Cobalamin C Deficiency Shows a Rapidly Progressing Maculopathy With Severe Photoreceptor and Ganglion Cell Loss.

PURPOSE: To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease. METHODS: Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients. RESULTS: Patients carried homozygous or compound heterozygote mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Late-onset patients had a normal exam. All early-onset patients showed a maculopathy; older subjects had a retina-wide degeneration (n = 4; >7 years of age). In general, retinal changes were first observed before 1 year of age and progressed within months to a well-established maculopathy. Pseudocolobomas were documented in three patients. Measurable visual acuities ranged from 20/200 to 20/540. Nystagmus was present in 8/11 patients; 5/6 patients had normal ERGs; 1/6 had reduced rod-mediated responses. Spectral-domain OCT showed macular thinning, with severe ganglion cell layer (GCL) and outer nuclear layer (ONL) loss. Inner retinal thickening was observed in areas of total GCL/ONL loss. A normal lamination pattern in the peripapillary nasal retina was often seen despite severe central and/or retina-wide disease. CONCLUSIONS: Patients with early-onset cblC and MMACHC mutations showed an early-onset, unusually fast-progressing maculopathy with severe central ONL and GCL loss. An abnormally thickened inner retina supports a remodeling response to both photoreceptor and ganglion cell degeneration and/or an interference with normal development in early-onset cblC.

Atypical Williams syndrome in an infant with complete atrioventricular canal defect.

Williams-Beuren Syndrome (WBS) is a well-described microdeletion syndrome characterized by specific dysmorphic facial features, peripheral pulmonic stenosis, supravalvular aortic stenosis, hypercalcemia, feeding difficulties, gastroesophageal reflux, short stature, and specific intellectual disabilities (such as visual spatial problems). WBS is caused by 7q11.23 deletions that contain multiple genes known to contribute to the above phenotype. We report a neonate with a complete atrioventricular canal (CAVC) defect, an atypical cardiac lesion for WBS, and few typical phenotypic features of WBS, diagnosed at 20 days of life.

Ventricular Hypertrophy on Electrocardiogram Correlates with Obstructive Lesion Severity in Williams Syndrome.

OBJECTIVE: Williams syndrome (WS) is a congenital, multisystem developmental disorder affecting 1 in 8000 live births. Cardiovascular abnormalities are present in 80% of WS patients. The present study sought to characterize fully the electrocardiographic findings in WS and correlate findings with anatomic pathology. DESIGN: A retrospective review was performed of the electrocardiograms (ECGs) of patients with WS evaluated at the Children's Hospital of Philadelphia from January 1, 1980 through December 31, 2007. When available, the five most recent ECGs in each patient were evaluated. Ventricular hypertrophy was diagnosed based on previously reported voltage criteria in normal populations. RESULTS: There were 187 patients with 499 ECGs for evaluation. Median age at study ECG was 8.0 years (range 0.1-58.9); median number of ECGs per patient was 2.7 (range 1-5). Heart rate, PR interval, and QRS interval were normal for age. Right ventricular hypertrophy (RVH) was present on 44% (219/499) of ECGs. Left ventricular hypertrophy (LVH) was present on 30% (150/499) of ECGs. Fifty-seven percent (106/187) of subjects had ≥1 ECG demonstrating RVH, and 39% (72/187) had ≥1 ECG demonstrating LVH. The severity of right- and left-sided obstructive lesions correlated with the ECG presence of RVH (P < .0001, odds ratio 21.8) and LVH (P < .001, odds ratio 14.5-61), respectively. CONCLUSIONS: Electrocardiographic intervals in patients with WS follow expected trends seen in normal patients. Voltage criteria for RVH and LVH are commonly met on ECGs of patients with WS. The presence of ventricular hypertrophy on ECG in WS correlates with lesion severity.

Relation of ventricular ectopic complexes to QTc interval on ambulatory electrocardiograms in Williams syndrome.

Williams syndrome (WS) is a congenital, developmental disorder affecting 1 in 8,000 live births. The corrected QT (QTc) interval is prolonged in 13% of patients with WS. No data exist characterizing the ambulatory electrocardiographic findings in WS. A retrospective review of all patients with WS evaluated at our institution from January 1, 1980 to December 31, 2007 was performed. Patients with ≥1 ambulatory electrocardiogram (AECG) with sinus rhythm and measurable intervals were included. QTc measurements were made at the minimum and maximum heart rate. Logistic regression analysis was used to evaluate the correlation of ventricular ectopic complexes with QTc measurements. A statistical probability of p <0.05 was considered significant. Of 270 patients identified, 32 had AECGs available for review. Complete data were available for 56 AECGs from 26 patients (15 female; 58%). Their mean age was 15.6 ± 7.2 years at the initial AECG and 20.6 ± 8.6 years for all AECGs. The QTc interval increased with increasing heart rate. Ventricular premature complexes occurred in 40 (73%) of 56 AECGs and 21 (81%) of 26 patients. Ventricular tachycardia occurred in 5 (9%) of 56 AECGs and 4 (15%) of 26 patients. The mean length of ventricular tachycardia was 3.6 ± 0.5 beats at a rate of 171 ± 40 beats/min. The QTc interval at the minimum heart rate correlated directly with age (p <0.001), total ventricular premature complexes (p = 0.007), ventricular couplets (p = 0.002), and ventricular tachycardia (p = 0.011). The QTc interval at the maximum heart rate correlated directly with age (p <0.001), total ventricular premature complexes (p = 0.016), and ventricular couplets (p = 0.006). In conclusion, the QTc interval correlated with ventricular ectopic complexes in patients with WS. The type of ventricular ectopic complexes suggested an alternate etiology of the QTc prolongation seen in WS from that seen in congenital long QT syndrome.

Abnormalities of cardiac repolarization in Williams syndrome.

Williams syndrome (WS) affects 1 in 8,000 live births and has a high risk of sudden death. No previous studies have evaluated corrected QT (QTc) prolongation in WS. Retrospective review of all patients with WS evaluated at our institution from January 1, 1980 to December 31, 2007 was performed. WS was diagnosed by a medical geneticist and/or by fluorescence in situ hybridization. Patients with ≥1 electrocardiogram (ECG) with sinus rhythm and measurable intervals were included. Normal control ECGs were identified from a large clinical database. Corrected JT (JTc) interval was calculated when QRS and QTc intervals were prolonged. QTc interval ≥460 ms and JTc interval >340 ms were defined as prolonged. Prevalence comparisons were made using Fisher's exact test. Statistical probability of <0.05 was considered significant. Of 270 patients identified, 188 had ECGs for review. Complete data were present in 499 of 517 ECGs (patients' mean age 10.3 ± 9.9 years); 1,522 normal ECGs of age-similar patients composed the control group. QTc prolongation prevalences were 2.0% in controls and 13.6% in WS (p <0.0001); in those, JTc prolongation prevalences were 1.8% in controls and 11.7% in WS (p <0.0001). Four patients died during follow-up; 2 had QTc prolongation and 1 died during noncardiac surgery. Another patient with QTc prolongation sustained cardiac arrest during a procedure. In conclusion, cardiac repolarization is prolonged in WS. Presence of prolonged cardiac repolarization may contribute to the high incidence of periprocedural mortality in these patients. All patients with WS should be screened for cardiac repolarization abnormalities, especially before surgery.

Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin.

Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues.

Immune abnormalities are a frequent manifestation of Kabuki syndrome.

Kabuki syndrome (KS) is associated with multiple organ system involvement. Characteristic features include long palpebral fissures with everted lower lids, prominent ears, skeletal abnormalities, mental retardation, and short stature. An increased incidence of infection has been reported in KS, and a few patients have been noted to have immune defects. However, the frequency and severity of the immune deficiency has not been clearly defined. Immunologic evaluation of 19 consecutive individuals with KS was performed at The Children's Hospital of Philadelphia. Decreased IgA levels were noted in 15/19 individuals (79%), 2 of whom had undetectable levels. Eight patients (42%) also had low total IgG levels. Specific IgG subclass abnormalities were found in 6 of 13 patients evaluated. IgM levels were less frequently decreased. One patient failed to generate anti-tetanus antibodies despite immunization. This study suggests that hypogammaglobulinemia is a frequent finding in children with KS. The pattern of antibody abnormalities seen in children with KS resembles common variable immune deficiency (CVID). Due to this increased susceptibility to infection, children with KS should have immunologic evaluations at the time of diagnosis in order to reduce preventable morbidity and mortality.

Newborn screening by tandem mass spectrometry for medium-chain Acyl-CoA dehydrogenase deficiency: a cost-effectiveness analysis.

OBJECTIVE: To determine whether newborn screening by tandem mass spectrometry (MS/MS) for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is cost-effective versus not screening and to define the contributions of disease, test, and population parameters on the decision. METHODS: A decision-analytic Markov model was designed to perform cost-effectiveness and cost-utility analyses measuring the discounted, incremental cost per life-year saved and per quality-adjusted life-year saved of newborn screening for MCADD compared with not screening. A hypothetical cohort of neonates made transitions among a set of health states that reflected clinical status, morbidity, and cost. Outcomes were estimated for time horizons of 20 and 70 years. Probabilities and costs were derived from a retrospective chart review of a 32-patient cohort treated over the past 30 years at the Children's Hospital of Philadelphia, clinical experience with MCADD patient management, patient-family interviews, cost surveys, state sources, and published studies. In addition to older patients who came to medical attention by symptomatic presentation, our patient group included 6 individuals whose MCADD had been diagnosed by supplemental newborn screening. Estimates of the expected net changes in costs and life expectancy for MCADD screening were used to compute the incremental cost-effectiveness ratios. Sensitivity analyses were performed on key input variables, and 95% confidence intervals (CIs) were computed through second-order Monte Carlo simulations. RESULTS: In our base-case analysis over the first 20 years of life, the cost of newborn screening for MCADD was approximately 11,000 dollars(2001 US dollars; 95% CI: <0-33,800 dollars) per life-year saved, or 5600 dollars (95% CI: <0-17,100 dollars) per quality-adjusted life-year saved compared with not screening. Over a 70-year horizon, the respective ratios were approximately 300 dollars (95% CI: <0-13,000 dollars) and 100 dollars (95% CI: <0-6900 dollars). The results were robust when tested over plausible ranges for diagnostic test sensitivity and specificity, MCADD prevalence, asymptomatic rate, and screening cost. CONCLUSIONS: Simulation modeling indicates that newborn screening for MCADD reduces morbidity and mortality at an incremental cost below the range for accepted health care interventions. At the 70-year horizon, the model predicts that almost all of the additional costs of screening would be offset by avoided sequelae.

MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation.

Maple syrup urine disease (MSUD) is an inborn error of amino acid metabolism, which affects the brain tissue resulting in impairment or death if untreated. Imaging studies have shown reversible brain edema during acute metabolic decompensation. The purpose of this paper is to describe the diffusion-weighted imaging (DWI) and spectroscopy findings during metabolic decompensation and to assess the value of these findings in the prediction of patient outcome. Six patients with the diagnosis of MSUD underwent conventional MR imaging with DWI during acute presentation with metabolic decompensation. Spectroscopy with long TE was performed in four of the six patients. Follow-up examinations were performed after clinical and metabolic recovery. DWI demonstrated marked restriction of proton diffusion compatible with cytotoxic or intramyelinic sheath edema in the brainstem, basal ganglia, thalami, cerebellar and periventricular white matter and the cerebral cortex. This was accompanied by the presence of an abnormal branched-chain amino acids (BCAA) and branched-chain alpha-keto acids (BCKA) peak at 0.9 ppm as well as elevated lactate on proton spectroscopy in all four patients. The changes in all six patients were reversed with treatment without evidence of volume loss or persistent tissue damage. The presence of cytotoxic or intramyelinic edema as evidenced by restricted water diffusion on DWI, with the presence of lactate on spectroscopy, could imply imminent cell death. However, in the context of metabolic decompensation in MSUD, it appears that changes in cell osmolarity and metabolism can reverse completely after metabolic correction.