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Iran J Child Neurol. 2014 Autumn Vol 8 No 4 Suppl. 1
Leukodystrophies with Intracranial Calcications
How to Cite This Article: Mahvelati Shamsabadi F. Leukodystrophies with Intracranial
Calcications. Iran J Child Neurol. Autumn 2014;8;4(Suppl.1):16-17.
Farhad MAHVELATI SHAMSABADI MD
Child Neurologist, Pediatric
Neurology Research Center, Mod
Children’s Hospital, Tehran, Iran
Corresponding Author:
Mahvelati Shamsabadi F. MD
Pediatric Neurology Research
Center, Shariati Ave, Tehran, Iran
Tel: +98 912 1099758
Fax: +98 21 22909559
E-mail:fmshamsa@yahoo.com
The leukodystrophies are a heterogeneous group of diseases, which primarily
affect white matter. An integrated description of the clinical, neuroimaging and
pathophysiological features is crucial for categorizing these disorders. A group of
leukoencephalopathies are associated with calcications. In this article, we review
these disorders briey.
Aicardi-Goutieres Syndrome: Aicardi-Goutieres syndrome (AGS) is a genetically
heterogeneous autosomal recessive group of encephalopathies with 5 subtypes.
Classic AGS is characterized by cerebral atrophy, white matter abnormalities,
intracranial calcications, chronic CSF lymphocytosis, and elevated CSF alpha-
interferon. Broadly speaking, 2 clinical presentations have been delineated: an early
onset neonatal form, highly reminiscent of congenital infection seen particularly
with TREX1 mutations, and a later-onset presentation, sometimes occurring after
several months of normal development and occasionally associated with remarkably
preserved neurologic function. Severe neurologic dysfunction becomes clinically
apparent in infancy, and manifests as progressive microcephaly, spasticity, dystonic
posturing, profound psychomotor retardation, and often death in early childhood.
Outside the nervous system, thrombocytopenia, hepatosplenomegaly, and elevated
hepatic transaminases along with intermittent fever may also erroneously suggest an
infective process. It is important to exclude of pre-/perinatal infections, in particular
the TORCH complex. Genetic screening for mutations in the four genes known to
cause AGS allows denitive conrmation of the diagnosis in the majority (83%).
Cockayne ‘s syndrome: Cockayne syndrome is an autosomal recessive disease due
to a DNA repair defect. Patients show psychomotor developmental delay, dwarsm,
progeroid appearance, microcephaly, deafness, pigmentary retinal degeneration,
optic atrophy, and photosensitivity. Abnormal peripheral nerve conduction is due
to a demyelinating polyneuropathy. Neuroimaging shows brain atrophy of variable
degree, namely in brainstem and cerebellum; abnormally high signal intensity on
T2-weighted images throughout the hemispherical white matter; late involvement
of the subcortical bers; abnormal hyperintensity on T1-weighted images in the
basal ganglia corresponding to calcication.
Cystic leukoencephalopathy without megalencephaly (RNASET 2-decient
cystic leukoencephalopathy): It is caused by homozygous or compound
heterozygous mutation in the RNASET2 gene on chromosome 6q27. Neurologic
decits were noted within the rst months of life, and included severe intellectual
impairment, motor retardation, and spasticity. Brain MRI showed extensive cysts
within the anterior temporal lobes, ventricular enlargement, and white matter
disease. The signal intensities of the cysts were identical to those of cerebrospinal
uid. CT scans showed intracranial calcications in some subjects.
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Iran J Child Neurol. 2014 Autumn Vol 8 No 4 Suppl. 1
connective tissue. In the fourth decade, patients
developed neuropsychiatric symptoms, including
memory impairment, euphoria, loss of social inhibitions,
and impotency or frigidity. Neurologic examination
showed exaggerated deep tendon reexes, pathologic
reexes, and dysplasia. Patients usually die between
ages 35 and 45, and the later features of the disorder
resemble those of Alzheimer disease.
Globoid Cell Leukodystrophy (Krabbe Disease): The
manifestations of Krabbe disease are due to accumulation
of galactocerebrosides and galactosylsphingosine,
which in turn leads to loss of oligodendrocytes. Infantile
Krabbe disease presents in the rst 6 months of life as
hyperirritability, increased muscular tone, fever, and
developmental arrest. As the disease progresses, there
is further cognitive decline, myoclonus, opisthotonus,
nystagmus, and optic atrophy. Patients diagnosed in
infancy rarely survive beyond 2 years. In an estimated
10% of cases, symptoms begin after the patient has
begun to walk; these are considered “late-onset.” Central
motor signs include spasticity, ataxia, and weakness. Of
late-onset patients, 20% have abnormal peripheral nerve
conduction studies with uniform slowing of conduction
velocities.
Demyelination of the deep WM, progressively involving
the subcortical white matter. Calcications within the
thalami, basal ganglia, and corona radiata shown by CT
scan.
Cerebrotendinous xanthomatosis: Also called
cerebral cholesterosis, is an autosomal recessive form
of xanthomatosis. it is characterized by progressive
cerebellar ataxia beginning after puberty and by juvenile
cataracts, juvenile or infantile onset chronic diarrhea,
childhood neurological decit, and tendineous or
tuberous xanthomas. The initial clinical manifestation
may be neonatal cholestasis or chronic diarrhea from
infancy. In 75% of cases, cataract is the rst nding,
often appearing in childhood. Pyramidal signs and/or
cerebellar ataxia are present in the 20s or 30s. Patients
may experience extrapyramidal manifestations (dystonia
and atypical parkinsonism), and peripheral neuropathy.
MRI shows bilateral hyperintensity of the dentate nuclei
and cerebral and cerebellar white matter.
Leukoencephalopathy with calcications and cysts:
Triad of leukoencephalopathy, cerebral calcications
and cysts (LCC) is a recently reported rare disease
named ‘Labrune syndrome’. The clinical presentation
is insidious and variable. Typically, initial symptoms
are of raised intracranial pressure, later followed
by focal neurologic decits resulting in spasticity,
dystonia, seizures, and cognitive decline. Cerebroretinal
microangiopathy with calcications and cysts, an
autosomal recessive disorder caused by mutation in the
CTC1 gene that shows phenotypic similarities to Labrune
syndrome. CRMCC includes the neurologic ndings of
intracranial calcications, leukodystrophy, and brain
cysts, but also includes retinal vascular abnormalities
and other systemic manifestations, such as osteopenia
with poor bone healing, a high risk of gastrointestinal
bleeding, hair, skin, and nail changes, and anemia and
thrombocytopenia. Although Coats plus syndrome
and Labrune syndrome were initially thought to be
manifestations of the same disorder, namely CRMCC,
molecular evidence has excluded mutations in the CTC1
gene in patients with Labrune syndrome, suggesting that
the 2 disorders are not allelic.
Naku-Hakola’s disease: Affected patients had onset in
the third decade of pain and swelling following strain
of the wrist or ankle; fractures occurred after minor
accidents. Radiographs showed cystic rarefactions in the
epiphyseal regions of bones. The cysts contained jelly-
like material and microscopically showed membranous
and lamellar structures between fatty and collagenous
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Keywords: Leukodystrophy; Calcication; Bbrain
white matter; Children