Imaging and clinical features of metachromatic leukodystrophy:

a study in 9 Tunisian children

C. Drissi, I. Kraoua*, I. Rebaï*, S. Nagi, N. Gouider-Khouja*, M. Ben HamoudaNeuroradiology and * * Pediatric Neurology Departments –National Institute of Neurology – Tunis – Tunisia PEDIATRICS : PD 19

Introduction

•  Metachromatic leucodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by deficiency of arylsulfatase A activity resulting in demyelination within the central and peripheral nervous system.

• 3 clinical forms: – Late-infantile (<3 years)– Juvenile (<16 years)– Adult (>16 ans)

Costello et al ,2009

Objective

• The aim of this study is to describe the imaging and clinical features of MLD in 9 Tunisian children.

• The results are analyzed and discussed with a literature review.

• Retrospective study (2005-2011)• 9 children from 8 families with confirmed MLD • Followed in the department of Pediatric Neurology at

the National Institute of Neurology of Tunis • Brain MRI was performed in all cases• Imaging and Clinical data are analyzed

Patients and methods

Results

• 9 children : 2 / 7 ♂ ♀

• Mean age: 32 months (17 months – 6 years)

• 8 patients with late infantile MLD with a mean age at onset of 16 months

• One patient with a juvenile form with age at onset of 4 years

8/9

7/9

Results

• Psychomotor regression: 8/9• Irritability : 8/9• Epilepsy : 3/9 (uncontrolled in one case)• Learning disabilities and gait disturbance: 1 case

(juvenile form)

Results

Clinical presentation

0

2

4

6

8

10

12

Typical signs

Atypical signs

Results

Examination 

Results

• Brain MRI showed bilateral symmetric areas of T2 hyperintensity involving supra-tentorial deep white matter in 8 cases, sparing U fibers in most cases (6/8).

• In all of these 8 cases, a pattern of radial stripes was seen.

• In 2 cases, it also involved cerebellar white matter, the posterior limb of the internal capsule and the pyramidal tract within the crus cerebri.

MRI

T2 hyperintensity of the supratentorial white matter, and displaying the radial stripes pattern

U fibers spared U fibers involved

T2 hyperintensity of the posterior limb of the internal capsule

and the pyramidal tract within the crus cerebriT2 hyperintensity of the cerebellar white matter,

Results

• Corpus callosum was involved in all cases, atrophic in one case and presenting with a hyperintensity in all other 8 cases.

• The hyperintensity involved the splenium in 5 cases, the genu in 1 case and the entire corpus callosum in 1 case.

• Severe cortical atrophy was seen in one case.

MRI

Corpus callosum involvement

genu T2 hyperintensitysplenium T2 hyperintensity

atrophy

Results

• CSF analysis : hyperproteinorachia: 9/9

• NCV Studies: demyelinating neuropathy: 9/9

• Arylsulfatase A activity : very low : 8/8

Investigations 

Metachromatic leukodystrophy MLD

• Incidence 0.6 – 1.85 / 100.000 live birth

• Pathophysiology3-O-sulfogalactosylceramide galactosylceramide

• Sulfatides accumulation and oligodendrocytes death• Demyelination of central and peripheral nervous system

Arylsulfatase A (ASA)

X(sulfatide)

Arvan et al, 2011

MLD

3 clinical forms 

Clinical form Late infantile Juvenile Adult

Age at onsetyeras

2nd  year(< 3 )

3 – 16  > 16

Presentation Psychomotor regression, irritability

Learning disabilities, behavior disorders

Dementia« schizophrenia »

Examination Pyramidal signs, hypertonia, abolished deep tendon reflexes, optic atrophy

Pyramidal signs, ataxia dementia

Outcome death

2 – 6 years 10 – 20 years 30 ans

Arvan et al, 2011

MLD

MRI• Periventricular WM abnormalities,with a more or

less symmetrical distribution. • The white matter lesions are highly confluent.• In later onset cases involvement is often

predominantly frontal, whereas in early-onset cases occipital predominance can be observed.

• The arcuate fibers are relatively spared, but become involved in the later stages.

MLD

MRI

Typically a pattern of radiating stripes– lysosomal storage disorders

(Krabbe, GM1)– relative myelin sparing?– lipid storage?

Van der Voorn et al, AJNR, 2005

MLD

• Probably the first abnormalities to be noted on MRI are in the corpus callosum (CC).

• CC is always affected, connecting the lesions from both sides.

MRI

T2 hyperintensity of the splenium of the CC in the unique case without involvement of WM

MLD

MRI

• Cerebral WM atrophy occurs in advanced stages. • Some patients show bilateral involvement of :– the posterior limb of the internal capsule,– the cerebellar white matter,– pyramidal tracts in the brain stem, especially in the more

advanced cases. • No contrast enhancement is seen.• A MR severity scoring method has been proposed by

Eichler et al.Eichler F et al, AJNR, 2009

MLD

MRI

• Diffusion weighted-imaging :– Hyperintensity with low ADC values

in deep white matter• MR-Spectroscopy:– decreased choline peak– Myoinositol peak– Lactates

Sener RN,AJNR, 2002Sener RN, Acta Radiologica 2003

MLD

CSF : hyperproteinorachia

NCV studies : demyelinating neuropathy

Biochemical diagnosis : ASA activity+++

Molecular  diagnosis: 22q13.3-qter, ARSA gene > 100 mutations Genotype / phenotype correlation

Diagnosis 

Groeschel et al, 2011

MLD

• Symptomatic forms: symptomatic treatment

• Presymptomatic forms:

Hematopoietic stem cell transplantation

Clinical research: gene therapy, enzyme replacement therapy

• Genetic counselling

Treatment

Batzios et al, 2012; Biffi et al, 2011Gieselmann et al, 2011

Arvan et al, 2011

Conclusions

• Imaging features in MLD are non specific but can be highly suggestive in children presenting with psychomotor regression

• The diagnosis, confirmed by specific biological tests, allows genetic counseling