Objective: To identify possible novel variants in a HSP family from Greece. 

Background: Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder with a few reported patients presenting the combination of infantile hypotonia, severe intellectual disability, progressive hypertonia and spasticity, coupled with variable cerebellar involvement and white matter loss on brain magnetic resonance imaging (MRI).

Methods: We investigated a Greek family with three siblings affected with a phenotype characterized by the 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; (e) cerebellar hypoplasia/atrophy on brain MRI.

Results: Genetic analysis of the family using whole exome sequencing (WES) identified a novel compound heterozygous mutation of the AP4M1A gene segregating with the phenotype in all the three probands (c.521dupT, p.V174fs and c.T955C, p.C319R). The mutation was confirmed by sanger sequencing and the unaffected parents were found to be carriers of the variants.

Conclusions: We reported on a Greek family with a phenotype of early-onset epilepsy, developmental delay and progressive spastic paraplegia, due to a previously unreported AP4M1 mutation.  The AP4M1 gene encodes a subunit of the heterotetrameric adaptor protein (AP) complex that mediates vesicle trafficking of glutamate receptors between the trans-Golgi network (TGN) to the synaptic membrane, and thereby contribute to regulate brain development and neurotransmission.

References: Bettencourt C, Lopez-Sendon JL, Garcia-Caldentey J et al. Exome sequencing is a useful diagnostic tool for complicated forms of hereditary spastic paraplegia. Clinical genetics 2014: 85: 154-158.

Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta neuropathologica 2013: 126: 307-328.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genotype-phenotype-correlations-and-expansion-of-the-molecular-spectrum-of-ap4m1-related-hereditary-spastic-paraplegia/