Citations

ABSTRACT Aims X‐linked McLeod neuroacanthocytosis syndrome (MLS) is a rare neurodegenerative disorder characterised by the presence of red blood cell acanthocytosis and a chorea syndrome. Analogous to Huntington's disease (HD), MLS displays cognitive and behavioural symptoms besides the progressive movement disorder. This study aimed to describe the neuropathology of MLS in the largest case series to date. Methods Clinical data were collected, and neuropathological assessments were performed on eight male MLS patients originating from Finland, New Zealand, Switzerland, Scotland and the United States. Results Macroscopic data were available from six patients, with five showing atrophy of the basal ganglia, which was more pronounced in the caudate nucleus and to a lesser extent in the putamen and pallidum. Histology revealed neuronal loss and accompanying gliosis in the basal ganglia of all patients. The extent of these alterations varied widely, with a decreasing gradient of severity from the caudate nucleus to the putamen and the pallidum, mirroring the macroscopic findings. In addition, we detected intraneuronal vacuoles in the striatum in half of the patients. Conclusions MLS neuropathology is characterised macroscopically by atrophy and microscopically by neuronal loss and gliosis of the basal ganglia, with a decreasing gradient of severity from the caudate nucleus, the putamen to the pallidum. Analogous to the grading system for HD, we propose a neuropathological grading system for MLS based on the current observations in the largest MLS cohort examined to date. Standardised criteria are crucial for neuropathological assessment of this extremely rare disease.

Choline acetyltransferase (ChAT; EC 2.3.1.6 ) catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. Mutations in genes encoding ChAT affecting motility exist in Caenorhabditis elegans and Drosophila , but no CHAT mutations have been observed in humans to date. Here we report that mutations in CHAT cause a congenital myasthenic syndrome associated with frequently fatal episodes of apnea (CMS-EA). Studies of the neuromuscular junction in this disease show a stimulation-dependent decrease of the amplitude of the miniature endplate potential and no deficiency of the ACh receptor. These findings point to a defect in ACh resynthesis or vesicular filling and to CHAT as one of the candidate genes. Direct sequencing of CHAT reveals 10 recessive mutations in five patients with CMS-EA. One mutation (523insCC) is a frameshifting null mutation. Three mutations (I305T, R420C, and E441K) markedly reduce ChAT expression in COS cells. Kinetic studies of nine bacterially expressed ChAT mutants demonstrate that one mutant (E441K) lacks catalytic activity, and eight mutants (L210P, P211A, I305T, R420C, R482G, S498L, V506L, and R560H) have significantly impaired catalytic efficiencies.