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Alhaddad, B.* ; Schossig, A.* ; Haack, T.B. ; Kovács-Nagy, R.* ; Braunisch, M.C.* ; Makowski, C.* ; Senderek, J.* ; Vill, K.* ; Müller-Felber, W.* ; Strom, T.M. ; Krabichler, B.* ; Freisinger, P.* ; Deshpande, C.* ; Polster, T.* ; Wolf, N.I.* ; Desguerre, I.* ; Wörmann, F.* ; Rötig, A.* ; Ahting, U.* ; Kopajtich, R. ; Prokisch, H. ; Meitinger, T. ; Feichtinger, R.G.* ; Mayr, J.A.* ; Jungbluth, H.* ; Hubmann, M.* ; Zschocke, J.* ; Distelmaier, F.* ; Koch, J.*

PRUNE1 deficiency: Expanding the clinical and genetic spectrum.

Neuropediatrics 49, 330-338 (2018)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations.Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms.Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reportedmissensemutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene.Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Prune1 Deficiency ; Microcephaly ; Refractory Epilepsy ; Spasticity ; Developmental Delay; Linkage Analysis; Apoptosis; Cdc42gap; Mutation; Nm23-h1; Bnip-2
ISSN (print) / ISBN 0174-304X
e-ISSN 1439-1899
Journal Neuropediatrics
Quellenangaben Volume: 49, Issue: 5, Pages: 330-338 Article Number: , Supplement: ,
Publisher Thieme
Publishing Place Rudigerstr 14, D-70469 Stuttgart, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)