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- Title
Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia.
- Authors
Bettencourt, Conceição; Salpietro, Vincenzo; Efthymiou, Stephanie; Chelban, Viorica; Hughes, Deborah; Pittman, Alan M.; Federoff, Monica; Bourinaris, Thomas; Spilioti, Martha; Deretzi, Georgia; Kalantzakou, Triantafyllia; Houlden, Henry; Singleton, Andrew B.; Xiromerisiou, Georgia
- Abstract
<bold>Background: </bold>Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.<bold>Methods: </bold>We investigated a Greek HSP family using whole exome sequencing (WES).<bold>Results: </bold>A novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI.<bold>Conclusions: </bold>We review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission.
- Subjects
PARAPLEGIA; EPILEPSY; ATAXIA; CEREBRAL atrophy; GENETIC mutation; GENETIC disorders; NEURODEVELOPMENTAL treatment
- Publication
Orphanet Journal of Rare Diseases, 2017, Vol 12, p1
- ISSN
1750-1172
- Publication type
journal article
- DOI
10.1186/s13023-017-0721-2