Development of a Psychosine Assay to Identify Therapeutic Small Molecules for Krabbe Disease

Abstract

Background: Leukodystrophies are a group of rare genetic diseases that affect myelin, the major constituent of brain and spinal cord white matter. An integrated description of the clinical, neuroimaging and pathophysiological features is crucial for categorizing myelin disorders. Purpose: To describe the clinical/biochemical evaluation of 60 patients with a white matter disorder. Method: All patients were evaluated in neurogenetics clinics. A full medical history was taken and the following were performed: neuroimaging studies (CT, MRI with spectroscopy), ophthalmologic and auditory evaluations, neurophysiologic studies (EEG, ERG, EMG/ NCV), hormone and biochemical tests, muscle biopsy with OXPHOS analysis, screening for IEMs (lysosomal studies; peroxisomal/sterol panels; cholestanol dosage; organic acids, sulfatides and aminoacid chromatography; analysis of GAG) and, when indicated, nerve/skin biopsy for EM studies, karyotype and molecular tests. Results: In forty patients it was possible to establish a diagnosis for the leukodystrophy. X-ALD, metachromatic leukodystrophy and Krabbe disease were the commonest inborn errors of metabolism implicated in the pathophysiological of the “metabolic leukodystrophies”. Infantile Refsum disease, Canavan disease, AMACR deficiency, Niemann-Pick type C were other rare IEMs diagnosed. It was worthy of note the fact that Vanishing White Matter disease was a leading cause of leukodystrophies in our patients (eight patients). Conclusion: Almost 50% of patients with white matter abnormalities remain without a specific diagnosis even after an exhaustive investigation. Therefore a specific protocol for investigation is crucial. Treatment options are becoming a reality for some disorders, so reaching a specific diagnosis is important so that patients can be offered appropriate therapeutics.