AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model

Journal article

Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain development and function; they are characterized by extensive genetic and clinical variability. We performed clinical, genetic, biochemical, and molecular analyses on two consanguineous families with microcephaly exhibiting an NDD. Detailed clinical investigation and molecular diagnosis were performed using whole-exome sequencing (WES), followed by Sanger sequencing for the affected families. WES revealed disease-causing homozygous variants in two families associated with microcephaly and NDDs. In family A and family B, we identified two previously reported homozygous variants (c.3978G>A; Trp1326* and c.4309C>A; p.Arg1437Ser) in the ASPM gene. Both the variants were further confirmed using bi-directional Sanger sequencing. In the present study, we presented literature review regarding the NDDs and microcephaly associated with ASPM pathogenesis. These findings contribute to studies of genotype–phenotype correlation, genetic counseling of the families, inclusion of ASPM in newborn screening, and further understanding of human brain function and development

Authors: Deng, R; Medico-Salsench, E; Nikoncuk, A; Ramakrishnan, R; Lanko, K

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer
• Journal: Acta Neuropathologica
• Volume: 146
• Issue: 2
• Pages: 353-368
• Publication date: 2023-04-29
• DOI: 10.1007/s00401-023-02579-9
• EISSN: 1432-0533
• ISSN: 0001-6322
• Language: English
• Keywords: Phenotype; Spasticity; Microcephaly; Compound heterozygosity; Hereditary spastic paraplegia; Motor neuron; Spinal muscular atrophy; Gene; Spinal cord; Zebrafish; Genetics; Neuroscience; Biology; Medicine