Kleine-Levin syndrome

Gene: EXT1

Comment when marking as ready: Associated with phenotypes Chondrosarcoma 215300; Exostoses, multiple, type 1 133700 in OMIM and G2P. Incidence of association with narcolepsy with cataplexy appear to be restricted to one family

Created: 5 Jan 2017, 2:34 p.m.

Comment on phenotypes: Also associated with Chondrosarcoma 215300; Exostoses, multiple, type 1 133700

Created: 5 Jan 2017, 2:20 p.m.

Comment on publications: Poster presentation which is summarised in the reviewer's comments

Created: 5 Jan 2017, 2:09 p.m.

I don't know

Exome sequencing of the patient and her unaffected sister revealed 110 mutations in the patient. Of these mutations, 41 were identified as unique to the patient. Interestingly, EXT1 was among them. The mutation c.G1019A produced the amino-acid change p.R340H. The same change was observed in another HME family, namely, codon 340 was mutated from R(Arginine) to L(Leucine) instead of to H(Histidine), as was the case in our patient.

Created: 26 Dec 2016, 11:23 a.m.

Narcolepsy with Cataplexy associated with hereditary multiple exostoses (1)
Hereditary multiple exostoses (HME) has thus far been linked with mutations in three genes: EXT1 which maps to chromosome 8q24.1, EXT2 which maps to 11p13 and EXT3 which maps to the short arm of Chromosome 19 (though its exact location has yet to be precisely determined). It is thought that normal chondrocyte proliferation and differentiation may be affected, leading to abnormal bone growth.
Case Report: A 48-year-old man with HME and familial narcolepsy with cataplexy was referred due to sleep episodes since the age of 44 and severe catapleptic attacks two years later. He presented obesity (BMI 35.1 Kg/ m2) and multiple osteochondromas causing deformity of the forearm, pelvis, knees and irritation of tendon and muscles. Neurological examination including EEG and cranial CT were normal.
PSG showed disturbed nocturnal sleep and 2 SOREMPs on MSLT with a mean sleep latency of 3.5 minutes. HLA genotyping was DRB1*15:01-DQB1*06:02 positive. Genetic study for HME did not show any mutation in the implicated genes only 6 polymorphisms had been detected. Patient’s unique sister with the same HLA genotype is clinically unaffected.
Conclusion. To our knowledge this is the first report of a familial case of NC associated to autosomal dominant HME. Future assessment should include a genetic work-up including the new generation exome sequencing to identify a potential pathogenic mutation.
(1) Reference. Reimão R and Diament A. Periodic hypersomnia, congenital ectodermal disorders and multiple exostoses. Arq Neuropsiquiatr. 1989,47(1):76-9.

Created: 26 Dec 2016, 11:22 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Familial case of narcolepsy with cataplexy NT1 associated with multiple exostoses

Publications

• Journal Sleep Research 2012
• 21(Suppl 1)

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice