Clinic and genetic evaluation of variegate porphyria (VP) in a large family from the Balearic Islands

Abstract

Variegate porphyria (VP) (an autosomal dominant disease), is clinically characterized by skin photosensitivity and/or acute neurovisceral crises and biochemically by high levels of faecal protoporphyrin and coproporphyrin. It results from the partial deficiency of protoporphyrinogen oxidase (PPOX gene). Genetic heterogeneity has been reported in this gene, although no genotype-phenotype correlation has been evidenced. We have sequenced 27 members of a single large Majorcan family with several individuals that exhibit VP symptoms: two of the eight patients had only skin symptoms (25%), one patient had only acute visceral crises (12.5%), one patient had both manifestations (12.5%) and the rest were completely asymptomatic (50%). In eight individuals, a T>A transversion at the intron 6 consensus splicing site was found (IVS6+2T>A), but only four of them presented clinical symptoms. We have also detected four polymorphic positions, three non-coding and one non-synonymous coding: c.-414A>C; IVS2+121G>C; c.1188G>A and IVS12+34C>T. Although IVS12+34C>T change has been reported to cause VP, generalized linear model (GLM) analyses showed no significant association between these SNPs and phenotypic manifestations. Only three mtDNA haplogroups were detected in this family: H, K and U(5a1). Two of them are relatively common in Balearic Islands. Our family evidenced a positive correlation between the clinically overt VP and haplogroup H. Thus, it seems that, in this family, the haplogroup H could be involved in the expression of the disease. The GLM analyses evidenced an association between haplogroup H, mutation IVS6+2T>A and clinically overt variegate porphyria.

Evaluation of gonadotropin‐releasing hormone agonist treatment for prevention of menstrual‐related attacks in acute porphyria

“…Progesterone medication caused most problems, as attacks were triggered in five of nine women with progesterone add‐back. There is substantial evidence in the literature that progesterone is a potent inducer of porphyria attacks (1, 8, 18). As progesterone usually has negative impact on porphyria symptoms, it is important to find a safe regime for add‐back therapies or a regime to avoid progesterone add‐back.…”

“…Abdominal pain, constipation, muscle and back pain, muscular weakness, paresthesia and various psychiatric symptoms are common porphyria manifestations. Clinical symptoms of porphyria are more common in women than in men, especially in their reproductive age (1, 8). Cyclical AIP attacks during the luteal phase of the menstrual cycle have been reported in 10–30% (6, 9–14).…”

Novel PPOX mutations in two variegate porphyria pedigrees

“…Clinical presentation of VP varies from no overt clinical symptoms, chronic photosensitivity to acute neurovisceral crises. Penetrance of 40% and 50% has been reported in two pedigrees of VP carrying variant p. R59W and IVS6 + 2T > A, respectively (11,12). Haplogroup H of mtDNA is also associated with the penetrance 12 .…”

Quantitative Structural Insight into Human Variegate Porphyria Disease

“…VP is a type of acute hepaticporphyria (9 -11), which is characterized by an abnormal pattern of porphyrin excretion. VP has been found worldwide (12)(13)(14)(15) and is particularly prevalent in the white population of South Africa (ϳ3 in 1000), especially VP caused by the R59W founder mutation (16,17).…”