Clinical trial NCT01325025: Imaging Study of the White Matter Lesions in Children With Metachromatic Leucodystrophy
Official title: Study of the Natural History of Cerebral White Matter Involvement in Metachromatic Leukodystrophy, Using High-field MRI and Diffusion Tensor Imaging
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Late Infantile Metachromatic Leukodystrophy
Keywords: Metachromatic Leukodystrophy
Demyelinating Diseases
Magnetic Resonance Imaging
Diffusion Tensor Imaging
Relaxometry
Spectroscopy
Longitudinal Studies
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: European Leukodystrophy Association
First posted: 2011-03-29
Enrollment: 29
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL

Brief summary: High-field MRI and diffusion tensor imaging with 3D reconstruction of the myelin tracks, in combination with multivoxel proton spectroscopy, will allow to precise more accurately the evolution of the white matter lesions in patients affected with Metachromatic Leukodystrophy (particularly in the initial phase of the disease). This will increase the knowledge of the disease and provide new indicators for the selection and evaluation of patients eligible for new therapeutic approaches.

Detailed description: 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 6 months) white and grey matter lesions in 10 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 and 6 months) will also include neurological evaluation to correlate the imaging, cognitive and motor functions. Children will be included over a period of 5 years. The total duration of the study will be 5.5 years. Controls will include 25 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 if necessary. 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.

Eligibility criteria: Inclusion Criteria (patients):

* Children with proven metachromatic leukodystrophy (MLD) with decreased activity of arylsulfatase A enzyme in leukocytes and abnormal excretion of urinary sulfatides
* Age ≥ 1 year and ≤ 6 years
* Recently diagnosed (within \< 18 months)

Inclusion Criteria (control):

* Children with partial cryptogenic epilepsy or with a suspected brain lesion on conventional MRI, who should have high-field MRI to detect structural abnormalities that could benefit from surgical resection
* Age ≥ 1 year and ≤ 6 years

Exclusion Criteria:

* Evolutive heart, pulmonary, renal or gastrointestinal disease
* Contra-indication to sedation
* Contra-indication to MRI (implanted magnetic material)

Primary outcomes:
measure: Assess the natural history of the white matter and cortex lesions in MLD using diffusion tensor imaging (DTI)and relaxometry/ high field MRI.
timeFrame: At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients
Secondary outcomes:
measure: Assess the natural history of the white matter and cortex lesions in MLD using using multi-voxel spectroscopic imaging.
timeFrame: At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients
measure: Assess the evolution of cortical atrophy,
timeFrame: At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients
measure: Correlate the neuroimaging parameters with motor function measure (Gross Motor Function Measure) and cognitive tests (BSID, WPPSI).
timeFrame: At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients
Other outcomes:
Locations:
city: Gif-sur-yvette
country: France
facility: Unité de recherche biomédicale, Neurospin, I2BM / DSV / SAC/ CEA,
city: Paris
country: France
facility: Service de Neurologie Pédiatrique, Hôpital Bicêtre
city: Paris
country: France
facility: Bâtiment Lavoisier - Unité INSERM U 663,Hôpital Necker Enfants Malades
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Caroline Sevin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: