Cardiac Ultrasound Findings in Infants with Severe (Hurler Phenotype) Untreated Mucopolysaccharidosis (MPS) Type I.

BACKGROUND: Serious cardiac valve disease and left ventricular hypertrophy occur in most untreated older children with severe mucopolysaccharidosis type I. Although it is assumed that early intervention prevents these processes, evaluation of cardiac findings in these infants has not yet been reported. METHODS: We reviewed echocardiograms of 13 untreated infants < 1 year of age with severe mucopolysaccharidosis type I who had undergone evaluation for hematopoietic cell transplantation. We recorded left ventricular chamber dimensions, septal and posterior wall thicknesses, ventricular function, and aortic sinus diameters. We evaluated mitral and aortic valves for increased thickness, regurgitation, and stenosis. RESULTS: Average age (7M, 6F) was 221 (range 25-347) days. Left ventricular chamber dimension was ≥2 SD of normal in 3/13; wall thicknesses were ≥2 SD of normal in 2/13 infants. Systolic function was normal. Mitral valves were thickened in all infants; mitral regurgitation was present in 9/13, but significant in only three infants. Aortic valves were thickened in 10/13, but no infant had significant aortic regurgitation. Neither mitral nor aortic stenosis occurred. Aortic roots were dilated to ≥2 SD of normal in 5/13. CONCLUSIONS: Characteristic cardiac features of severe mucopolysaccharidosis type I can be seen in infancy. Mitral and aortic valve thickening are nearly universally present, even in the youngest infants. In 20-30 % of infants, other abnormalities such as left ventricular dilation, increased wall thickness, and mild mitral/aortic regurgitation may occur. Aortic root dilation is a frequent finding. Early intervention with enzyme replacement therapy may minimize the incidence and severity of cardiac findings in these infants. SUMMARY: Serious cardiac valve disease and left ventricular hypertrophy occur in most untreated older children with severe mucopolysaccharidosis type I. Although it is assumed that early intervention prevents these processes, evaluation of cardiac findings in these infants has not yet been reported. In our study of 13 infants with severe untreated MPS I < 1 year of age, mitral and aortic valve thickening was nearly universally present and aortic root dilation was frequent. Despite this, we found a lower incidence of left ventricular hypertrophy and both a lower incidence and milder expression of mitral and aortic valve dysfunction than previously reported in older children. These findings suggest that earlier intervention, including neonatal screening, may be of benefit to children with severe MPS I.

Enzyme replacement therapy for mucopolysaccharidosis VI: long-term cardiac effects of galsulfase (Naglazyme®) therapy.

Characteristic cardiac valve abnormalities and left ventricular hypertrophy are present in untreated patients with mucopolysaccharidosis type VI (MPS VI). Cardiac ultrasound was performed to investigate these findings in subjects during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB, rhN-acetylgalactosamine 4-sulfatase, galsulfase, Naglazyme®). Studies were conducted in 54 subjects before ERT was begun and at specific intervals for up to 96 weeks of weekly infusions of rhASB at 1 mg/kg during phase 1/2, phase 2, and phase 3 trials of rhASB. At baseline, mitral and aortic valve obstruction was present and was significantly greater in those ≥12 years of age. Mild mitral and trace aortic regurgitation were present, the former being significantly greater in those <12 years. Left ventricular hypertrophy, with averaged z-scores ranging from 1.6-1.9 SD greater than normal, was present for ages both <12 and ≥12 years. After 96 weeks of ERT, ventricular septal hypertrophy regressed in those <12 years. For those ≥12 years, septal hypertrophy was unchanged, and aortic regurgitation increased statistically but not physiologically. Obstructive gradients across mitral and aortic valves remained unchanged. The results suggest that long-term ERT is effective in reducing intraventricular septal hypertrophy and preventing progression of cardiac valve abnormalities when administered to those <12 years of age.

Increased longevity and metabolic correction following syngeneic BMT in a murine model of mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive inherited disease caused by deficiency of the glycosidase α-L-iduronidase (IDUA). Deficiency of IDUA leads to lysosomal accumulation of glycosaminoglycans (GAG) heparan and dermatan sulfate and associated multi-systemic disease, the most severe form of which is known as Hurler syndrome. Since 1981, the treatment of Hurler patients has often included allogeneic BMT from a matched donor. However, mouse models of the disease were not developed until 1997. To further characterize the MPS-I mouse model and to study the effectiveness of BMT in these animals, we engrafted a cohort (n=33) of 4-8-week-old Idua(-/-) animals with high levels (88.4±10.3%) of wild-type donor marrow. Engrafted animals displayed an increased lifespan, preserved cardiac function, partially restored IDUA activity in peripheral organs and decreased GAG accumulation in both peripheral organs and in the brain. However, levels of GAG and GM3 ganglioside in the brain remained elevated in comparison to unaffected animals. As these results are similar to those observed in Hurler patients following BMT, this murine-transplantation model can be used to evaluate the effects of novel, more effective methods of delivering IDUA to the brain as an adjunct to BMT.

Pre-transplant risk factors affecting outcome in Hurler syndrome.

Allogeneic transplantation remains the standard of care for patients with Hurler syndrome. As enzyme replacement therapy (ERT) has become available, controversy has emerged in regards to whether the use of enzyme in the peri-transplant period is appropriate. An analysis was performed on 74 patients with Hurler syndrome transplanted at the University of Minnesota between 1990 and 2003, before our use of ERT associated with transplant, with the intention of determining if patients at higher risk during the transplant can be identified based on evaluations and events before transplantation. Age, the presence of hydrocephalus, a history of cardiovascular issues or upper airway obstruction before transplant was not associated with significant differences in survival. In contrast, patients who had a history of lower airway disease, including reactive airway disease or bronchiolitis, or a history of pneumonia, had a significantly inferior outcome based on OS. The risk for serious respiratory complications was also assessed by evaluating the incidence of intubation. Overall, 31% of these patients were intubated. The risk of intubation was higher in older patients and in those with a history of lower airway disease. These findings have implications for the care of patients with high-risk features.

Continued neurocognitive development and prevention of cardiopulmonary complications after successful BMT for I-cell disease: a long-term follow-up report.

I-cell disease or mucolipidosis type II, a rare inherited storage disorder of lysosomal enzyme localization, is characterized by dysostosis multiplex, progressive severe psychomotor retardation and death by 5-8 years from congestive heart failure and recurrent pulmonary infections. A 19-month old girl with I-cell disease received a bone marrow transplant (BMT) from an HLA-identical carrier brother. At the age of 7 years, 5 years after BMT, she has no history of respiratory infections. Her cardiac function remains normal with a shortening fraction of 47%, and she continues to gain neurodevelopmental milestones, albeit at a very slow rate. Musculoskeletal deformities have worsened despite BMT. This is the first report describing neurodevelopmental gains and prevention of cardiopulmonary complications in I-cell disease after BMT.

Open-lung biopsy guides therapy in children.

BACKGROUND: Open-lung biopsy is uncommon in children. Modern indications and outcomes are unknown. METHODS: This is a retrospective review of 64 open-lung biopsies (58 patients) from 1976 to 1996. Open-lung biopsies were used to grade vasculopathy in 8 patients (12% of 64) with pulmonary hypertension and in 10 patients (16% of 64) with combined pulmonary hypertension and lung parenchymal disease. Forty-six biopsies (72%) were obtained to diagnose parenchymal disease. Comparisons were made between biopsies performed from 1976 to 1989 and from 1990 to 1996. RESULTS: In the period 1990 to 1996, there were significantly more infants (p = 0.03), comorbid disease (p = 0.009), extracorporeal membrane oxygenation support (p < 10(-4)), and ventilator dependence (p = 0.05) and significantly less immunocompromise (p = 0.04). A definitive diagnosis was made in 43 of 64 cases (67%) and altered workup in 63 of 64 cases (98%). No correlation existed between Heath-Edwards grade of microangiopathy and catheterization data. Definitive diagnosis was most strongly associated with a nonimmunocompromised patient (p < 10(-4)). Although only one death (1.5%) was related to open-lung biopsy, the procedure was associated with a 30% inhospital mortality rate and an 11% morbidity rate. Of the 19 deaths, 1 patient died from the procedure, 13 died from their diseases, and 5 had support withdrawn. Death was associated with preoperative ventilator dependence (p < 10(-4)) and extracorporeal membrane oxygenation (p = 0.007). CONCLUSIONS: Pediatric open-lung biopsy commonly alters the diagnostic workup (98%). It is recommended for children who have been supported for 2 weeks by extracorporeal membrane oxygenation and for those with combined pulmonary hypertension and parenchymal lung disease. It is less useful in immunocompromised children.

Usefulness of surveillance endomyocardial biopsy after pediatric cardiac transplantation.

Endomyocardial biopsy remains the 'gold standard' for the diagnosis of acute rejection after cardiac transplantation, but few guidelines exist to determine the indications for its use in pediatric cardiac transplant recipients. To determine the usefulness of surveillance endomyocardial biopsy, 176 biopsies were reviewed from 12 patients, aged 0.5-16 (average 9.7) yr, maintained on cyclosporine, azathioprine and prednisone immunosuppression, and followed 2.8-45.5 (average 26.3) months after cardiac transplantation. Children old enough to cooperate (n = 6) underwent biopsy on nine occasions in the first 6 months after transplantation and quarterly thereafter. Children too young to cooperate (n = 6) underwent biopsy with general anesthesia on four occasions in the first 6 months after transplantation and every 6 months thereafter. Additional biopsies were performed as warranted by symptoms or noninvasive tests. A new episode of acute rejection was present in 13 biopsies (7%); continuing or resolving rejection in 19 others (11%). Remaining biopsies had no evidence of rejection (82 biopsies, 47%), had lymphocytic infiltrates insufficient for diagnosis (47 biopsies, 27%), were inadequate for diagnosis (14 biopsies, 8%), or were consistent with ischemia (1 biopsy, 0.5%). During the first 6 postoperative months, eight of 101 biopsies were positive for rejection, three occurring on routine surveillance biopsy. After 6 months, five of 75 biopsies showed a new episode of rejection, only one occurring on routine surveillance biopsy. Based on this data, it is concluded that: 1) episodes of rejection are relatively uncommon with triple drug immunosuppression; 2) surveillance biopsies in the first 6 months after cardiac transplantation may show unsuspected rejection; and 3) routine surveillance biopsies more than 6 months after cardiac transplantation are unlikely to show rejection in the absence of symptoms or other tests.

Antibody response of pediatric solid organ transplant recipients to immunization against influenza virus.

We studied the immunogenicity of the 1992-1993 trivalent split-virus influenza vaccine in pediatric solid organ transplant recipients (PSOTRs) and their healthy siblings. One month after immunization, 41 (82%) of 50 subjects achieved protective titers of antibodies to influenza A, and 30 (60%) to influenza B, rates similar to those in healthy siblings. Achievement and persistence of protective titers occurred significantly more often in children with preexisting antibody. We recommend annual immunization of PSOTRs, their household contacts, and health care workers; immunologically naive PSOTRs may benefit from immunization before transplantation.

Echocardiographic-guided internal jugular venous cannulation in children with heart disease.

OBJECTIVE: To determine if cannulation of the internal jugular vein (IJV) with echocardiographic guidance increases the success and decreases the complications of the procedure when performed in children with heart disease. DESIGN: Twenty-five consecutive pediatric patients with heart disease who underwent IJV cannulation with echocardiographic guidance between September 1986 and March 1992. SETTING: University hospital referral center serving a four-state area. PATIENTS AND OTHER PARTICIPANTS: Ambulatory patients were admitted for this procedure and then discharged at its completion; others included hospitalized patients. All patients were between the ages of 6 weeks and 21.8 years. All patients underwent IJV cannulation performed by a member of the Pediatric Cardiology Division at the University of Minnesota, Minneapolis. All patients either underwent heart transplant, and IJV access was obtained to perform an endomyocardial biopsy or had congenital heart disease, and the IJV was cannulated to perform a heart catheterization. Written consent was obtained either from the patient, if 18 years of age or older, or a parent or legal guardian. INTERVENTION: Cannulation of the IJV using echocardiographic guidance. MAIN OUTCOME MEASURES: Would IJV cannulation with echocardiographic guidance improve safety and diminish complications of the procedure when performed in pediatric patients with heart disease? We compared the results of our evaluation with published results in which echocardiographic guidance was not used. RESULTS: Cannulation of the IJV with echocardiographic guidance was performed successfully on 138 occasions in 25 pediatric patients. There were no lasting complications and no deaths using this method of venous access. CONCLUSIONS: As in the adult population, IJV cannulation with the assistance of echocardiography increases the success of the procedure and decreases the number of complications. Furthermore, echocardiographic guidance allows for repeated IJV cannulation in pediatric patients, regardless of age.

Resting Tl-201 scintigraphy in the evaluation of coronary artery disease in children with Hurler syndrome.

Severe coronary artery disease may occur early in the course of mucopolysaccharidosis. The authors present radiologic, scintigraphic, and pathologic findings in five patients with Hurler syndrome. Thallium-201 myocardial scintigraphy and selective coronary angiography obtained within 2 days to 6 months were correlated in five patients. Postmortem examination of the coronary arteries was obtained in one patient within hours of angiography. Interobserver agreement on grading of scintigraphic abnormalities was poor. Nonspecific findings on Tl-201 studies included septal abnormalities in all five patients. Scintigraphic findings were corroborated by angiography and postmortem results in only 3 of 5 patients. Our findings suggest that resting Tl-201 scintigraphy has limited value in the detection of coronary artery disease in patients with Hurler syndrome.

Cytomegalovirus colitis in a pediatric heart transplant patient.

Cytomegalovirus colitis is one of the sequelae of cytomegalovirus infection in transplant patients and can be associated with severe consequences. This case details the clinical, radiographic, and laboratory features of this infection in a child after heart transplantation where early recognition and treatment resulted in complete resolution of the disease.

Pediatric heart transplantation: results of 2- and 5-year follow-up.

Pediatric heart transplantation has become an accepted method of treatment for certain pediatric heart disease. From July 1986 to January 1993, we performed 25 orthotopic pediatric heart transplantations at the University of Minnesota Hospital and Clinics in 16 male patients and nine female patients. The average age was 8.5 years with a range from 7 days to 18 years. Three of the patients were younger than 1 year of age. The indications for transplantation included congenital heart disease in six patients and cardiomyopathy in 19 patients. Four of the patients with congenital heart disease had previously undergone a cardiac surgical procedure. Two patients with cardiomyopathy had mechanical assist devices in place at the time of transplantation. Donor age ranged from 2 months to 36 years. The donor organ ischemic time ranged from 60 minutes to 329 minutes, with an average of 191 minutes. Follow-up ranged from 6 to 84 months. Overall, there were seven deaths (28%) in the patients undergoing transplantation. Of the seven deaths, four (16%) were early (within 30 days) and three (14.3%) were late. The four early deaths were a result of donor organ failure, and the three late deaths a result of acute rejection. The 2-year survival for patients with a minimum 24-month evaluation was 79% (15 of 19). Of 12 patients available for 5-year assessment, 75% (9 of 12) were alive and doing well at the time this article was written. Pediatric heart transplantation can provide good intermediate and long-term survival for selected pediatric patients.

Outcome after referral for pediatric transplantation.

Although heart, heart-lung, or lung transplantation is performed in more than 200 children annually, the number of patients referred for such procedures is considerably greater, and little is known about the outcome of those referrals. To determine the outcome of pediatric transplant referrals we reviewed the follow-up of 31 patients evaluated at our institution for heart (24), heart-lung (three), or lung (four) transplantations between January 1991 and September 1992. Indications included hypoplastic left heart syndrome (seven patients), cardiomyopathy or myocarditis (seven patients), and postoperative congenital heart disease (10 patients) for heart transplantation; Eisenmenger's syndrome (three patients) for heart-lung transplantation; and primary pulmonary hypertension (two patients), broncho pulmonary dysplasia, and cystic fibrosis for lung transplantation. Only 14 of 31 referred patients were listed for transplantation; the remaining 17 patients either improved when medical therapy was maximized (nine patients), died within days of referral (three patients), refused (two patients), chose alternate surgery (one patient), were medically unacceptable (one patient), or are currently undecided (one patient). To date 7 of 14 patients listed have undergone successful heart transplantation; the remaining seven patients either improved and did not require transplantation (two patients), refused (one patient), died waiting (one patient), are currently awaiting a donor (one patient), or underwent Norwood procedure because of donor unavailability (two patients). Thus including patients who died before listing, only 14 of 31 referrals (45%) were deemed in need of a transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Children with mucopolysaccharidosis: perioperative care, morbidity, mortality, and new findings.

The perioperative care, morbidity, and mortality in 30 patients with mucopolysaccharidosis (MPS) are presented. They underwent a detailed preoperative assessment and were anesthetized 141 times. An intravenous induction technique was used in most patients. It was easier to see the vocal cords, during laryngoscopy, in children with Hurler syndrome (HS) when they were younger (23 v 41 months, P < or = .01) and smaller (12 v 15 kg, P < or = .05). Preoperative obstructive breathing was associated with a significantly higher incidence of postextubation obstruction (P < or = .05). A total of 28 children underwent bone marrow transplantation (BMT); this reversed upper airway obstruction and also reversed intracranial hypertension. In children with HS, the incidence of odontoid dysplasia was 94%; 38% demonstrated anterior C1-C2 subluxation. Head and neck manipulation was limited in children with cervical spine defects. None of the 30 patients experienced spinal cord morbidity. One child suffered an intraoperative stroke; another, pulmonary edema. Severe and extensive coronary obstruction was responsible for 2 intraoperative deaths. Coronary angiography underestimated coronary artery disease.

Results of a right ventricular outflow patch for pulmonary atresia with intact ventricular septum.

BACKGROUND: Although overall outcome has improved, pulmonary atresia with intact septum remains a difficult surgical and clinical problem. To determine whether an early right ventricular outflow patch will result in biventricular repair for this lesion, we reviewed the long-term follow-up (5.8 +/- 0.8 years) of 19 newborns who underwent repair between 1979 and 1990. METHODS AND RESULTS: An early right ventricular outflow patch was placed in 15 of 19 newborns; in the remaining four, this was preceded by an aortopulmonary shunt. Prostaglandin E1 infusion postoperatively eliminated the need for shunt in 14 of 15. Coronary sinusoids were ligated in three newborns. Based on right ventricular morphology, the newborns were divided into two groups: group 1 (tripartite, n = 9) and group 2 (bipartite and monopartite, n = 10). Before surgery, group 1 had significantly larger right ventricular volumes (23.6 +/- 3.7 versus 5.2 +/- 1.1 ml/m2, p < 0.002). Five-year survival was 79% for the entire series. Four infants, all group 2, died within 12 months of their initial surgery. Fourteen of 15 survivors (nine group 1 and five group 2) currently are acyanotic and New York Heart Association functional class I. A biventricular repair was achieved in 12 of 15, and three other children are awaiting evaluation. All 15 survivors had significant right ventricular and tricuspid annulus growth. CONCLUSIONS: Our data suggest that early placement of a right ventricular outflow patch in infants with pulmonary atresia and intact ventricular septum, regardless of right ventricular anatomy, results in an excellent chance for biventricular repair.

Hemodynamically significant suture line obstruction immediately after heart transplantation.

Mechanical complications after heart transplantation are uncommon. We describe a case of hemodynamically significant suture line obstruction that was recognized immediately after heart transplantation using transesophageal echocardiography. Transesophageal echocardiography has proved to be a powerful tool in recognizing mechanical complications in the early posttransplant period.