Is NIPA1-associated hereditary spastic paraplegia always 'pure'? Further evidence of motor neurone disease and epilepsy as rare manifestations.

Pathogenic variants in the nonimprinted in Prader-Willi/Angelman syndrome (NIPA1) gene typically present with pure hereditary spastic paraplegia (HSP) but complex cases are described. We present a patient with childhood idiopathic generalised epilepsy (IGE) who later developed HSP. She rapidly deteriorated 27 years later with clinically definite amyotrophic lateral sclerosis (ALS). Her family history included HSP, IGE and motor neurone disease. Genetic testing identified a pathogenic variant in the NIPA1 gene associated with spastic paraplegia 6 (SPG6). This case provides the first description of NIPA1 in a family with epilepsy, ALS and thus complex HSP.

First report of somatic mosaicism for mutations in STK11 in four patients with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant cancer predisposition syndrome characterised by gastrointestinal polyposis and mucocutaneous pigmentation. Mutations in STK11, a serine-threonine protein kinase, have been associated with PJS in up to 100 % of published series. The hypothesis that a further genetic locus for PJS exists is controversial. No mutations in any other genes have been described in association with PJS. To date, no instances of somatic mosaicism for STK11 have been described. DNA extracted from peripheral lymphocytes and buccal cells was screened by sequence analysis for mutations in STK11. Dosage analysis was undertaken by multiplex ligation-dependent probe amplification (MLPA). Four patients have been shown to have mosaicism in STK11: two had mosaic deletions of specific exons (2-3 and 3-10) of the STK11 gene; one had a mosaic nonsense mutation in exon 5; and one had a mosaic frameshift mutation in exon 8. This report details the first four reported cases of somatic mosaicism for STK11 associated with PJS. This shows that techniques in addition to direct sequencing such as MLPA must be used to assess for large scale genomic deletions in patients meeting clinical diagnostic criteria for PJS. This also adds further weight to the hypothesis of a single genetic locus for PJS.