Beschreibung:
<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Objectives</jats:title>
<jats:p>The term hereditary spastic paraplegia comprises an ever-expanding array of neurological disorders with distinct aetiologies. Spastic paraplegia gene 39 is one of the many genetically defined types with features of other organs and neurological systems in addition to paraspasticity. We describe a large kindred with a novel clinical phenotype as, in addition to spastic paraplegia, affected subjects suffered from a prominent cerebellar oculomotor dysfunction with two hitherto undescribed mutations of <jats:italic>PNPLA6</jats:italic>.</jats:p>
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<jats:title>Methods</jats:title>
<jats:p>Three of five genetically tested family members of a large kindred were affected by spastic gait and a unique and prominent cerebellar oculomotor dysfunction. Further clinical, imaging, laboratory and videonystagmographic data were analyzed. Genetic analysis was done using next-generation sequencing.</jats:p>
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<jats:title>Results</jats:title>
<jats:p>The most salient clinical feature, in addition to paraspasticity, in three of five subjects was cerebellar oculomotor dysfunction with an upbeating nystagmus provoked by downward gaze. Genetic analysis revealed two hitherto unknown sequence variants in the <jats:italic>PNPLA6</jats:italic> gene, a splice-site variant c.1635 + 3G > T and a missense variant c.3401A > T, p.(Asp1134Val). In addition to cerebellar oculomotor dysfunction, compound-heterozygous siblings presented with paraspasticity and a moderate hypogonadotropic hypogonadism in the female. A paternal uncle being homozygous for the splice-site variant of <jats:italic>PNPLA6</jats:italic> presented with increased lower limb reflexes and an unstable gait. Treatment with 4-aminopyridine, a potassium channel blocker, lead to meaningful improvement of clinical symptoms.</jats:p>
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<jats:title>Conclusions</jats:title>
<jats:p>The unique and prominent cerebellar ocular motor disorder in our family broadens the spectrum of clinical phenotypes associated with variations in the PNLA6 gene. The finding of paraspasticity with cerebellar oculomotor dysfunction alongside inconspicuous brainstem imaging may raise suspicion of complex HSP with PNPLA6 mutations.</jats:p>
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