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

Study of the Natural History of Cerebral White Matter Involvement in Metachromatic Leukodystrophy, Using High-field MRI and Diffusion Tensor Imaging

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.

Study Overview

• Status: Completed
• Conditions: Late Infantile Metachromatic Leukodystrophy
• Intervention / Treatment: Other: High-field MRI (3 Teslas)

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Gif-sur-yvette, France
    • Unité de recherche biomédicale, Neurospin, I2BM / DSV / SAC/ CEA,
  • Paris, France, 94275
    • Service de Neurologie Pédiatrique, Hôpital Bicêtre
  • Paris, France
    • Bâtiment Lavoisier - Unité INSERM U 663,Hôpital Necker Enfants Malades

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 4 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients; Patients with a metachromatic leukodystrophy	Other: High-field MRI (3 Teslas); anatomical location; conventional anatomical sequence T1, T2, FLAIR; diffusion tensor sequence (21 directions); high angular resolution diffusion (HARDI) sequence; field map; reflexology T1, T2; spectroscopic imaging sequence
Other: Control; Epileptic population	Other: High-field MRI (3 Teslas); anatomical location; conventional anatomical sequence T1, T2, FLAIR; diffusion tensor sequence (21 directions); high angular resolution diffusion (HARDI) sequence; field map; reflexology T1, T2; spectroscopic imaging sequence

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the natural history of the white matter and cortex lesions in MLD using diffusion tensor imaging (DTI)and relaxometry/ high field MRI.	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.	At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients

Secondary Outcome Measures

Outcome Measure	Time Frame
Assess the natural history of the white matter and cortex lesions in MLD using using multi-voxel spectroscopic imaging.	At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients
Assess the evolution of cortical atrophy,	At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients
Correlate the neuroimaging parameters with motor function measure (Gross Motor Function Measure) and cognitive tests (BSID, WPPSI).	At inclusion (T0) and 12 months for control. At T0 then at 6 months for patients

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: European Leukodystrophy Association

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: March 9, 2011
• First Submitted That Met QC Criteria: March 28, 2011
• First Posted (Estimate): March 29, 2011

Study Record Updates

• Last Update Posted (Estimate): August 2, 2016
• Last Update Submitted That Met QC Criteria: July 31, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Longitudinal Studies; Magnetic Resonance Imaging; Diffusion Tensor Imaging; Spectroscopy; Relaxometry; Metachromatic Leukodystrophy; Demyelinating Diseases
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Demyelinating Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Leukoencephalopathies; Hereditary Central Nervous System Demyelinating Diseases; Sulfatidosis; Leukodystrophy, Metachromatic
• Other Study ID Numbers: P071232

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No