ABSTRACT
BACKGROUND: Hereditary primary microcephaly (MCPH) is mainly characterised by decreased occipitofrontal circumference and variable degree of intellectual disability. MCPH with a dominant pattern of inheritance is a rare condition, so far causally linked to pathogenic variants in the ALFY, DPP6, KIF11 and DYRK1A genes. OBJECTIVE: This study aimed at identifying the causative variant of the autosomal dominant form of MCPH in a Brazilian family with three affected members. METHODS: Following clinical evaluation of two sibs and their mother presenting with autosomal dominant MCPH, array comparative genome hybridisation was performed using genomic DNA from peripheral blood of the family members. Gene and protein expression studies were carried out in cultured skin fibroblasts. RESULTS: A 382 kb microduplication at 10q23.31 was detected, encompassing the entire PTEN, KLLN and ATAD1 genes. PTEN haploinsufficiency has been causally associated with macrocephaly and autism spectrum disorder and, therefore, was considered the most likely candidate gene to be involved in this autosomal dominant form of MCPH. In the patients' fibroblasts, PTEN mRNA and protein were found to be overexpressed, and the phosphorylation patterns of upstream and downstream components of the mammalian target of rapamycin (mTOR) signalling pathway were dysregulated. CONCLUSIONS: Taken together, our results demonstrate that the identified submicroscopic 10q23.31 duplication in a family with MCPH leads to markedly increased expression of PTEN and reduced activity of the mTOR signalling pathway. These results suggest that the most probable pathomechanism underlying the microcephaly phenotype in this family involves downregulation of the mTOR pathway through overexpression of PTEN.
Subject(s)
Chromosome Duplication , Chromosomes, Human, Pair 10 , Microcephaly/genetics , Microcephaly/metabolism , PTEN Phosphohydrolase/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Adolescent , Adult , Child , Child, Preschool , DNA Copy Number Variations , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Microcephaly/diagnosis , Neuroimaging , Pedigree , Exome Sequencing , Young AdultABSTRACT
Basal ganglia calcifications (BGC) may be present in various medical conditions, such as infections, metabolic, psychiatric and neurological diseases, associated with different etiologies and clinical outcomes, including parkinsonism, psychosis, mood swings and dementia. A literature review was performed highlighting the main neuropsychological findings of BGC, with particular attention to clinical reports of cognitive decline. Neuroimaging studies combined with neuropsychological analysis show that some patients have shown progressive disturbances of selective attention, declarative memory and verbal perseveration. Therefore, the calcification process might represent a putative cause for dementia syndromes, suggesting a probable link among calcinosis, the aging process and eventually with neuronal death. The increasing number of reports available will foster a necessary discussion about cerebral calcinosis and its role in determining symptomatology in dementia patients.
As calcificações dos gânglios da base (BGC) podem estar presentes em diversas condições médicas, como infecções, doenças metabólicas, psiquiátricas e neurológicas, associadas a diferentes etiologias e desfechos clínicos, incluindo parkinsonismo, psicose, alterações de humor e demência. Realizamos revisão da literatura destacando os principais achados neuropsicológicos das BGC, com especial atenção para os relatos de declínio cognitivo. Estudos de neuroimagem combinados com análise neuropsicológica mostram que alguns pacientes apresentam distúrbios progressivos de atenção seletiva, memória declarativa e perseverança verbal. Portanto, o processo de calcificação pode representar uma causa imputável para síndromes demenciais, sugerindo uma provável ligação entre a calcinose, o processo de envelhecimento e a morte neuronal. O número crescente de relatos disponíveis promoverá uma discussão necessária sobre calcinose cerebral e seu papel na determinação da sintomatologia em pacientes demenciais.
