Imaging Study of the White Matter Lesions in Children With Metachromatic Leucodystrophy (HCIT-MLD)

• Assess the natural history of the white matter and cortex lesions in MLD using diffusion tensor imaging (DTI)and relaxometry/ high field MRI. [ Time Frame: At inclusion (T0) and 12 months for control. At T0 then at 4, 8, 12 and 18 months for patients ] [ Designated as safety issue: No ]
  The following parameters will be studied: quantitative measurements of mean diffusivity, longitudinal and transverse fractional anisotropy in ROIs (regions of interest), 3D-tractographic reconstruction of the myelin tracks.
  
  

• Assess the natural history of the white matter and cortex lesions in MLD using using multi-voxel spectroscopic imaging. [ Time Frame: At inclusion (T0) and 12 months for control. At T0 then at 4, 8, 12 and 18 months for patients ] [ Designated as safety issue: No ]
  
• Assess the evolution of cortical atrophy, [ Time Frame: At inclusion (T0) and 12 months for control. At T0 then at 4, 8, 12 and 18 months for patients ] [ Designated as safety issue: No ]
  
• Correlate the neuroimaging parameters with motor function measure (Gross Motor Function Measure) and cognitive tests (BSID, WPPSI). [ Time Frame: At inclusion (T0) and 12 months for control. At T0 then at 4, 8, 12 and 18 months for patients ] [ Designated as safety issue: No ]
  

Metachromatic Leukodystrophy (MLD) is a rare autosomal recessive disorder caused by the deficiency of the Arylsulfatase A enzyme (ARSA), resulting in accumulation of galactosyl sulfatide (cerebroside sulfate), a major constituent of the myelin sheath. Accumulation of sulfatides leads to a progressive degeneration of the white matter in the central and peripheral nervous systems (CNS, PNS) and to a neuronal degeneration. The late-infantile form of MLD, which is usually diagnosed in the second year of life, is the most frequent and severe form of the disease. The prognosis is severe, leading to vegetative stage or death within few years after the diagnosis. There is no treatment for patients affected with this early-onset form of the disease.

Conventional MRI (1.5 Tesla) shows extensive involvement of the cerebral white matter (hypo-T1, hyper- T2 and FLAIR signals) indicative of rapidly progressing leukodystrophy. Early cortical atrophy reflects associated neuronal involvement. Proton MR spectroscopy demonstrates abnormalities of choline and N-acetyl-aspartate (demyelination, neuronal loss), which are non-specific but can serve as indicators to monitor the effects of any therapeutic intervention.

In early-onset forms of MLD, conventional MRI becomes abnormal at a relatively advanced stage of the disease and the neuroradiological diagnosis may be difficult before the age of 2 - 2 1/2 years of age. Moreover, topography and extent of detectable lesions are poorly correlated with the disease severity.

In order to improve information provided by neuroimaging, this study aims to investigate prospectively and longitudinally (over a period of 18 months) white and grey matter lesions in 15 MLD children aged 1 to 6 years, using high-field MRI (3 Teslas) and diffusion tensor imaging (DTI) with 3D reconstruction of the myelin tracks. The time interval between diagnosis and inclusion will not exceed 18 months, thus patients will be included at an early stage of their disease. Each time-point (T0, 4 months, 8 months, 12 months and 18 months) will also include neurological evaluation to correlate the imaging, cognitive and motor functions. Children will be included over a period of 2.5 years. The total duration of the study will be 4.5 years. Controls will include 20 age-matched children with cryptogenic partial epilepsy who should have a high-field MRI to detect structural abnormalities. Controls will have a MRI and cognitive evaluation at T0 and 12 months. This study will increase our knowledge of the natural history of MLD and provide new indicators for the selection and evaluation of patients eligible for new therapeutic approaches.