Leukodystrophies in idiopathic adult‐onset ataxia: Frequency and phenotype in 105 patients

Abstract

Here, we systemati-cally screened a representative cohort of patients with adult-onset ataxia for underlying leukodystrophies and analyzedits phenotypic presentation.One hundred five ataxia patients from independent fami-lies were recruited as a continuous series from the ataxiaclinic in T€ubingen according to the following inclusion crite-ria: (1) age of onset of ataxia 16 years, (2) family historyconsistent with autosomal-recessive inheritance, and (3)prior exclusion of Friedreich ataxia in patients with age ofonset 25 years and prior exclusion of common subtypesof spinocerebellar ataxia (SCA1, -2, -3, -6, -7, -17) inpatients with onset 25 years. All patients underwent abasic screening that included serum levels of very-long-chainfatty acids for X-linked adrenoleukodystrophy/adrenomyelo-neuropathy (ALD/AMN) and enzyme activities for meta-chromatic leukodystrophy (MLD), GM1 gangliosidosis,GM2 gangliosidosis variants (Tay-Sachs disease [TS] andSandhoff disease [SD]), and Krabbe disease (KD) in culturedleukocytes. If phenotypic evidence or MR imaging was sug-gestive of other types of neurometabolic disorders, we alsoperformed the respective genetic or biochemical testing, forexample, screening for Niemann-Pick disease type C (NPC)in patients with vertical-gaze palsy, for cerebrotendinousxanthomatosis (CTX) in cases of cognitive dysfunction, andfor leukencephalopathy with brainstem and spinal cordinvolvement and lactate elevation (LBSL) or vanishing whitematter disease (VWMD).Standardized clinical characterization included signs ofcorticospinal tract affection, dystonia, peripheral polyneu-ropathy (muscular atrophy or absent reflexes in combinationwith pallhypesthesia), or psychiatric comorbidities (exceptfor depression, as it is a common and unspecific feature ofchronic progressive disease