viernes, 3 de noviembre de 2017

Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia | Orphanet Journal of Rare Diseases | Full Text

Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia | Orphanet Journal of Rare Diseases | Full Text

New Articles For BioMed Central:

Orphanet Journal of Rare Diseases

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

  • Conceição BettencourtEmail authorView ORCID ID profile,
  • Vincenzo SalpietroEmail author,
  • Stephanie Efthymiou,
  • Viorica Chelban,
  • Deborah Hughes,
  • Alan M. Pittman,
  • Monica Federoff,
  • Thomas Bourinaris,
  • Martha Spilioti,
  • Georgia Deretzi,
  • Triantafyllia Kalantzakou,
  • Henry HouldenEmail author,
  • Andrew B. Singleton and
  • Georgia Xiromerisiou
Contributed equally
Orphanet Journal of Rare Diseases201712:172
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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