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 Hamouda Neuroradiology 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 ( ) 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

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 cerebri T2 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 hyperintensity splenium 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 / live birth Pathophysiology 3-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 formLate infantileJuvenileAdult Age at onset yeras 2 nd year (< 3 ) 3 – 16> 16 PresentationPsychomotor regression, irritability Learning disabilities, behavior disorders Dementia « schizophrenia » Examination Pyramidal signs, hypertonia, abolished deep tendon reflexes, optic atrophy Pyramidal signs, ataxiadementia Outcome death 2 – 6 years10 – 20 years30 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, 2002 Sener 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, 2011 Gieselmann 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