Barth's syndrome-like disorder: a new phenotype with a maternally inherited A3243G substitution of mitochondrial DNA (MELAS mutation).

An Argentine male child died at 4.5 years of age of a lethal mitochondrial disease associated with a MELAS mutation and a Barth syndrome-like presentation. The child had severe failure to thrive from the early months and for approximately two years thereafter. In addition, the patient had severely delayed gross motor milestones, marked muscle weakness, and dilated cardiomyopathy that progressed to congestive heart failure. He also had persistently elevated urinary levels of 3-methylglutaconic and 2-ethylhydracrylic acids and low blood levels of cholesterol. Detailed histopathologic evaluation of the skeletal muscle biopsy showed high activity of succinate dehydrogenase, a generalized decrease of COX activity, and abundant ragged-red fibers. Electron microscopic studies revealed multiple mitochondrial abnormalities in lymphocytes and monocytes, in the striated muscle, and in the postmortem samples (muscle, heart, liver, and brain). Biochemical analysis showed a pronounced and constant lactic acidosis, and abnormal urinary organic acid excretion (unchanged in the fasting and postprandial states). In addition, in CSF there was a marked increase of lactate and beta-hydroxybutyrate (beta-HOB) and also a high systemic ratio beta-HOB/acetoacetate. Enzymatic assay of the respiratory chain in biopsied muscle showed 10% of complex I activity and 24% of complex IV activity compared with controls. Molecular studies of the mitochondrial genome revealed an A to G mutation at nucleotide pair 3243 in mitochondrial DNA, a well-known pathogenetic mutation (MELAS mutation) in all the patient's tissues and also in the blood specimens of the probands mother and sibs (4 of 5). The diagnosis of MELAS mutation was reinforced by the absence of an identifiable mutation in the X-linked G4.5 gene of the propositus. The present observation gives additional evidence of the variable clinical expression of mtDNA mutations in humans and demonstrates that all clinical variants deserve adequate investigation to establish a primary defect. It also suggests adding Barth-like syndrome to the list of phenotypes with the MELAS mutation.

Surgical ligation of a persistent arterial duct in one of conjoined thoracopagus twins prior to surgical separation.

One of conjoined thoracopagus twins, with separate hearts and a common pericardial sack, presented with respiratory distress because of a persistent arterial duct causing congestive heart failure in the neonatal period. Surgical ligation of the duct was performed prior to subsequent separation, with an excellent outcome.

Superoinferior ventricles with criss-cross atrioventricular connections and intact ventricular septum.

We report a 6-year-old girl with superoinferior ventricles, criss-cross atrioventricular (AV) relationships with solitus atria, a D-loop, L-transposition of the great arteries, subpulmonary stenosis, but without a ventricular septal defect (VSD). The diagnosis was made by echocardiographic examination and was strengthened by cardiac catheterization and angiocardiography. Balloon atrial septostomy in the neonatal period and a modified Blalock-Taussig shunt at the age of 16 months were performed to alleviate hypoxia. Following the shunt operation, the clinical condition of the patient deteriorated with progressive cardiac enlargement, congestive heart failure, and tricuspid regurgitation. We assume that the absence of a VSD contributed to this deterioration. Subsequent improvement was obtained with balloon enlargement of the atrial septal defect and a bidirectional Glenn anastomosis.

Percutaneous balloon dilatation in congenital mitral stenosis.

A three year old girl with severe congenital mitral stenosis was successfully treated by percutaneous balloon dilatation of the mitral valve. Cardiac catheterisation and cross sectional and Doppler echocardiography indicated that the orifice of the mitral valve had doubled in area. A small atrial septal defect was found at follow up cardiac catheterisation and angiography. Balloon dilatation of the mitral valve is a reasonable alternative to surgical treatment for typical congenital mitral stenosis even in young children.

Double inlet ventricle. Lung biopsy findings and implications for management.

The lung was biopsied in 20 children with double inlet ventricle and pulmonary hypertension aged 2 months to 14 years. Eleven patients had two patent atrioventricular valves, three atresia of the right valve, and six hypoplasia of the left valve. Severe pulmonary arterial medial hypertrophy occurred in the nine children less than 1 year of age. The findings did not suggest a period of normality after birth when the pulmonary artery might have been banded most effectively. Of the 11 older patients, eight had medial hypertrophy and three intimal proliferation with medial atrophy. Six patients with medial hypertrophy had some reduction in pulmonary arterial pressure after banding. It is recommended that the pulmonary artery be banded as early as possible, and rebanded early if a satisfactory result is not obtained, particularly in patients destined for a Fontan-Kreutzer procedure. Early atrial septectomy should reduce the arterial and venous abnormalities seen in left atrioventricular valve hypoplasia.

Pulmonary arterial development in infants with large perimembranous ventricular septal defects associated with overriding of the aortic valve.

Intracardiac anatomy and pulmonary vascular structure were studied in 13 cases having large perimembranous ventricular septal defects associated with overriding of the aortic valve, 12 of whom died aged 2 days-9 months. In all cases the ventricular septal defect and aorta were of the same size, but the diameter of the pulmonary orifice was usually greater. Quantitative morphometric techniques were used to study the lungs. Structural adaptation to extra-uterine life was shown to have occurred normally in the 4 patients who died as neonates. In the cases aged 2 months-4 years, there was an increase in arterial medial thickness and extension of muscle, while the intra-acinar arteries were larger than normal in size and normal in number. Intimal proliferation was seen in 1 case at 4.5 months, but such proliferation caused significant obstruction only in one child aged 4 years. These findings emphasize the rapidity with which structural adaptation to extra-uterine life can occur in the patient with a large unrestrictive ventricular septal defect. A rapid increase in muscularity can be seen by 2 months of age. Should banding of the pulmonary artery be required in patients with more complicated intracardiac abnormalities in whom it is desirable to achieve a normal pulmonary vascular bed, our findings encourage its early performance, particularly in those destined for a Fontan repair.

An unusual case of rapidly progressive primary pulmonary hypertension in childhood.

A 7-year-old child died with primary pulmonary hypertension only 6 months after the onset of symptoms. Autopsy demonstrated severe pulmonary arterial medial hypertrophy and intimal proliferation. This case emphasizes the rapidity with which pulmonary vascular obstruction may occur, death resulting from potentially reversible structural abnormalities. It also demonstrates the variability in pulmonary vascular pathology in primary pulmonary hypertension and the necessity of biopsying the lung in order to predict those in whom vasodilator therapy might be helpful.

Pulmonary vascular disease in children with truncus arteriosus.

Pulmonary vascular structure was analyzed using quantitative morphometric techniques in lung biopsy (n = 17) and/or postmortem specimens (n = 18) from 23 patients aged 18 days to 13 years, with truncus arteriosus (TA) type I or II. All 14 patients younger than age 1 year, showed abnormal extension of muscle and an increase in pulmonary arterial medial thickness (p less than 0.01 in 18 of 24 biopsy and autopsy specimens), whereas 6 showed intimal proliferation. Structural abnormalities were usually potentially reversible, even in 5 infants with a pulmonary arteriolar resistance of greater than or equal to 8 units X m2. Abnormalities were more severe in 9 patients aged 3.5 to 13 years, 6 with medial atrophy and 4 with pulmonary arteriolar resistance of greater than 8 units X m2 that also showed intimal fibrosis, with or without plexiform lesions or hyalinized arteries. Findings indicate that biopsy specimens are helpful in assessing the severity of pulmonary vascular disease, and are representative of the entire pulmonary vascular bed (avoiding the lingula); however, interpretation can be difficult if a biopsy specimen is taken of only the peripheral intraacinar arteries, distal to the most damaged vessels. An intracardiac repair is recommended by 6 months, at which time severe pulmonary arterial medial hypertrophy and intimal proliferation can be expected to prejudice the repair.

Pulmonary vascular structure in patients dying after a Fontan procedure. The lung as a risk factor.

Pulmonary vascular structure was analysed in the lungs of 12 patients who had had a Fontan repair, 11 of whom died. Of the eight patients with a low pulmonary blood flow preoperatively, pulmonary vascular structure was almost normal in seven, but in the remaining patient many intra-acinar arteries contained organised occlusive thrombi. Of the four patients with an increased pulmonary blood flow immediately before operation, there was a significant increase in pulmonary vascular smooth muscle despite three of the patients having had a pulmonary arterial band. The findings suggest that it is more difficult for patients with an increased pulmonary blood flow to fulfil the Fontan criteria for repair, and even when the pulmonary vascular resistance is less than 4 units/m2 there may be significant pulmonary vascular abnormalities likely to increase right atrial afterload and prejudice the outcome of a Fontan repair.