C. Drissi, I. Kraoua *, I. Rebaï *, S. Nagi , N. Gouider - Khouja *, M. Ben Hamouda

1. Imaging and clinicalfeatures of metachromaticleukodystrophy: a study in 9 Tunisianchildren C. Drissi, I. Kraoua*, I. Rebaï*, S. Nagi, N. Gouider-Khouja*, M. Ben Hamouda Neuroradiology and * * PediatricNeurologyDepartments –National Institute of Neurology – Tunis – Tunisia PEDIATRICS : PD 19

2. Introduction • Metachromaticleucodystrophy (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

3. 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.

4. Patients and methods • Retrospectivestudy (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

5. Results • 9 children : 2 ♂ / 7 ♀ • Meanage: 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

6. Results 8/9 7/9

7. Results Clinicalpresentation • Psychomotorregression: 8/9 • Irritability : 8/9 • Epilepsy : 3/9 (uncontrolled in one case) • Learning disabilities and gaitdisturbance: 1 case (juvenileform)

8. Results Examination Typical signs Atypical signs

9. Results MRI • 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 cruscerebri.

10. T2 hyperintensity of the supratentorial white matter, and displaying the radial stripes pattern U fibersspared U fibersinvolved

11. T2 hyperintensity of the posterior limb of the internal capsule T2 hyperintensity of the cerebellar white matter, and the pyramidal tract within the cruscerebri

12. Results MRI • 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.

13. Corpus callosuminvolvement genu T2 hyperintensity splenium T2 hyperintensity atrophy

14. Results Investigations • CSF analysis :hyperproteinorachia: 9/9 • NCV Studies: demyelinatingneuropathy: 9/9 • Arylsulfatase A activity : verylow : 8/8

15. Metachromaticleukodystrophy MLD • Incidence • 0.6 – 1.85 / 100.000 live birth • Pathophysiology 3-O-sulfogalactosylceramidegalactosylceramide • Sulfatides accumulation and oligodendrocytes death • Demyelination of central and peripheralnervous system X (sulfatide) Arylsulfatase A (ASA) Arvan et al, 2011

16. MLD 3 clinicalforms Arvan et al, 2011

17. 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.

18. MLD MRI Typically a pattern of radiatingstripes • lysosomalstoragedisorders (Krabbe, GM1) • relative myelinsparing? • lipidstorage? Van der Voornet al, AJNR, 2005

19. MLD MRI • 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. • T2 hyperintensity of the splenium of the CC in the unique case without involvement of WM

20. MLD MRI • Cerebral WM atrophy occurs in advanced stages. • Some patients show bilateralinvolvement 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 enhancementisseen. • A MR severityscoringmethod has been proposed by Eichler et al. Eichler F et al, AJNR, 2009

21. MLD MRI • Diffusion weighted-imaging : • Hyperintensity with low ADC values in deep white matter • MR-Spectroscopy: • decreased choline peak • Myoinositolpeak • Lactates Sener RN,AJNR, 2002 Sener RN, Acta Radiologica 2003

22. MLD Diagnosis • CSF : hyperproteinorachia • NCV studies: demyelinatingneuropathy • Biochemicaldiagnosis:ASA activity+++ • Moleculardiagnosis: • 22q13.3-qter, ARSA gene • > 100 mutations • Genotype / phenotypecorrelation • Groeschel et al, 2011

23. MLD Treatment • Symptomaticforms:symptomatictreatment • Presymptomaticforms: Hematopoietic stem cell transplantation Clinicalresearch: genetherapy, enzyme replacement therapy • Geneticcounselling • Batzios et al, 2012; Biffi et al, 2011 • Gieselmann et al, 2011 • Arvan et al, 2011

24. 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