Search

The development of biomarkers for amyotrophic lateral sclerosis (ALS, the commonest phenotype of MND) is a priority to reduce diagnostic delay, allow earlier assessment of therapeutic activity, and provide pathogenic insight.Liquid chromatography tandem mass spectrometry with label-free quantification was used to quantify CSF proteins in individual participant samples. A longitudinal cohort comprised patients with ALS (n=43) and primary lateral sclerosis (PLS, n=6). A cross-sectional cohort comprised healthy (n=20) and disease control patient CSF samples (Parkinson’s disease n=20, MND mimic disorders n=12).Among 773 identified proteins, significantly elevated levels of three macrophage-derived chitinase proteins were detected in the ALS group, specifically chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1) and chitinase-3-like protein 2 (CHI3L2). Levels correlated with rate of disease progression (CHIT1 r=0.56, p<0.001; CHI3L1 r=0.31, p=0.028; CHI3L2 r=0.29, p=0.044), and levels of the axonal degeneration marker phosphorylated neurofilament heavy chain (r=0.62, p<0.001; r=0.49, p<0.001; r=0.41, p<0.001). Levels of CHI3L1, but not CHIT1 or CHI3L2, increased over time in those with low initial values (gradient=0.005 log abundance units/month, p=0.001).Microglial activation has been implicated in the pathogenesis of MND and neuroinflammatory pathways are a major target of therapeutic interest. CSF chitinases may be potential pharmacodynamic as well as diagnostic biomarkers.

BackgroundMutations in the protein gelsolin result in hereditary systemic amyloidosis, characterised by onset of corneal lattice dystrophy in the third decade, a slowly progressive cranial neuropathy and cutis laxa. To date four dominantly inherited gelsolin mutations have been identified, two mutations resulting in the classical syndrome and two mutations resulting in renal-predominant amyloidosis.MethodsWe identified a family in which four individuals in three generations presented with corneal lattice dystrophy and neurological symptoms. Detailed clinical neurological and ophthalmological assessment and investigations including neurophysiology and imaging were performed. Whole exome sequencing was undertaken in three family members.ResultsWhole exome sequencing revealed a novel variant in the gelsolin gene (c. G1738A; p. E580K), dominantly inherited and predicted to be pathogenic. Examination, neurophysiological testing and imaging revealed the presence of distal upper limb weakness and wasting, corneal lattice dystrophy and cervical myelopathy in all affected family members.ConclusionThe E580K mutation described in this family is in a conserved calcium-sensitive actin-binding domain that displays sequence homology with other actin-depolymerising proteins. Mutations in this domain may result in abnormal gelsolin-actin interactions and changes in calcium sensitivity may render the protein susceptible to the same aberrant proteolytic cascade as with other known mutations.