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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2984_Библиотеки_им_академика_М_И_Перельмана
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S. Sundaram, S. V. Chandrasekharan and S. S. Nair
212
phenotype with rapid progression due to involvement of both brain and
peripheral nerves. The common clinical presentation includes
developmental delay or psychomotor regression, ataxia, progressive spastic
quadriparesis, dysphagia, blindness, deafness, seizures, diffuse atrophy and
weakness [4].
Table 1. Clinical features of MLD subtypes
MLD subtypes
Age of onset
Clinical features
Prognosis
Late infantile
MLD
6 months – 2
years
Progressive loss of motor
developmental milestones followed
by speech and intellectual functions,
hypotonia followed by spasticity,
peripheral neuropathy
Death within 5
years of onset
Juvenile MLD
Early: 4-6 years
Late: 6-15 years
Progressive deterioration in school
performance followed by gait
disturbances, seizures can occur,
peripheral neuropathy is very
common
Slower progression
than late infantile
form
Adult MLD
≥16 years
Predominant neuropsychiatric
symptoms or dementia as initial
manifestations, followed by gait
disturbances, ataxia and spastic
paraparesis, peripheral neuropathy
may be seen
Very slow
progression, mean
survival is 12 years
but can extend up to
decades
7.1. Late Infantile Form
The late infantile form presents typically with difficulty in walking as
the initial symptom. Later, there is progressive loss of previously attained
motor developmental milestones followed by decline in speech and
intellectual functions. Occasionally, patients can present with features of
peripheral neuropathy such as muscular hypotonia and hyporeflexia/
areflexia, later on, followed by appearance of corticospinal tract
involvement (spasticity, and hyperreflexia) [4]. Ataxia, spastic paresis, and
optic atrophy are also common accompaniments of this form. Systematic
review of literature has shown that nearly 61% patients present with motor
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or gait abnormalities and 39% with seizures [50]. Loss of both motor and
cognitive functions is often rapid with neurological deficits in the form of
pseudobulbar palsy resulting in impaired feeding and swallowing, seizures
and severe psychomotor retardation and decerebrate state. Death typically
occurs within 5 years of onset of clinical symptoms [3].
7.2. Juvenile Form
Juvenile form of MLD can be further subdivided into early and late
juvenile forms which is based on the age of onset and clinical features.
Early juvenile form usually presents with gradual deterioration in school
performance as the first symptom in the majority. Progressive gait
disturbances follow cognitive manifestations. In others, they can present
with difficulty in walking and spasticity followed by intellectual decline.
Seizures can occur. Clinical examination reveals ataxia, hyperreflexia
followed by hyporeflexia, as the disease progress. Juvenile type progresses
more slowly when compared to late infantile type. Gall bladder
involvement can result in acute cholecystitis or pancreatitis in a few,
however, visceral involvement is usually asymptomatic in MLD [3].
Late juvenile type progresses slower than early juvenile type and
presents with behavioral disturbances or mental subnormality. Decline in
school or work performance may be reported as the first complaint.
Seizures may occur at any age and may be the only presenting symptom of
this type of MLD. Death usually occurs within 10-15 years of diagnosis,
mostly before 20 years of age. [4]. The various clinical presentations in
decreasing frequency includes inattention and difficulties at school (66%),
gait difficulties (26%), tremor or ataxia (18%), neuropathy (13%) and
seizures (5%) [50].
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S. Sundaram, S. V. Chandrasekharan and S. S. Nair
214
7.3. Adult Type of MLD
Patients with the adult type may have an even slower progression than
those with the late juvenile form. Hagemann et al. in 1995 gave an account
of 25 patients with adult onset MLD. The mean age of onset was 23 years
with the most common presentation being dementia in 40.5% of the cohort
and behavioral disturbances in 32.4%. Other common presentations were
ataxia (21.6%), paraparesis (10.8%), peripheral neuropathy (10.8%) and
psychosis (2.7%). In contrast to the late infantile form, combination of
mental and behavioral symptoms and ataxia predominate the clinical
picture in adult MLD [51]. Seizures were also reported in 12% of the
patients [50]. Frontal subcortical type of dementia characterized by
personality and behavior changes, inattention, poor working memory and
apathy predominate. The progression may range from years to decades. As
the dementia advances, self-care skills are lost and patients require help for
activities of daily living [4].
Genotype-phenotype correlations have been identified in late onset
MLD. P426L homozygotes typically starts with gait disturbance due to
spastic paraparesis or cerebellar ataxia. Those with heterozygous mutation
of I179S presents with inappropriate or disorganized behavior and social
dysfunction which is often misdiagnosed as schizophrenia or schizo-
affective disorder [52].
7.4. Atypical Manifestations of MLD
Congenital form of MLD: The onset of MLD below one year of age is
extremely rare. Occasional case reports of congenital MLD has been
described. In one report, a newborn presented with abdominal distension
and pronounced cyanosis and died within 24 hours of birth. Autopsy
revealed multisystem involvement and extensive metachromatic deposits
in cerebral white matter thus confirming the diagnosis of MLD. No genetic
tests were done since this case was described prior to discovery of ARSA
gene [53].
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Cranial nerve involvement: Patients presenting with symptoms
suggestive of cranial nerve involvement prior to the cerebral white matter
involvement is seldom reported. There is a case report of a two and half
year old girl who had manifested initially with right lateral palsy and
bifacial weakness prior to the gait disturbances. MRI showed multiple
cranial nerve enhancement along with other radiological features of MLD
[54]. Cranial nerve involvement can also occur in Krabbe disease [48].
Figure 4. Cauda equina involvement in MLD: MRI brain A) axial T2W and B) FLAIR
showing periventricular hyperintensity, lumbosacral spine C) sagittal sequence and
D&E) axial showing clumping and enhancement of roots.
Cauda equina involvement: Cauda equina involvement has been
reported previously in patients with MLD who had presented with
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S. Sundaram, S. V. Chandrasekharan and S. S. Nair
216
peripheral neuropathy. MRI of lumbosacral spine revealed clumping and
enhancement of caudal equina (Figure 4) [5]. Simultaneous involvement of
cranial nerves and caudal equina have been observed in late infantile MLD
and Krabbe disease. The exact pathogenesis of the contrast enhancement of
roots and cranial nerves is unclear. A breakdown of blood nerve barrier
due to sulfatide accumulation and inflammatory changes subsequent to this
has been proposed as one plausible explanation [48].
8. DIAGNOSIS OF THE DISEASE
In routine clinical practice, confirmation of a definitive diagnosis of
MLD is made by molecular genetic testing. If the clinical features and the
MRI of brain shows a classical pattern of MLD, apart from genetic
analysis of ARSA, other diagnostic investigations are not generally
warranted. However, if alternative differentials are under consideration
during evaluation of the patient, then electroneurographic studies and ASA
enzyme levels can serve as ancillary tests in narrowing the differential
diagnosis. Biopsy of the nerve to demonstrate metachromatic granules are
not required routinely in the current era of molecular genetics.
Histopathological analysis of a nerve tissue was used in the past for the
diagnosis before genetic testing became widely available and affordable. In
a typical scenario, it is not recommended since it is an invasive test, but
can be pursued according to the clinical picture and when the confirmatory
tests are inconclusive. CSF study and electroneurography are no longer
necessary in routine clinical settings, but can be used for monitoring the
treatment response and also in research settings [4].
8.1. Magnetic Resonance Imaging (MRI) of the Brain
Damage to CNS myelin in MLD is visualized in MRI as bilateral
symmetric confluent sheets of high signal intensity in T2 weighted (T2W)
and fluid-attenuated inversion recovery (FLAIR) sequences predominantly
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in periventricular white matter. These lesions are hypointense in T1
weighted (T1W) sequences (Figure 5, A-D). These radiological features
are suggestive of demyelinating pattern corroborating with the pathological
evidence. The white matter of frontal, parieto-occipital and temporal
regions are involved. Subsequently, the lesions extend to centrum
semiovale but spares subcortical U fibers in the early stages suggestive of
centripetal pattern [55]. The other structures classically affected include
internal capsule, descending cortical spinal tracts, corpus callosum and
cerebellar white matter (Figure 6). The sparing of perivascular white
matter gives a distinctive ‘tigroid' or 'leopard skin appearance’, but this
sign is not specific for MLD and is observed in other leukodystrophies as
well. The lesions do not enhance on gadolinium administration. The
subcortical U fibers can get involved when the disease process advances.
Figure 5. MRI brain T2W axial sections showing A) bilateral symmetric
periventricular white matter hyperintensity (arrow head) along with typical tigroid
pattern (long arrow), subcortical U fibers are spared (short arrows), B&C) The T2W
hyperintensity signals appear hypointense in T1W axial and sagittal sequences and
D) hyperintense in FLAIR sequence, E) The DWI axial sequence shows hyperintensity
in periventricular white matter and the corresponding areas, F) ADC sequence are
hypointense suggesting diffusion restriction.
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Figure 6. MRI of T2W axial sections showing affected regions of the brain in MLD.
A) hyperintensity of the frontal and parieto-occipital white matter (white arrows),
corpus callosum (black arrow) and bilateral symmetric hypo intensity of thalamus
(arrowhead), B) leopard appearance, C) hyperintense posterior limb of internal
capsule, D and E) hyperintensity of temporal white matter (white arrow) and
corticospinal tract at the level of midbrain and pons (black arrow), F) hyperintensity of
cerebellar white matter.
In the late stages, the cerebral and cerebellar atrophy ensues [56]. Although
MLD is regarded as a predominant white matter disorder, T2 hypo
intensity in the thalamus and atrophy of the thalamic and caudate nuclei
points towards an additional gray matter pathology. Corpus callosal
involvement shows a peculiar pattern of involvement, a diffuse high signal
intensity of splenium in the early stages, later becoming curvilinear and
progressing to atrophy [57].
A scoring system has been developed for MLD and it serves as a
valuable tool for assessing disease severity and evaluating response to
treatment. MRI-MLD scoring consists of maximum score of 34 points.
This is analogous to the scoring system devised for adrenoleukodystrophy
which has proven to be an efficient tool in guiding the treatment strategy
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[58]. The major brain areas assessed in the scoring system are frontal white
matter (periventricular, central and U fibers), parieto-occipital white matter
(periventricular, central and U fibers), temporal white matter
(periventricular, central and U fibers), corpus callosum (genu and
splenium) and projection fibers (posterior and anterior limbs of internal
capsule and midline pons). Each of the subareas is graded as 0, 1 or 2. The
grade 0 indicates normal intensity, 1 faint hyperintensity and 2 dense
hyperintensity. A global atrophy measure is also included to distinguish
between ventricular enlargement or inner widening (1 point) and inner and
outer CSF space widening (2 points). In addition to these categories, the
basal ganglia and thalamus are also scored, but as 0 and 1 based on
decreased signal intensities. Cerebellum (white matter and atrophy) is also
given either 0 or 1 point. Three stages are defined based on the total score:
mild disease, 1– 6, moderate disease, 7–15, and severe disease, 16 –34
[59].
8.2. Advanced MR Imaging of the Brain
Diffusion weighted (DWI) and apparent diffusion coefficient (ADC)
images show linear pattern of diffusion restriction in the periventricular
white matter and corpus callosum (Figure 5 E & F). The DWI shows
hyperintensity whereas the corresponding ADC is hypointense suggestive
of diffusion restriction. The diffusion restriction is related to the
accumulation of sulfatides within the oligodendrocytes and myelin edema
[60]. This finding is not specific for MLD as diffusion restriction is also
observed in other leukodystrophies such as adrenoleukodystrophy,
Canavan’s disease and Krabbe disease [61]. In diffusion tensor imaging
(DTI), the fractional anisotropy (FA) is decreased and the mean diffusivity
(MD) and radial diffusivity (RD) are increased in patients when compared
to controls. Changes are also noted in the normal appearing white matter
which suggest alterations in brain microstructure. DTI can be a useful tool
to monitor response to HSCT [62].
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220
Magnetic resonance spectroscopy (MRS) in MLD shows a reduced
N-acetylaspartate (NAA) in gray and white matter, elevated choline and
myo-inositol (Figure 7). The MRS picture differs between the various
clinical forms of MLD [63, 64]. Reduced NAA peak and elevated choline
/creatinine (Cho/Cr) ratio are commonly found in late infantile form
whereas elevated myo-inositol predominates in juvenile form [60].
Reduction in NAA peak reflects neuronal distress and increase in myo-
inositol peak correspond to either galactosylceramide accumulation or
secondary glial activation. NAA level is considered a sensitive disease
marker, correlated to clinical motor and cognitive function performance,
which can be used to assess treatment efficacy. An elevated lactate peak
correlates with anaerobic metabolism from myelin destruction and elevated
choline peaks with cell membrane degradation due to the accumulation of
sulfatides [65].
Figure 7. Magnetic resonance spectroscopy of MLD: A) images from left
periventricular intermediate TE* (135ms) shows normal metabolic resonances with
mild increase in choline peak at 3.2 ppm with preserved NAA peak, B) short TE
(30ms) shows myoinositol peak at 3.5ppm.
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8.3. Arylsulfatase-A Enzyme Analysis
Biochemical analysis in MLD refers to measurement of ASA activity
in leukocytes or cultured fibroblasts. It provides an easy, fast, and non-
invasive method for diagnosing MLD. ASA activity is also present in urine
but the enzyme normally has low specific activity in urine. An activity of
less than 10% of normal controls using the usual synthetic substrate-based
assay is diagnostic of MLD. The assay is carried out using p-nitrocatechol
sulfate (pNS) as the substrate. Since arylsufatase B also releases sulfate
from pNS, conditions of the assay are adjusted and carried out at pH 4.9,
rather than at pH 6, which favours arylsulfatase B activity. Further, the
presence of chloride and pyrophosphate in the assay system inhibit
arylsulfatase B more than arylsulfatase A. Hence, by this method,
arylsulfatase B contributes only 2 percentage of activity [66]. There is
considerable variability in enzyme activities among individuals. ASA
activity in cultured fibroblasts varies with culture conditions and the
presence of the pseudo-deficient allele, which accounts for 5–15% of
residual enzyme activity, which could lead to an incorrect diagnosis of
carrier status. Normal ASA activity is seen in patients with saposin B
deficiency, which is another limitation. The artificial substrate used for the
biochemical tests for ASA is water soluble and does not require the help
from saposin B for hydrolysis of this substrate [3]. ASA activity in
cultured amniotic cells or chorionic villus samples was used previously for
prenatal diagnosis. The main hurdle of this approach is a 2-3-week delay in
obtaining sufficient cell growth for the testing [67].
8.4. Urinary Sulfatide Levels in MLD
Urine sulfatide determinations are also a useful test for the diagnosis of
MLD. All patients with MLD excrete large amounts of sulfatides in their
urine. High performance liquid chromatography (HPLC), tandem mass
spectrometry (TMS), and thin-layer chromatography (TLC) are the various
methods which can be used to measure the urine sulfatide levels [68-70].
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