14800-DvRappard

51 Slowly progressive psychiatric symptoms: think metachromatic leukodystrophy 3 INTRODUCTION Metachromatic leukodystrophy (MLD) is a lysosomal disorder caused by biallelic mutations in ARSA , resulting in arylsulfatase A (ASA) deficiency and sulfatide accumulation in the central and peripheral nervous system. Sulfatides are major myelin lipids, and their accumulation leads to demyelination. MLD is one of the most common leukodystrophies with an estimated incidence of 1.4-1.8 per 100.000. Greenfield first described its pathological features – widespread demyelination and neuroglial sclerosis – in 1933. Numerous clinical and pathological studies have broadened our knowledge of this disease. 1 Based on age at onset, MLD is divided into three clinical subtypes: late-infantile (onset before 30 months), juvenile (2.5 to 16 years) and adult (after 16 years. Level of residual ASA activity is correlated to the subtype, with (almost) no activity resulting in the late-infantile type. This form presents with rapid psychomotor regression, ataxia and weakness, sometimes also areflexia due to severe peripheral neuropathy. 2 Spasticity, dysphagia and seizures follow. The juvenile form often presents with deterioration in school performance due to disturbed attention, reduced processing speed, impaired executive functioning and behavioral abnormalities. First neurological signs are slowly progressive ataxia and a pyramidal syndrome. The adult form is characterized by intellectual and behavioural changes such as memory deficits and emotional instability. 2 Mild polyneuropathy usually develops as the disease progresses. With early disease onset, disease progression is fast; in later onset forms, deterioration is insidious. Eventually, all acquired skills are lost and patients die, depending on the clinical subtype, within a few years or decades after first symptoms. Diagnosis of MLD is made through clinical presentation, typical brain MRI abnormalities (Figure 1), measurement of ASA activity in leukocytes, sulfatide levels in urine and ARSA mutation analysis. 1 MRI shows bilateral symmetric abnormal hyperintense T2 signal changes starting in the corpus callosum, subsequently involving the periventricular white matter, before spreading to the central and subcortical white matter. 1 Still, diagnosing MLD may be challenging in juvenile and adult-onset patients when psychiatric symptoms precede the neurological signs, and this is not rare: Hyde et al describe 129 cases, half of whom with a disease onset between 10 and 30 years. Fifty- three percent of these presented with psychotic symptoms. 3