 Nystagmus in 1st year of life
 Delayed motor and cognitive
milestones
 Ataxia
• Prototype of hypomyelination
syndrome: Involving WM
only
• Normal myelination pattern
 Sequence to look for
maturation
 < 1 year of life: ↑ T1
 > 1 year of age: ↓ T2 for myelin
compaction, delays ↑ T1
 Pattern of ↑ T1
 At birth: Corticalspinal tract,
Rolandic gyri
 4 months: Splenium, Anterior
limb of the internal capsule, deep
cerebellar white matter and brain
stem
 6 months: Genu of corpus
callosum, paracentral WM of
occipital and parietal lobes
 8 months: Nearly adult
configuration with lack of
myelination of frontal subcortical
WM in T1
Pelizaeus-Merzbacher disease
A
B
C
3-month-old male infant, with history of nystagmus, hypotonia and developmental delay
A: Axial T1 of the basal ganglia level shows lack of normal T1 hyperintensity of the posterior limb of
the internal capsule (orange arrows) in this 3 month old, normally expected to be myelinated at birth.
B: Axial T2 of the basal ganglia level shows a lack of T2 hypointensity from normal myelin compaction
with some expansion of the posterior limb of the internal capsule from edematous change (orange
arrows).
C: Axial T2 through the cerebellum shows diffuse T2 hyperintensity of the cerebellar white matter
(yellow arrows), normally expected to be myelinated with decrease in T2 signal. There is only mild
myelin compaction in the dorsal brainstem (blue arrow).
Back to case list
X-LINKED
ADRENOLEUKODYSTROPHY
X-linked Adrenoleukodystrophy
•
•
•
•
•
1: 20,000 - 70,000
Peroxisomal disorder
Chromosome X
Mutation of ABCD1 gene
Impaired oxidation of very
long chain fatty acids 
accumulation of very long
chain fatty acids in
tissues throughout body
• Affects myelin, spinal
cord, peripheral nerves,
adrenal cortex and Leydig
cells of the testes
• Classic Radiographic
Findings:
 Symmetrical, confluent T2
hyperintensity
 Early: peritrigonal
(parietooccipital white
matter), splenium of corpus
callosum
 Late: corticospinal tract,
fornix, visual and auditory
pathway
 Enhancement and restricted
diffusion in peripheral zone
of active disease
 Spared subcortical U fiber
X-linked Adrenoleukodystrophy
9-year-old boy with history of developmental
delayed
A: Axial FLAIR shows symmetric T2 prolongation
involving the splenium (orange arrow), periatrial
(blue arrows) and capsular white matter (pink
arrows) is seen in this classic pattern of X-linked
adrenoleukodystrophy.
B: DWI image shows peripheral areas of
diffusion restriction (green arrows), indicative of
acute demyelination
A
B
C: Coronal T1 post contrast shows
enhancement (purple arrow) of the
intermediate zone of demyelination
which is typical of progressive X-ALD.
in
C
long
D
D: MRI spectroscopy of the involved
white matter demonstrates decrease
NAA (yellow arrow), elevation of
choline (red arrow) and myo-inositol
(blue arrow) with significant presence
of lactate (orange arrow) and lipid
break down products including very
chain fatty acid molecules in the 0.9
to 2.4 ppm range (pink star).
Back to case list
METACHROMATIC
LEUKODYSTROPHY
Metachromatic Leukodystrophy
•
•
•
•
1: 100,000 in USA
Autosomal recessive
Lysosomal storage disorder
Defect in arylsulfatase-A
(ARSA) accumulation of
sulfatides in both PNS and
CNS  demyelination with
lack of perivascular
inflammation and uptake within
macrophages of
metachromatic granules
• Risk: Habbanite Jews and
Navajo Indians
• Clinical presentation: toddler
with visual and oromotor
impairment and abdominal
pain
• Classic Radiographic
Findings: Confluent butterflyshaped T2 hyperintensity
involving deep cerebral white
matter
 Early: spares subcortical Ufibers
 Late: involves subcortical Ufibers and corpus callosum
 No enhancement  lack of
inflammation
 Tigoid appearance  spared
perivenular myelin
Metachromatic leukodystrophy
6-year-old girl, progressive hypotonia
A: Axial T2 FLAIR shows diffuse white matter
demyelination with symmetrical, confluent
areas of T2 hyperintensity in a "butterfly"
pattern within frontoparietal deep
periventricular white matter (orange arrows)
and corpus callosum (blue arrows).
A
B
B: Axial T2 image above the ventricles shows
confluent symmetric involvement of the
centrum semiovale with sparing of the
subcortical U fibers (yellow arrows) as well as
the perivenular myelin (pink arrows) giving the
appearance of a "tigroid" pattern.
C: Post contrast imaging shows no
enhancement, due to the lack of parenchymal
inflammation seen with this disease.
D: There is decreased diffusion seen in the
areas of active demyelination (green arrows).
C
D
Back to case list
ALEXANDER DISEASE
Alexander Disease
•
•
•
•
Fibrinoid leukodystrophy
Rare
Autosomal dominant
Mutation of glial fibrillary acidic
protein (GFAP)
• Chromosome 17 (17q21)
• Rosenthal fiber
intracytoplasmic astrocytic
inclusion  leading to
oligocytic dysfunction
• 3 forms
 Infantile (most common): birth –
2 years
 Juvenile: 2-12 years
 Adult : > 12 years old
• Clinical presentation
 Macrocephaly
 Seizure
 Developmental delay
 Symmetrical T2 hyperintense
bifrontal WM
• Classic Radiographic
Findings:
 Confluent T2 hyperintensity
involving periventricular white
matter with frontal to occipital
gradient
 Basal ganglia involvement in
infantile form
 Nodular areas of enhancement
 Extension to subcortical white
matter in late stage
Alexander Disease
3-year-old girl with
developmental delay
A
B
C
D
A-D: Axial FLAIR images show
confluent areas of FLAIR
hyperintensity involving subcortical
U-fiber and periventricular white
matter predominantly in bifrontal
lobes with some parietal and
occipital lobes as well as
periaqueductal gray matter and
cerebellum (orange arrows).
Involvement of the caudate head
and putamen is also noted (blue
arrow).
Back to case list
LEIGH SYNDROME
Leigh syndrome
•
Synonym: subacute necrotizing
encephalomyelopathy
•
•
A group of heterogenous diseases
involving mitochondrial metabolism
•
Autosomal recessive, X-linked
•
Progressive neurodegeneration leading
to respiratory failure and death
•
1:32,000
•
Clinical presentations: usually by age
 Restricted diffusion in acute
of 2 years
phase
 Psychomotor delay/regression
 MRS: ↑ choline, ↓ NAA, ↑ lactate
 Hypotonia
peak
 Progressive BS & BG dysfunction:
ataxia, ophthalmoplegia, ptosis,
Remark: lower BS (pons, medulla) with
swallowing & respiratory difficulties, minimal BG involvement = SURF1
dystonia
mutation
Diagnostic clue
 Bilateral, symmetrical
 ↑ T2/FLAIR hyperintensity
 Locations:
 Basal ganglia (BG): putamen >
caudate heads > globi pallidi
 Brainstem (BS): periaqueductal
gray matter, substantia
nigra/subthalamic nuclei, pons,
medulla
 Thalami and dentate nuclei
Leigh syndrome
Differential diagnosis:
• Profound perinatal asphyxia 
appropriate clinical history, low APGAR
• MELAS  asymmetric/unilateral
• Glutaric aciduria type 1  opercular
widening
• Wilson disease  T1 shortening GP from
hepatic failure
Leigh syndrome (non-SURF1)
7-year-old girl with history of spasticity and
developmental delays
A-B: Axial T2 (A) and FLAIR (B) image shows
T2 hyperintensity of the bilateral caudate and
putamen (orange arrows) as well as the corpus
callosum and periventricular white matter (blue
arrows). The bilateral caudate heads appear
swollen, while the putamina appear atrophic.
Note the cavitation of the splenium and
periatrial white matter (pink arrows).
A
B
C: Axial b=1000 DWI image shows
decreased diffusion corresponding
to bright signal of the bilateral
caudate heads and some spots in
the putamina (yellow arrows). This
correlates with more acute injury.
D: MR spectroscopy of the basal
ganglia shows a prominent lactate
doublet peak at 1.4ppm (green
arrow).
C
D
Leigh syndrome (SURF1 mutation)
8-month-old with history of
seizure
A: Axial T2 image at the level
of the lower medulla shows
abnormal T2 hyperintensity of
the central gray structures (blue
arrow).
A
B
C
D
B-D: Axial DWI b=1000 shows
focal symmetric bilateral
diffusion restriction of the
pontine tegmentum, midbrain
tegmentum the subthalamic
nuclei, and cerebral peduncles
(orange arrows).
Back to case list
MELAS
(MITOCHONDRIAL MYOPATHY ENCEPHALOPATHY
LACTIC ACIDOSIS AND STROKE-LIKE EPISODE)
MELAS
• Synonym: Mitochondrial
myopathy, Encephalopathy,
Lactic acidosis and Stroke-like
episodes
• Mitochondrial disorder
• Multiple mutations of
mitochondrial DNA
• Defect in oxidative
phosphorylation of the brain
parenchyma and vessels
• Clinical presentation
 Weakness and exercise
intolerance
 Neuropsychiatric changes
 Migraines
 Cardiomyopathy
 Diabetes
 Hearing loss
• Classic Radiographic
Findings:
 Stroke-like lesions
indistinguishable from vascular
infarction, but typically does not
follow a vascular distribution
 Usually involve posterior
cerebral hemispheres and basal
ganglia
 Multiple stroke-like lesions of
varying age
 Consider MELAS in
unexplained strokes in pediatric
patients and young adults
MELAS
20-year-old female with history of new onset left
facial droop, and visual loss. Additional history
of prior stroke
A-B: Axial FLAIR images shows FLAIR
hyperintensity and swelling of the right temporal
lobe, occipital, and insular cortex (orange arrows).
In addition, the pulvinar region of the thalamus is
also involved (yellow arrow) in the these stroke-like
lesions. This involves both the PCA and MCA
arterial distributions.
A
B
Note the atrophy of the left occipital lobe and left
temporal lobe tip from prior stroke-like involvement
(blue arrow).
C: Axial ADC image shows decreased signal of the
right posterior parietal lobe consistent with an acute
stroke-like lesion (pink arrows).
C
D
D: Coronal T2 image shows right temporal and
occipital hyperintensity and swelling from acute
stroke-like lesion (orange arrow). Note the focal
hyperintensity and swelling in the inferior left
cerebellar hemisphere (green arrow) which showed
no diffusion restriction consistent with a subacute
lesion.
Back to case list
CANAVAN DISEASE
Canavan disease
• Synonym: spongiform
leukodystrophy
• 1: 6,000 – 14,000 among
Ashkenazi Jews
• 1: 40 carrier risk
• Autosomal recessive
• Chromosome 17
• Defect of aspartoacylase 
accumulation of N-acetyl
aspartic acid in brain and urine
• Clinical presentation
 Macrocephaly
 Seizure
 Hypotonia
• Classic Radiographic
Findings:
 Symmetrical confluent T2
hyperintensity
 Location:
 Peripheral WM: subcortical U-fiber
involved early
 Deep gray matter: thalami, globi
pallidi, dentate nuclei
 Early sparing internal capsule,
corpus callosum,
 Restricted diffusion in acute
phase
 No enhancement
 Highly suggestive : ↑NAA on
MRS
Canavan disease
4-month-old boy with history of
macrocephaly and seizure
A-B: Axial DWI (b=1000) images show
restricted diffusion in the subcortical Ufibers of the frontal and occipital lobes
and corpus striatum (orange arrows).
A
C
C: Axial T2 on a followup
imaging in 3 months of the
same patient shows
increased T2 signal of the
bilateral caudate and putamen
(blue arrows).
B
D
D: MRI spectroscopy of the
affected left parietal white
matter demonstrates
significant elevation of NAA
(pink arrow) and relative
decrease in choline (green
arrow).
Back to case list
KRABBE DISEASE
Krabbe disease
•
Synonym: Globoid cell
leukodystrophy
•
1:100,000 in USA and Europe
•
6:1,000 in Israel
•
Autosomal recessive
•
Deficiency of lysosomal
galactocerebroside b-galactosidase
•
Accumulation of galactosylceramide
and psychosine within
oligodendroglia and Schwann cells
in early period of myelin turnover
•
Formation of globoid cell
(hematogeneous oftenmulinuclearted macrophages):
Hallmark of Krabbe disease
•
4 forms




•
Infantile: 3 - 6 months
Late infantile: 6 months – 3 years
Juvenile: 3 - 8years
Adult : > 8 years
Classic presentation of Infantile
form
 Early: Irritability, hypertonia,
hyperesthesia, psychomotor arrest
 Late: Rapid deterioration, elevated
protein in CSF, neurological
evidence of WM disease, optic
atrophy and death
•
Classic Radiographic Findings:
 Confluent areas of T2 hyperintensity
 Involving bilateral central WM,
corticospinal tract, basal ganglia and
thalami
 Cranial nerve and peripheral nerve
enlargement and enhancement
Krabbe disease
20-month-old girl with history of
seizure, and developmental delay
A
C
B
D
A-B: Axial T2 images shows diffuse
confluent white matter T2 hyperintensity
and atrophy with some sparing of
subcortical U-fibers (orange arrows).
Note the atrophy of the involved bilateral
thalami, brain stem and corticospinal
tract in cerebral peduncle (blue arrows).
C: Axial FLAIR image shows symmetric,
confluent T2 hyperintensity of the central
white matter with involvement of the
corticospinal tract (posterior limb of the
internal capsule) (pink arrows) and
sparing of the subcortical white matter
(red arrows).
D: Axial T1 postcontrast shows enlarged
bilateral cranial nerve V (green arrows),
a hallmark of metabolite deposition in
Krabbe disease.
Back to case list
TAY-SACHS DISEASE
Tay-Sachs disease
•
Tay-Sachs and Sandhoff diseases
are both GM2 gangliosidoses, and
are clinically indistinguishable
•
Autosomal recessive
•
Lysosomal storage disorder
•
b-hexosaminodase A deficiency
(Sandhoff disease is deficiencies
in both A and B subunits)
•
Accumulation of
glycosphingolipids (GM2
gangliosides) in brain
•
•
1:30 carrier frequency in
Ashkenazi Jewish and French
Canadians
3 Forms:
 Infantile: symptom onset in 1st year
 Juvenile: 2-6 years
 Adult: 1st-3rd decades
•
Clinical presentation
 Infant: psychomotor retardation
 Juvenile/Adult: atypical spinocerebellar
ataxia
•
Classic Radiographic Findings:
 Infantile
 T1 hyper/T2 hypo thalami (CT
hyperdense)
 Mild T2 hyper striatum
 Location: thalami, striatum, cerebral >>
cerebellar WM
 Deep white matter delayed myelination
with callosal sparing
 Juvenile/adult
 Cerebellar atrophy
 Location: rare striatal and mass-like
brainstem involvement
 No contrast enhancement
 No corpus callosum involvement
Tay-Sachs disease
A
B
C
2-year-old boy with history of seizure and feeding dysfunction
A: Axial CT shows bilateral diffuse symmetric hyperintensity of the thalami (orange arrows).
B: Axial T1 image shows diffuse T1 hyperintensity of the thalami (orange arrows), and lack of normal
T1 bright myelination of the posterior periventricular white matter (pink arrows). There is sparing of the
corpus callosum.
C: Axial T2 image shows heterogeneous signal of the thalami (orange arrows) (more specific to TaySachs) and increased T2 signal of the basal ganglia (red arrows). There is loss of normal T2
hypointense myelin compaction of the periventricular white matter (blue arrow) with sparing of the
corpus callosum
Back to case list
Summary: Predominantly White Matter
Pelizaeus Merzbacher disease
Metachromatic
Leukodystrophy
Causes
Classic Radiographic findings
Remarks
Hypomyelination
Location: Isolated WM involvement
•
Description: Hypomyelination compared to
patient’s age
•
Location: Anterior and posterior deep white
matter
•
•
•
Lysosomal storage
disorder
Description: Confluent butterfly-shaped T2
hyperintensity involving deep cerebral white
matter
X-linked
adrenoleukodystrophy
Peroxisomal
disorder
Location: Posterior/peritrigonal white matter
Description: Confluent T2hyperintensity
involving predominantly parietooccipital
white matter (posterior) and splenium of
corpus callosum
Alexander disease
Other
Leukodystrophy
(Mutation of glia fibrillary
acidic protein (GFAP))
Location: Anterior periventricular >
subcortical white matter
± BG, thalami, brain stem, cerebellum,
fornix, optic chiasm, spinal cord
•
•
•
•
•
•
•
•
•
•
Description: Confluent T2hyperintensity
involving predominantly frontal white matter
(anterior)
Prototype of
hypomyelination
Lack of normal myelin
maturation
Anterior and posterior
Central WM
Sparing subcortical U fiber
in early course
No enhancement
Tigroid appearance
Posterior location
Central WM
Restricted diffusion and
enhancement in the edge
of the lesions
Can be frontal (anterior) in
atypical cases (10%)
Anterior predominantly
Central WM
Enhancement in the edge
of the lesions
Macrocephaly
Summary: Predominantly Gray matter
Leigh syndrome
- Non- SURF1
mutation
Causes
Classic Radiographic findings
Remarks
Mitochondrial
disease
Location:
BG: putamen > caudate heads > globi
pallidi
BS: periaquedutal gray matter,
substanita nigra/subthalamic nuclei
Thalami and dentate nuclei
•
•
Restricted diffusion in
acute phase
No contrast
enhancement
Description: Symmetrical areas of
T2/FLAIR hyperintensity with restricted
diffusion in acute phase
Leigh syndrome
- SURF1 mutation
Mitochondrial
disease
Location: Lower BS (pons, medulla)
with mild BG involvement
•
Lower BS (pons,
medulla) with mild BG
involvement
•
Consider MELAS for
unexplained strokes
in pediatric patients
Description: Symmetrical areas of
T2/FLAIR hyperintensity with restricted
diffusion in acute phase
MELAS
Mitochondrial
disorder
Location: Posterior cerebral
hemisphere and basal ganglia
Description: Stroke-like lesions,
varying age. Do not follow vascular
territory.
Summary: Both Gray and White matter
Canavan
disease
Tay-Sachs
disease
Causes
Classic Radiographic findings
Remarks
Other
Leukodystrophy:
Autosomal
recessive
Location:
Peripheral WM: subcortical U-fiber
Deep Gray matter: Globi pallidi, thalami
• ↑ NAA
(Deficiency of
enzyme
aspartoacylase)
Description: Conflent T2 hyperintenisty involving
subcortical U-fiber, globi pallidi, thalami with early
sparing of the internal capsule and corpus
callosum
Lysosomal
storage disorder
Location: Thalami, striatum, cerebral >>
cerebellar WM
Description:
- Areas of T1 hyper/T2 hypointensity involving
thalami
- Hyperdensity on CT
- Deep white matter delayed myelination
Krabbe disease
Lysosomal
storage disorder
Location: Central WM, corticospinal tract
basal ganglia, and thalami
Description: Symmetrical confluent areas of
T2/FLAIR hyperintensity involving central WM,
cortical spinal tract, BG and thalami
Cranial nerve and peripheral nerve enlargement
and enhancement
•
•
No enhancement
Restricted diffusion in
acute phase
•
No contrast
enhancement
No corpus callosum
involvement
•
•
Cranial nerve and
peripheral nerve
enlargement and
enhancement
Conclusion
• Inherited metabolic disorders affecting the brain are
complex, heterogeneous and have varied clinical
symptoms, but primarily present with progressive
functional deterioration without treatment
• Cross-sectional imaging can be helpful, especially
MRI, which can be tailored to narrow the differential
diagnosis and guide further evaluation and treatment.
Bilateral symmetric findings are typical.
• Characteristic imaging findings and patterns
suggesting metabolic brain disease should prompt
further genetic/ metabolic evaluation, particularly when
the clinical history is nonspecific.
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http://www.webmd.com/a-to-z-guides/inherited-metabolic-disorder-typesand-treatments