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Cystic Leukodystrophies
M.R Ashrafi
Professor of Pediatric Neurology
Children’s Medical Center
Tehran University of Medical Sciences
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Leukodystrophies
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The term leukodystrophy was introduced by
Bielschowsky and Henneberg in 1928 .
Leukoencephalopathies comprise all
inherited and acquired disorders that
selectively or predominantly involve the
white matter of the CNS irrespective of the
underlying pathophysiologic mechanism and
histopathologic basis .
The term Leukodystrophy should be
restricted to inherited diseases that affect
myelin development and maintenance .
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Leukodystrophies
Powers (2004) classified
leukodystrophies as disorders that are
known or presumed to have :
1- A genetic causation
2- A progressive clinical course
3- A predominant and usually
confluent involvement of the CNS .
4- A primary lesion of myelin or
myelinating cells .
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Leukodystrophies
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Leukodystrophies are frequently recognized
on MRI, but their identification remains a
challenge.
Their diagnosis is important for
prognostication, palliative and experimental
treatment, as well as family screening.
The diagnostic strategy rests upon
clinical clues and MRI patterns,
complemented by appropriately
selected electrophysiological and
laboratory testing.
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Leukodystrophies
 The
leukodystrophies may be
classified according to
enzymatic defect , pathology ,
etiology , affected organells and
age of onset.
 Classification
of WMDs
according to Brain MRI
findings seems to be applied
and clinically oriented .
Leukoencephalopathies
Pathologic Classification
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Hypomyelinating ( PMD )
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Dysmyelinating
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Demyelinating ( ADEM , MS )
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Spongiform ( Canavan , MLC )
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Cystic ( MLC , RNAse T2 Deficiency )
( ALD , MLD , Krabbe’s Disease )
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Cystic Leukoencephalopthies
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In addition to demyelination, several
leukodystrophies and
leukoencephalopathies present with
cystic lesions.
Cystic changes in white matter can be
seen in many neurodegenerative
disorders ,and in nonprogressive
conditions such as stroke and
periventricular leukomalacia after
neonatal hypoxic ischemia.
Cystic Leukoencephalopthies
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Megalencephalic leukoencephalopathy with
subcortical cysts (MLC).
Cystic leukoencephalopathy without
megalencephaly (RNAse T2 deficiency).
Congenital CMV infection
Cerebroretinal microangiopathy
with calcifications and cysts.
Aicardi-Goutieres syndrome
Mitochondrial leukoencephalopathies
COL4A1 associated disorder
Alexander's disease
Greatly dilated Virchow Robin or perivascular
spaces.
Leukoencephalopathy with macrocephaly and
mild clinical course (van der Knaap Disease)
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Megalencephalic leukoencephalopathy with
subcortical cysts first described by van der Knaap in
1995
Autosomal Recessive
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Malegalencephy
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Mild clinical course
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leukoencephalopathy
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(occuring in the first year of life)
( ataxia , seizures , pyramidal signs )
( subcortical cysts in temporal and parietal regions )
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CYSTIC LEUKOENCEPHALOPATHY
WITHOUT MEGALENCEPHALY
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Cystic leukoencephalopathy without
megalencephaly also known as
leukoencephalopathy with bilateral
anterior temporal lobe cysts (LBATCs)
was first described by Olivier et al. in 1998
and since then, fewer than 30 cases have
been described .
Olivier M, Lenard HG, Aksu F, GärtnerJ.
A new leukoencephalopathy
With bilateral anterior temporal lobe cysts.
Neuropediatrics
1998;29: 225-228
CYSTIC LEUKOENCEPHALOPATHY
WITHOUT MEGALENCEPHALY
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The distinctive findings of this rare condition
are bilateral temporal lobe cysts combined
with a specific pattern of multifocal white
matter lesions, with an apparently
nonprogressive condition characterized by
normocephaly or microcephaly ,
severe psychomotor delay with variable
degrees of tone and reflex abnormalities .
CYSTIC LEUKOENCEPHALOPATHY
WITHOUT MEGALENCEPHALY
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There has been some controversy in
the literature as to whether the recently
described condition  bilateral anterior
temporal lobe cysts (LBATCs)  is in
fact the end result of congenital
Cytomegalovirus (CMV) infection of the
developing brain.
RNAse T2-Deficient
Leukoencephalopathy
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A subset of subjects with subcortical cysts
and leukoencephalopathy without
megalencephaly appear to have mutations in
RNase T2, encoded by RNAseT2 (Henneke
et al., 2005 , 2009).
This is a recently described disorder and
shares clinical and neuroradiological features
with congenital CMV infection.
In RNAse T2-deficient leukoencephalopathy
there is no evidence of CMV infection, and
familial cases suggest autosomal-recessive
inheritance.
RNAse T2-Deficient
Leukoencephalopathy
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Affected subjects have normo or microcephaly,
developmental delay, and epilepsy, in some cases.
MRI reveals striking abnormalities, with multifocal
white-matter abnormalities, and temporal lobe
cystic structures similar to those seen in CMV.
CT reveals scattered calcifications in some
patients.
The pathophysiologic mechanism eliciting a clinical
and radiologic phenotype so reminiscent of
congenital CMV remains unknown .
CYSTIC LEUKOENCEPHALOPATHY
WITHOUT MEGALENCEPHALY
Congenital Cytomegalovirus
Infection
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Infants with congenital CMV infection may
present acutely in the neonatal period with
evidence of encephalopathy, neonatal
hepatitis, thrombocytopenia, and anemia,
or may present chronically with progressive
microcephaly, developmental delay, and
sensorineural hearing loss.
These subjects may pose diagnostic
challenges when MRI reveals cerebral whitematter abnormalities.
Congenital Cytomegalovirus
Infection
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These patients are often characterized as
having unsolved leukoencephalopathies.
CMV include multi focal cerebral
white-matter lesions located in the
deep white matter, predominantly in
the parietal region, associated with
dilated temporal horns and subcortical
cysts in the temporal lobe [van der
Knaap et al., 2004].
Cerebroretinal Microangiopathy With
Calcifications and Cysts (CRMCC)
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In 1988, Tolmie and co-workers reported on
two sisters with bilateral Coats disease
(retinal telangiectasia and retinal exudates),
intracranial calcification, sparse hair, and
dystrophic nails.
Subsequently Crow et al. [2003]
documented skeletal defects with a tendency
to fractures, a mixed cerebellar and
extrapyramidal movement disorder and a
leukodystrophy , termed Coats plus
syndrome.
Leukoencephalopathy with
extensive brain calcifications and
parenchymal cysts
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The association of brain calcifications (basal ganglia,
cerebellar grey nuclei, and white matter),
leukoencephalopathy and cysts is a very uncommon
disorder which was first reported in three unrelated
children by Labrune et al. in 1996 .
These patients also had progressive intracerebral
cysts without retinal abnormalities.
Leukoencephalopathy with cerebral calcifications and
cysts (LCC) is a recently described and extremely
rare entity of unknown origin .
Labrune P, Lacroix C, Goutieıres F, et al. Extensive brain calcifications,
leukodystrophy,and formation of parenchymal cysts: a new progressive
disorder due to diffuse cerebral microangiopathy.
Neurology 1996;46:1297–301
CRMCC / LCC / Coat’s plus syndrome
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CRMCC, LCC, and Coats' plus syndrome
reflect a spectrum of affected patients with
presumed microvascular disorders
affecting the brain, eyes, liver, intestines,
and bones.
An underlying genetic etiology has not been
identified, although reports of affected
siblings, male and female probands, and
children born to consanguineous families
suggest an autosomal-recessive inheritance
pattern.
Cerebroretinal Microangiopathy With
Calcifications and Cysts (CRMCC)
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Visual symptoms leading to an ophthalmologic
examination before or after the onset of neurologic
symptoms.
Ophthalmologic evaluation
identifies bilateral retinal
telangiectasias and
retinal exudates.
Cerebroretinal Microangiopathy With
Calcifications and Cysts (CRMCC)
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Patients may develop spontaneous
fractures of the long bones or skull and have
documented osteopenia.
Life-threatening intestinal bleeding may
occur, and many patients are found to have
cirrhosis or portal hypertension.
Less often, patients may have dystrophic
nails, hyperpigmented skin lesions, and
sparse hair with premature graying.
Cerebroretinal Microangiopathy With
Calcifications and Cysts (CRMCC)
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The clinical presentation of this brain disorder
includes progressive extrapyramidal and
pyramidal signs, slowed cognitive
Performances and seizures .
Because of progressive neurologic symptoms
varying by age and ranging from hypotonia
and focal motor deficits to ataxia and
extrapyramidal symptoms, neuroimaging is
often performed and suggests the diagnosis.
Cerebroretinal Microangiopathy With
Calcifications and Cysts (CRMCC)
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Neuroimaging demonstrates large progressive
calcifications of cerebral white matter, basal ganglia,
thalamus, cerebellar white matter, and dentate.
Cerebroretinal Microangiopathy With
Calcifications and Cysts (CRMCC)
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Abnormally increased signal intensity can be noted in
the cerebellar and cerebral peduncles and in both
hemispheric white matter, whereas the cortical grey
matter is spared.
Cerebroretinal Microangiopathy With
Calcifications and Cysts (CRMCC)
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Additionally, leukoencephalopathy and parenchymal
cysts are notable and often progressive findings.
Ring enhancement of the cysts wall can also
be observed .
Leukoencephalopathy with extensive brain
calcifications and parenchymal cysts
Cerebral leukoencephalopathy with calcifications and cysts operated for
signs of increased intracranial pressure: case report
Surgical Neurology 72 (2009) 177–181
Leukoencephalopathy with
extensive brain calcifications and
parenchymal cysts
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Patients may succumb to complications of their
neurologic status, such as aspiration pneumonia,
although the clinical course is variable and slow
disease progression is described.
Aicardi-Goutieres Syndrome
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In 1984, Jean Aicardi and Francoise Goutières described
eight children from five families presenting with a severe early
onset encephalopathy, which was characterized by
calcification of the basal ganglia, abnormalities of the
cerebral white matter and diffuse brain atrophy.
An excess of white cells, chiefly lymphocytes, was found in
the cerebrospinal fluid (CSF), thus indicating an inflammatory
condition.
In 1988, Pierre Lebon and his colleagues identified the
additional feature of raised levels of interferon-alpha in
patient CSF in the absence of infection.
This observation supported the suggestion that AGS was an
inflammatory disease, as did the later finding of increased
levels of the inflammatory marker neopterin in CSF .
Following an original description of eight cases in 1984, the
condition was first referred to as 'Aicardi–Goutières
syndrome' (AGS) in 1992, and the first international meeting
on AGS was held in Pavia, Italy, in 2001.
Aicardi-Goutieres Syndrome
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AGS is a genetically heterogeneous disease resulting from
mutations in any of seven genes encoding nucleases or
putative nucleases:
TREX1 [Crow et aI., 2006]
RNAseH2 A, B, and C [Crow et aI., 2006].
SAMHDI [Rice et aI., 2009]
ADAR1
IFIH1
Approximately 83 percent of patients with characteristic
AGS-related clinical findings have mutations in TREX1,
RNAseH2A ,B , C [Rice et a!., 2007].
In most cases, except for IFIH1- and rare cases of TREX1- and
ADAR1-related disease, these mutations follow an autosomal
recessive inheritance pattern .
Rarely, this condition is inherited in an autosomal dominant
pattern, result from new mutations in the gene and occur in
people with no history of the disorder in their family .
Aicardi-Goutieres Syndrome
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Aicardi-Goutieres syndrome is a disorder that mainly
affects the brain, the immune system, and the skin.
Most newborns with Aicardi-Goutieres syndrome do not show
any signs or symptoms of the disorder at birth.
However, about 20 percent are born with a combination of
features that include an enlarged liver and spleen
(hepatosplenomegaly), elevated transaminases, Coombspositive hemolytic anemia , autoimmune thrombocytopenia,,
microcephaly, seizures, vasculitic skin lesions, and cerebral
calcifications.
Often, these patients are initially suspected of having a
congenital CMV, rubella, or HIV infection .
For this reason, Aicardi-Goutieres syndrome is
sometimes referred to as a "mimic of congenital
infection."
Aicardi-Goutieres Syndrome
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Within the first year of life most individuals with AGS
experience an episode of severe brain dysfunction
(encephalopathy), typically lasting for several
months.
During this phase of the disorder, affected babies
are usually extremely irritable and do not feed well.
Sterile pyrexias
Developmental regression
Microcephaly
They also have significant neuromuscular problems
including spasticity) ,dystonia and trunk hypotonia .
Aicardi-Goutieres Syndrome
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Over time , up to 40 percent of people with AGS have
painful, itchy skin lesions, usually on the fingers, toes, and ears
,that are usually worse in the winter .
These puffy, red lesions, which are called chilblains, are
caused by inflammation of small blood vessels.
AGS Diagnostic Criteria
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Laboratory:
Normal metabolic and infectious
screening.
An increase in the number of white
cells (particularly lymphocytes) in the
CSF, and high levels of interferonalpha activity and neopterin in the
CSF are important clues , however,
these features are not always present.
AGS Diagnostic Criteria
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Neuroradiological features :
Cerebral calcifications: Calcifications on CT are seen as areas
of abnormal signal, typically bilateral and located in the basal
ganglia, but sometimes also extending into the white matter.
Calcifications are usually better detected using CT scans and
can be missed completely on MRI .
White matter abnormalities: These are found in 75-100% of
cases, and are best visualized on MRI.
Signal changes can be particularly prominent in frontal and
temporal regions , and sometimes include cystic degeneration.
Cerebral atrophy: is seen frequently
Aicardi-Goutieres Syndrome
Aicardi-Goutieres Syndrome
Aicardi-Goutieres Syndrome
Progressive Cavitating Leukoencephalopathy
A Novel Childhood Disease
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The acute phase of PCL has features of severe
encephalopathy, with irritability and opisthotonic
posturing, but without increased intracranial
pressure or CSF evidence of infections.
The essential features of progressive cavitatory
leukoencephalopathy (PCL) are irregular asymmetric
patchy areas of white matter abnormality that evolve
to develop cystic degeneration.
The cystic changes involve especially the corpus
callosum, cerebral and cerebellar white matter, and
spinal cord, with varying degrees of contrast
enhancement.
SakkuBai Naidu, December 2005 ;58:929 –938
Ann Neurol Vol 58 No 6
Progressive Cavitating Leukoencephalopathy
A Novel Childhood Disease
Progressive Cavitating Leukoencephalopathy
A Novel Childhood Disease
SakkuBai Naidu, December 2005 ;58:929–938
Ann Neurol Vol 58 No 6
Progressive cavitating
leukoencephalopathy associated
with respiratory chain complex I deficiency
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Mitochondrial diseases are a heterogeneous,
relatively common group of multisystem disorders
mostly caused by the dysfunction of one or more
enzyme complexes of the OXPHOS system.
Complex I deficiency (OMIM #252010) is the
most frequent encountered defect of the
mitochondrial energy metabolism .
Clinical presentation of defect of complex I is
heterogeneous and includes an ample array of
clinical phenotypes, such as progressive
encephalocardiomyopathy, fatal lactic acidosis,
leukodystrophy, and Leigh syndrome .
Progressive cavitating
leukoencephalopathy associated
with respiratory chain complex I deficiency
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The presence of a severe progressive cystic
leukoencephalopathy combined with elevated
lactate should prompt a thorough
mitochondrial evaluation adding to the
spectrum of white matter lesions in
OXPHOS-related disorders .
Kohlschütter A, Bley A, Brockmann K, Gärtner J, KrägelohMann
I, Rolfs A, Schöls L (2010) Leukodystrophies and other
genetic metabolic leukoencephalopathies in children and adults.
Brain Dev 32:82–89
Progressive cavitating
leukoencephalopathy associated
with respiratory chain complex I deficiency
COL4A1 associated disorder
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COL4A1 mutations were recently identified as a monogenetic
cause of weakness of the basement vascular membranes,
resulting in small vessel disease and hemorrhage.
The manifestations are widespread, involving the brain and
eyes most commonly and other organs such as the kidneys.
There is a growing spectrum of pediatric presentations of
COL4A1 mutations.
The earliest presentation is antenatal or perinatal cerebral
hemorrhage.
Porencephaly presents as infantile hemiplegia with or without
recognized antenatal or perinatal events.
COL4A1 mutations were first described as a cause of perinatal
cerebral hemorrhage in mice and they were also identified in
humans with autosomal dominant porencephaly.
COL4A1 associated disorder
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In patients with a history of familial
intracranial hemorrhage and stroke; as well as
familial intraventricular hemorrhage and
porencephalic cysts in neonates, this disorder
should be considered as a possible cause of
cystic leukoencephalopathy [Gould et al., 2005].
The white matter change in COL4A1 when present
tends to be within the cerebral small vessel
distribution affecting the deep cerebral white
matter and subcortical white matter but sparing
the U-fibres.
The distribution tends to be bilateral, anterior, and
posterior in a symmetrical fashion.
The porencephaly when present can be unilateral or
bilateral.
COL4A1 associated disorder
COL4A1 associated disorder
Greatly dilated Virchow Robin
or perivascular spaces
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Significantly dilated perivascular spaces can
be seen in a small percentage of normal
children [Boddaert et aI., 2009; Groeschelet
aI., 2006; Artigas et aI.,1999] and with
higher frequency in children with migraines
[Lewis and Dorbad, 2000].
Autistic Spectrum Disorderes
Mucopolysaccharidosis (Hurler's/Scheie's
syndrome)
Structural chromosomal abnormalities
Greatly dilated Virchow Robin
or perivascular spaces/ MPS
Mucopolysaccharidosis
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Cystic Periventricular
Leukomalacia
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Cystic changes in white matter can be seen in many
neurodegenerative disorders ,and in
nonprogressive conditions such as stroke and
periventricular leukomalacia after neonatal hypoxic
ischemia.
Conclusion
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Approximately half of childhood
leukoencephalopathies remain
unclassified despite extensive
laboratory, instrumental and molecular
investigation [1].
Cystic leukoencephalopathies are a
group of rare genetic and acquired
disorders of white matter that must be
considered in any unclassified
leukoencephalopathies .
1- van der Knaap MS, Breiter SN, Hart AAM, Valk J. Defining
and categorizing leukoencephalopathies of unknown
origin: MR imaging approach. Radiology 1999;213:121–
Thank You for your attention
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