Neuropsychiatric disease (NPD) clustering in families with Autism Spectrum Disorder (ASD): genetic, epigenetic and environmental issues

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication/interaction and by unusual repetitive and restricted behaviors and interests. ASD often co-occurs in the same families with other neuropsychiatric diseases (NPD), such as intellectual disability, schizophrenia, epilepsy, depression and attention deficit hyperactivity disorder. Genetic factors have an important role in ASD etiology. Multiple copy number variants (CNVs) and single nucleotide variants (SNVs) in candidate genes have been associated with an increased risk to develop ASD. Nevertheless, recent heritability estimates and the high genotypic and phenotypic heterogeneity characteristic of ASD indicate a role of environmental and epigenetic factors, such as long noncoding RNA (lncRNA) and microRNA (miRNA), as modulators of genetic expression and further clinical presentation. Both miRNA and lncRNA are functional RNA molecules that are transcribed from DNA but not translated into proteins, instead they act as powerful regulators of gene expression. While miRNA are small noncoding RNAs with 22-25 nucleotides in length that act at the post-transcriptional level of gene expression, the lncRNA are bigger molecules (>200 nucleotides in length) that are capped, spliced, and polyadenylated, similar to messenger RNA. Although few lncRNA were well characterized until date, there is a great evidence that they are implicated in several levels of gene expression (transcription/post-transcription/post-translation, organization of protein complexes, cell– cell signaling as well as recombination) as shown in figure 1.

Dor abdominal aguda como apresentação de porfirias

As porfirias são um grupo de oito doenças metabólicas raras, em resultado de uma deficiência enzimática em cada uma das oito enzimas envolvidas na biossíntese do grupo heme. São doenças maioritariamente hereditárias, mas podem também ser adquiridas aquando da exposição a certos fatores ambientais e/ou patológicos. Estes fatores externos, denominados de porfirinogénicos também têm um papel preponderante no diagnóstico das porfirias, uma vez que mimetizam os sintomas clínicos de um ataque agudo de porfiria, contribuindo para subestimar esta doença, levando a um atraso no diagnóstico e diminuído o sucesso do prognóstico. Os ataques agudos de porfiria, nomeadamente na porfiria aguda intermitente, porfiria variegata, coproporfiria hereditária, e deficiência da desidratase do ácido delta-aminolevulínico, apesar de serem doenças multissistémicas, têm em comum como apresentação clínica, a dor abdominal aguda. A pesquisa de porfobilinogénio (PBG) na urina, através da realização do teste de Hoesch, é uma forma rápida e fácil de excluir a suspeita clínica de porfiria. Pretendemos com este trabalho, alertar para a necessidade de um diagnóstico laboratorial atempado, que pela sua simplicidade poderá descartar ou confirmar se a dor abdominal aguda, tão frequente nas urgências hospitalares, será ou não uma manifestação clínica de um ataque agudo de porfiria. Este estudo contribuirá não só para aumentar o nosso conhecimento acerca destas doenças, como também permitirá uma melhor compreensão dos mecanismos de patogenicidade das porfirias, o qual ainda permanece pouco conhecido.

Hyperprolinemia as a clue in the diagnosis of a patient with a psychiatric disorder

Background: Over the last few years, microdeletions of the 22q11.2 region responsible for DiGeorge syndrome, or velocardiofacial syndrome, have been increasingly related to neuropsychiatric disorders including schizophrenia and bipolar disorders. These signs seem to be related to certain genes located in the hemideleted region as the proline dehydrogenase (PRODH) and the catecholo-methyltransferase (COMT) genes. The PRODH or proline oxidase deficiency is responsible for hyperprolinemia type 1 (HPI) also causing psychiatric manifestations. Case Report: We describe a 17 year old boy with previous mild psychomotor and speech delay, mild cognitive impairment, and obsessive behaviours who started his adolescent psychiatric care presenting irritablemood and aggressive behaviour with schizophrenia symptoms that scored a “severely ill” level PANSS assessment. Symptoms got worse when he was treated with valproic acid and plasma aminoacids showing increase in alanine and proline, suggested a mitochondrial involvement of the proline metabolic pathway. Results: Mild dysmorphia suggested a possible 22q11.2 deletion genetically confirmed involving both the PRODH and COMT regions. HPI that can present with psychiatric features is however a recessive disorder and therefore the symptoms could not be solely explained by this genetic deletion. Additional investigations also showed disclosed a p.L289m (c.1865 T > A) mutation in the PRODH gene. Discussion: We believe that the association of this mutation together with the 22q11.2 deletion would lead to a decrease of functional protein. Although it may be difficult to diagnosis chromosomal abnormalities in patients with no clear malformations and mild dysmorphic features as in this patient we emphasize need to investigate the aetiology in patients with psychiatric symptoms, especially if they have other systemic manifestations such as developmental delay or psychotic symptoms, as it may be important in the management of the patients.