NOVEL 19 BP DELETION OF EXON 15 IN THE PBGD GENE AND NORMAL ERYTROCYTE PORPHOBILINOGEN ACTIVITY IN A PATIENT WITH ACUTE INTERMITTENT PORPHYRIA

R.Kauppinen, A.Yrjönen, E.Pishick

 

Research Program in Molecular Medicine, Biomedicum-Helsinki, University of Helsinki, Finland

 

 

A 36-year old Estonian patient experienced recurrent acute attacks related to the irregular menstrual cycle since 15 years of age. She had had one normal pregnancy and delivery at the age of 27, which normalised her menstrual cycle and she became symptom-free.  During the last four years she experienced two miscarriages and an ovarian cyst, which precipitated several monthly attacks. The diagnosis of AIP was established only recently when she was taken to the emergency area because of confusion, rhabdomyolysis (S-myoglobin 2144 mmol/l, CK up to 21806 mmol/l), severe hyponatremia (S-Na 108 mmol/l) because of  SIADH and hypokalemia (S-K 2.8 mmol/l). Transaminases were increased (ALT 128,AST 601 mmol/l). The acute attack had started 2 weeks earlier  with abdominal pain, restlessness and constipation. Sensomotor polyneuropathy was detected, and brain CT was normal and EEG showed predominance of slow waves in occipital areas suggesting diminished electrical activity. Two weeks later  when serum sodium level was  normal, brain MRI showed enlarged internal and external liquor space and decreased signal from neural hypophysis. After a month nerve conduction studies were normal despite slightly decreased muscle strength. She was treated with heme arginate twice because of a subsequent attack. Contraceptive pills were started to prevent acute attacks and she recovered fully from polyneuropathy within 6 months and has been symptom-free for a year. Erythrocyte PBGD activity was repeatedly normal (81-79-77 Upor/h/mg protein, normal 50-100) both during an acute attack (U-PBG 900 umol/l, U-DALA 570 umol/l) and in remission (U-PBG 300 umol/l, DALA 150 umol/l). Activities of Ly-PPOX and  E-CoproOX were normal, and E-UROD was low (54 coproporph/h/mg protein, normal 65-100). Plasma fluorescence emission maximum was at 619nm, faecal porphyrins were normal and in urinalysis the amount of uroporphyrins exceeded that of coproporphyrins (9000 vs 2000 nmol/l). The direct sequencing of the genomic DNA sample revealed only a 19 bp deletion in exon 15 (GAACTTGGGC ATCAGCCTGG CCAACTTGTT), which introduced an early stop codon ( L A A Q N T C C X) and caused a loss of function when evaluated using expression studies.