Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies

Quantitative MR spectroscopic imaging in metachromatic leukodystrophy: value for prognosis and treatment

OBJECTIVE: To determine whether proton magnetic resonance spectroscopic imaging is useful in predicting clinical course of patients with metachromatic leukodystrophy (MLD), an inherited white matter disorder treatable with haematopoietic cell transplantation (HCT). METHODS: 21 patients with juvenile or adult MLD (12 HCT-treated) were compared with 16 controls in the same age range. Clinical outcome was determined as good, moderate or poor. Metabolites were quantified in white matter, and significance of metabolite concentrations at baseline for outcome prediction was assessed using logistic regression analysis. Evolution of metabolic changes was assessed for patients with follow-up examinations. RESULTS: In this retrospective study, 16 patients with baseline scans were included, 5 with good, 3 with moderate and 8 with poor outcome, and 16 controls. We observed significant group differences for all metabolite concentrations in white matter (p<0.001). Compared with controls, patients had decreased N-acetylaspartate and glutamate, and increased myo-inositol and lactate, most pronounced in patients with poor outcome (post hoc, all p<0.05). Logistic regression showed complete separation of data. Creatine could distinguish poor from moderate and good outcome, the sum of glutamate and glutamine could distinguish good from moderate and poor outcome, and N-acetylaspartate could distinguish all outcome groups. For 13 patients (8 with baseline scans), one or more follow-up examinations were evaluated, revealing stabilisation or even partial normalisation of metabolites in patients with moderate and good outcome, clearly visible in the ratio of choline/N-acetylaspartate. CONCLUSION: In MLD, quantitative spectroscopic imaging at baseline is predictive for outcome and aids in determining eligibility for HCT

Quantitative MR spectroscopic imaging in metachromatic leukodystrophy : value for prognosis and treatment

OBJECTIVE: To determine whether proton magnetic resonance spectroscopic imaging is useful in predicting clinical course of patients with metachromatic leukodystrophy (MLD), an inherited white matter disorder treatable with haematopoietic cell transplantation (HCT). METHODS: 21 patients with juvenile or adult MLD (12 HCT-treated) were compared with 16 controls in the same age range. Clinical outcome was determined as good, moderate or poor. Metabolites were quantified in white matter, and significance of metabolite concentrations at baseline for outcome prediction was assessed using logistic regression analysis. Evolution of metabolic changes was assessed for patients with follow-up examinations. RESULTS: In this retrospective study, 16 patients with baseline scans were included, 5 with good, 3 with moderate and 8 with poor outcome, and 16 controls. We observed significant group differences for all metabolite concentrations in white matter (p<0.001). Compared with controls, patients had decreased N-acetylaspartate and glutamate, and increased myo-inositol and lactate, most pronounced in patients with poor outcome (post hoc, all p<0.05). Logistic regression showed complete separation of data. Creatine could distinguish poor from moderate and good outcome, the sum of glutamate and glutamine could distinguish good from moderate and poor outcome, and N-acetylaspartate could distinguish all outcome groups. For 13 patients (8 with baseline scans), one or more follow-up examinations were evaluated, revealing stabilisation or even partial normalisation of metabolites in patients with moderate and good outcome, clearly visible in the ratio of choline/N-acetylaspartate. CONCLUSION: In MLD, quantitative spectroscopic imaging at baseline is predictive for outcome and aids in determining eligibility for HCT

Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy

Objectives:To assess frequency of gallbladder polyposis and carcinoma in metachromatic leukodystrophy (MLD).Methods:We evaluated 34 patients with MLD (average age 16.7 years, age range 2-39 years) screened for gallbladder abnormalities by ultrasound. In the case of cholecystectomy, findings at pathology were reviewed.Results:Only 8 of 34 patients (23%) had a normal gallbladder at ultrasound. Gallbladder polyps were visible in 8 patients (23%). Cholecystectomy was performed in 11 patients (32%). In these, pathology revealed various abnormalities, including hyperplastic polyps, intestinal metaplasia, prominent Rokitansky-Aschoff sinuses, and sulfatide storage.Conclusions:Our results demonstrate that gallbladder involvement is the rule rather than the exception in MLD. The high prevalence of hyperplastic polyps, a known precancerous condition, and one death from gallbladder carcinoma at a young age suggest that MLD predisposes to neoplastic gallbladder abnormalities. As novel therapies for this patient group are emerging leading to increased life expectancy, we recommend screening for gallbladder abnormalities by ultrasound in order to prevent early deat