NPTX1‑related oculomotor apraxia: an intra‑hemispheric disconnection disorder

Oculomotor apraxia (OMA) is a rare and heavily disabling neurological disorder causing severe difficulties in the initiation and maintenance of voluntary eye movements when the head is stationary. If patients try to initiate saccades, they are grossly delayed and hypometric (stair-case). In contrast, patients can initiate large voluntary saccades when gaze is performed with combined eye–head or lid movements. Congenital forms, commonly known as infantile-onset saccade initiation delay, preferably affect horizontal eye movements and occur in various genetic disorders, e.g., in oculomotor apraxia type 1 and type 2, and ataxia telangiectasia.

Acquired forms of OMA are rare as OMA in patients probably requires bilateral fronto-parietal damage and involvement of fronto-collicular projections to the superior colliculus (SC). In the monkey, lesions of the frontal eye field (FEF) in the frontal cortex (Brodmann area 8) in combination with the posterior eye field or the SC elicit severe loss of voluntary eye movements. Apart from FEF lesions, associated structural brain abnormalities in OMA patients include vermal atrophy/hypoplasia and the agenesis of the corpus callosum. The latter may be a potential structural lesion site to account for the hypothesized inter-hemispheric abnormalities in OMA.

The aim of this study was to test competing pathophysiological hypotheses by functional and structural MRI, stating that OMA is related to either abnormal (i) inter-hemispheric or (ii) intra-hemispheric connectivity between the FEF and related oculomotor structures (oculomotor network) or (iii) both mechanisms. We tested these hypotheses in a patient with an adult-onset progressive OMA and a positive family history, in whom we recently identified a novel mutation in the Neuronal Pentraxin 1 (NPTX1) gene, with strong gene expression patterns in the frontal cortex.

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