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Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia
- 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 and
- Georgia Xiromerisiou
†Contributed equally
Orphanet Journal of Rare Diseases201712:172
© The Author(s). 2017
Received: 9 June 2017
Accepted: 25 October 2017
Published: 2 November 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.
Keywords
Whole exome sequencingAP4 complexEpilepsyHereditary spastic paraplegiaCerebellar hypoplasia
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