Pyridoxine responsiveness in novel mutations of the PNPO gene.

OBJECTIVE: To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations. METHODS: We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria. RESULTS: We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5'-phosphate (PLP). CONCLUSIONS: This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5'-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug-resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis.

Exercise capacity and exercise hypertension after surgical repair of isolated aortic coarctation.

There are contradictory reports whether exercise capacity is reduced in patients on long-term follow-up after coarctation repair. Data from unselected patient groups are missing. In a cross-sectional, long-term follow-up study of a tertiary congenital cardiology referral center, 260 patients (30.2+/-11.4 years old, 84 women), after surgical repair for isolated aortic coarctation (age at surgery 11.5+/-11.2 years), underwent a symptom-limited exercise test. Peak workload was 180+/-52 W, significantly less than the age- and height-related reference values (p<0.0005). A peak workload under 80% of expected was found in 200 patients (77%). Exercise performance of the patients was independent from age at surgery, type of surgery, or the systolic brachial-ankle blood pressure difference. The only exercise-limiting factor found was the chronic administration of diuretics to treat hypertension (p=0.005). Exercise hypertension, defined as a systolic blood pressure >2 SD above the load-dependent reference value, was found in 73 patients (28%). It was independently related to the systolic brachial-ankle blood pressure difference (p<0.0005) and diuretics administration (p=0.037). In conclusion, most patients after coarctation repair have a reduced exercise performance. This reduction is not related to the surgical results. Particularly, as these patients are at risk of early atherosclerosis, exercise should be promoted as primary prevention after restenosis, aortic or cerebral aneurysms, and severe exercise hypertension are ruled out.

Coarctation Long-term Assessment (COALA): significance of arterial hypertension in a cohort of 404 patients up to 27 years after surgical repair of isolated coarctation of the aorta, even in the absence of restenosis and prosthetic material.

OBJECTIVE: Recent studies have demonstrated that there is a loss of aortic compliance in patients after coarctation repair. The clinical effect of this and other mechanisms apart from restenosis on the rate of arterial hypertension is unknown. METHODS: From 1974 through 2000, 404 patients born before January 1, 1985, underwent surgical intervention for isolated aortic coarctation. From those 382 who are still alive, 273 patients aged 16 to 73 years (1-27 years after surgical intervention) underwent a structured clinical investigation according to a prospective protocol, including blood pressure measurement at all limbs, ambulatory blood pressure measurement, and symptom-limited exercise testing. RESULTS: Sixty-seven (25%) patients were already taking antihypertensive drugs, and another 63 (23%) patients had an increased ambulatory blood pressure. Still another 26 (10%) patients had a blood pressure during exercise exceeding 2 standard deviations of reference values. Only 117 (43%) patients had a normal blood pressure reaction. From those 156 patients with hypertension, only 21 (13%) had a systolic brachial-ankle blood pressure difference of greater than 20 mm Hg, suggesting restenosis. In the patient group without restenosis (n = 245), independent risk factors for hypertension were repair with prosthetic material, male sex, a residual brachial-ankle blood pressure difference, and older age at follow-up. CONCLUSIONS: The majority of patients were hypertensive at long-term follow-up after coarctation repair. This is caused by restenosis, defined by a gradient of greater than 20 mm Hg, in only a few patients. Even in those without prosthetic material or minimal-grade restenosis, there is a substantial incidence of arterial hypertension.