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Open Access 01-12-2017 | Research

Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia

Authors: Conceição Bettencourt, Vincenzo Salpietro, Stephanie Efthymiou, Viorica Chelban, Deborah Hughes, Alan M. Pittman, Monica Federoff, Thomas Bourinaris, Martha Spilioti, Georgia Deretzi, Triantafyllia Kalantzakou, Henry Houlden, Andrew B. Singleton, Georgia Xiromerisiou

Published in: Orphanet Journal of Rare Diseases | Issue 1/2017

Abstract

Background

Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.

Methods

We investigated a Greek HSP family using whole exome sequencing (WES).

Results

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.

Conclusions

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.

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Title: Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia
Authors: Conceição Bettencourt
Vincenzo Salpietro
Stephanie Efthymiou
Viorica Chelban
Deborah Hughes
Alan M. Pittman
Monica Federoff
Thomas Bourinaris
Martha Spilioti
Georgia Deretzi
Triantafyllia Kalantzakou
Henry Houlden
Andrew B. Singleton
Georgia Xiromerisiou
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2017
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-017-0721-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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