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Título

Mutational screening in brazilian patients with Acute Intermittent Porphyria disease

Resumo

Mutational screening in brazilian patients with Acute Intermittent Porphyria disease

Introduction: Acute Intermittent Porphyria (AIP) is a rare, genetically determined neurometabolic disorder with an autosomal dominant inheritance pattern and reduced penetrance. Pathogenic variants in the HMBS gene lead to a partial deficiency of the enzyme hydroxymethylbilane synthase, also called porphobilinogen deaminase (PBDG), the third enzyme in the heme group biosynthetic pathway. Deficiency in HMBS production leads to the accumulation of heme precursors, wich are toxic to cells. During puberty, the disease manifests itself and is characterized by intermittent neurovisceral attacks, including severe abdominal pain, peripheral neuropathy, and psychiatric manifestations. The combined prevalence of acute porphyrias is 5 cases per 100000. The Brasilian epidemiology is unknow. In a study carried on 2002 it was found seven mutations and in a 2015 study it was found nine variants.
Objectives: To evaluate the prevalence of genetic variants in the HMBS gene in a Brazilian cohort of patients admitted to a tertiary hospital presenting with an acute neuropathy associated with abdominal pain, psychiatric manifestations, or laboratory abnormalities suggestive of AIP.
Methods: Forty-nine consecutive probands were tested, of which thirty-four were women. Sanger sequencing from all HMBS exons was performed. Variants detected were classified according to ACMG criteria
Results: A pathogenic/likely pathogenic variant was found in twelve probands. Segregation analysis revealed additional seven carriers,of wich three had clinical manifestation. Eight variants found according to (NM_000190.4/ENST00000652429.1) were: three missense alterations (c.346C>T probably pathogenic; c.517C>T pathogenic; c.77G>A probably pathogenic), two nonsense alterations (c.973C>T pathogenic; c.912_913insT pathogenic); two splice site alterations (c.652-1G>A pathogenic; 499-1G>A pathogenic) and one frameshift variant (c.854_855insC pathogenic). The remaining thirty-seven probands had no variants, the remaining for genes are being tested for this cohort.
Conclusion: In this study, the molecular diagnosis was possible in 24.5% of probands tested with a clinical diagnosis of AIP. We found the most frequent abnormality (c.973C>T), a nonsense pathogenic variant observed in five unrelated individuals. We are now using a next-generation sequencing methodogy to search for the remaining genes associated with acute porphyria