Cheryl Rockman-Greenberg

Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia

CONTEXT Hypophosphatasia (HPP) is an inborn error of metabolism that, in its most severe perinatal and infantile forms, results in 50-100% mortality, typically from respiratory complications. OBJECTIVES Our objective was to better understand the effect of treatment with asfotase alfa, a first-in-class enzyme replacement therapy, on mortality in neonates and infants with severe HPP. DESIGN/SETTING Data from patients with the perinatal and infantile forms of HPP in two ongoing, multicenter, multinational, open-label, phase 2 interventional studies of asfotase alfa treatment were compared with data from similar patients from a retrospective natural history study. PATIENTS Thirty-seven treated patients (median treatment duration, 2.7 years) and 48 historical controls of similar chronological age and HPP characteristics. INTERVENTIONS Treated patients received asfotase alfa as sc injections either 1 mg/kg six times per week or 2 mg/kg thrice weekly. MAIN OUTCOME MEASURES Survival, skeletal health quantified radiographically on treatment, and ventilatory status were the main outcome measures for this study. RESULTS Asfotase alfa was associated with improved survival in treated patients vs historical controls: 95% vs 42% at age 1 year and 84% vs 27% at age 5 years, respectively (P < .0001, Kaplan-Meier log-rank test). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) were weaned from ventilatory support. This better respiratory outcome accompanied radiographic improvements in skeletal mineralization and health. CONCLUSIONS Asfotase alfa mineralizes the HPP skeleton, including the ribs, and improves respiratory function and survival in life-threatening perinatal and infantile HPP.

Asfotase alfa therapy for children with hypophosphatasia

Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6-12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti-asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826). Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.

Identifying Non–Duchenne Muscular Dystrophy–Positive and False Negative Results in Prior Duchenne Muscular Dystrophy Newborn Screening Programs: A Review

IMPORTANCE Duchenne muscular dystrophy (DMD) is a candidate for the recommended universal screening panel based on evidence that early corticosteroid treatment improves outcomes and on new genetic therapies that require early diagnosis for effectiveness. Elevated creatine kinase levels in the neonatal period are the initial screening marker in DMD newborn screening programs but is found in inherited muscle disorders other than DMD. Data are needed to inform protocols for future screening and follow-up testing and care in these patients. OBJECTIVES To review non-DMD muscle disorders identified by prior DMD screening programs and to investigate whether these programs failed to identify patients later diagnosed as having DMD (false-negative findings). EVIDENCE REVIEW Since 1975, 10 DMD newborn screening programs have provided opportunities to study screening protocols, outcomes, and parental responses. These programs used elevated creatine kinase levels in dried blood spots for the initial screening, with the diagnosis of DMD based on findings of clinical follow-up, muscle biopsy, or direct mutational testing of the DMD gene. Literature regarding these prior programs was reviewed in PubMed, and the programs were discussed directly with the directors when possible to identify diagnoses of non-DMD disorders and false negative results from 1975 to July 12, 2015. Data were collected from screening programs, which were active between 1975 and December 2011. Data were analyzed from March 26, 2015, to August 24, 2015. FINDINGS The 10 screening programs screened more than 1.8 million newborns between 1975 and 2011, and 344 were diagnosed with DMD. Of those screened, the majority were boys. Across all programs, 80 patients had positive results for non-DMD disorders, including Becker muscular dystrophy and forms of limb-girdle and congenital muscular dystrophies, and 21 patients had false-negative findings for DMD. CONCLUSIONS AND RELEVANCE Screening for DMD will result in identification of other muscle diseases. Future screening protocols should include infants of both sexes and include follow-up testing algorithms to evaluate patients who do not have DMD gene mutations but may have another muscle disorder associated with elevated neonatal creatine kinase levels. These programs will need to be aware that false-negative results are a possibility.

Cloacal exstrophy and related abdominal wall defects in Manitoba: Incidence and demographic factors

A retrospective descriptive study of omphalocele and exstrophic defects of the abdominal wall was carried out in Manitoba to determine the prevalence of these defects, changes in birth incidence with time and their etiologic heterogeneity. The incidence of isolated omphalocele was similar to that reported in other series but the overall incidence of other types of abdominal wall defects was high. Cloacal exstrophy, bladder exstrophy and amnion disruption defects contributed significantly to the number of cases ascertained and emphasized the heterogeneity of abdominal wall defects. There were fluctuations in birth incidence with time with cloacal exstrophy especially apparently being more common in 1980‐81. No specific demographic or environmental factors were documented in the cases seen in 1980‐81 which could explain the high incidence in these years. Cloacal exstrophy is, however, now appreciated to be much more common than first realized. Studies directed at elucidation of the causes of apparent changes in incidence of malformations such as omphalocele or exstrophic defects will have to take into account both the fluctuations in background incidence of these defects and the considerable diversity in their etiology.

Retrospective TREC testing of newborns with Severe Combined Immunodeficiency and other primary immunodeficiency diseases

In Manitoba, Canada, the overall incidence of Severe Combined Immunodeficiency (SCID) is three-fold higher than the national average, with SCID overrepresented in two population groups: Mennonites and First Nations of Northern Cree ancestries. T-cell receptor excision circle (TREC) assay is being used increasingly for neonatal screening for SCID in North America. However, the majority of SCID patients in Manitoba are T-cell-positive. Therefore it is likely that the TREC assay will not identify these infants. The goal of this study was to blindly and retrospectively perform TREC analysis in confirmed SCID patients using archived Guthrie cards. Thirteen SCID patients were tested: 5 T-negative SCID (3 with adenosine deaminase deficiency, 1 with CD3δ deficiency, and 1 unclassified) and 8 T-positive SCID (5 with zeta chain-associated protein kinase (ZAP70) deficiency and 3 with inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKKβ) deficiency). As a non-SCID patient group, 5 Primary Immunodeficiency Disease (PID) patients were studied: 1 T-negative PID (cartilage-hair hypoplasia) and 4 T-positive PID (2 common immune deficiency (CID), 1 Wiskott–Aldrich syndrome, and 1 X-linked lymphoproliferative disease). Both patient groups required hematopoietic stem cell transplantation. In addition, randomly-selected de-identified controls (n = 982) were tested. Results: all T-negative SCID and PID had zero TRECs. Low-TRECs were identified in 2 ZAP70 siblings, 1 CID patient as well as 5 preterm, 1 twin, and 4 de-identified controls. Conclusions: TREC method will identify T-negative SCID and T-negative PID. To identify other SCID babies, newborn screening in Manitoba must include supplemental targeted screening for ethnic-specific mutations.

The health system impact of false positive newborn screening results for medium-chain acyl-CoA dehydrogenase deficiency: a cohort study

BackgroundThere is no consensus in the literature regarding the impact of false positive newborn screening results on early health care utilization patterns. We evaluated the impact of false positive newborn screening results for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in a cohort of Ontario infants.MethodsThe cohort included all children who received newborn screening in Ontario between April 1, 2006 and March 31, 2010. Newborn screening and diagnostic confirmation results were linked to province-wide health care administrative datasets covering physician visits, emergency department visits, and inpatient hospitalizations, to determine health service utilization from April 1, 2006 through March 31, 2012. Incidence rate ratios (IRRs) were used to compare those with false positive results for MCADD to those with negative newborn screening results, stratified by age at service use.ResultsWe identified 43 infants with a false positive newborn screening result for MCADD during the study period. These infants experienced significantly higher rates of physician visits (IRR: 1.42) and hospitalizations (IRR: 2.32) in the first year of life relative to a screen negative cohort in adjusted analyses. Differences in health services use were not observed after the first year of life.ConclusionsThe higher use of some health services among false positive infants during the first year of life may be explained by a psychosocial impact of false positive results on parental perceptions of infant health, and/or by differences in underlying health status. Understanding the impact of false positive newborn screening results can help to inform newborn screening programs in designing support and education for families. This is particularly important as additional disorders are added to expanded screening panels, yielding important clinical benefits for affected children but also a higher frequency of false positive findings.

Successful therapy for protein-losing enteropathy caused by chronic neuronopathic Gaucher disease

Gaucher disease (OMIM #230800) is caused by β-glucosidase deficiency and primarily involves the mononuclear phagocyte system (also called Reticuloendothelial System or Macrophage System). The disease is classified into three main phenotypes based on the presence or absence of neurological manifestations: non-neuronopathic (type 1), acute neuronopathic (type 2) and chronic neuronopathic (type 3). Typical manifestations include hepatosplenomegaly, skeletal deformities, hematological abnormalities, interstitial lung fibrosis and neurodegeneration in neuronopathic cases. Mesenteric lymphadenopathy with resultant protein losing enteropathy (PLE) has only been rarely described. Mesenteric lymphadenopathy may lead to intestinal lymphatic obstruction and secondary lymphangiectasia resulting in chronic diarrhea, abdominal pain and weight loss. Fecal protein loss with secondary hypoalbuminemia can be significant. We report a male with Chronic Neuronopathic Gaucher disease (GD) (homozygous for c.1448T > C (NM_000157.3) GBA mutation) who at 16 years of age developed intractable abdominal pain, diarrhea and weight loss. This was caused by PLE secondary to intestinal lymphangiectasia caused by calcified mesenteric lymphadenopathy despite prior long term enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). His older similarly affected sister who had been receiving treatment with ERT and/or SRT remains stable on these treatments with no evidence of mesenteric lymphadenopathy. Medical management with total parenteral nutrition, daily medium chain triglyceride-oil (MCT) supplementation, low dose oral budesonide, continued oral SRT and an increased dose of parenteral ERT has stabilized his condition with resolution of the gastrointestinal symptoms and appropriate weight gain.

Ornithine transcarbamylase deficiency presenting as recurrent abdominal pain in childhood.

Recurrent abdominal pain remains one of the most common symptoms in pediatrics. We present the case of a 3-year-old girl who had recurrent episodes of abdominal pain requiring more than 13 visits to the emergency department. A diagnosis of ornithine transcarbamylase deficiency was eventually made. Urea cycle disorders often present beyond the neonatal period with frequent vomiting episodes; however, recurrent abdominal pain as a presenting symptom is unusual. Unnecessary invasive investigations of recurrent abdominal pain in childhood can be avoided by considering inborn errors of metabolism earlier in the differential diagnosis.

Enzyme replacement therapy in perinatal hypophosphatasia: Case report of a negative outcome and lessons for clinical practice

Enzyme replacement therapy (ERT) is a newly approved disease-modifying treatment for hypophosphatasia (HPP), a rare metabolic bone disorder. With an orphan drug and ultra-rare disease, sharing information about responders and non-responders is particularly important, as any one centres familiarity with its use will be limited. Nearly all published data in infants and very young children with life-threatening HPP are from three small clinical trials that have reported generally positive outcomes. We describe in detail a patient with perinatal HPP for whom treatment with ERT was not successful. Lessons learned from this case can inform clinical decision-making and provide topics for the research agenda. We also discuss practical and ethical challenges related to treatment of an ultra-rare disease with an expensive new medication in a publicly funded healthcare system.

Does specialist physician supply affect pediatric asthma health outcomes

BackgroundPediatrician and pediatric subspecialist density varies substantially among the various Canadian provinces, as well as among various states in the US. It is unknown whether this variability impacts health outcomes. To study this knowledge gap, we evaluated pediatric asthma admission rates within the 2 Canadian provinces of Manitoba and Saskatchewan, which have similarly sized pediatric populations and substantially different physician densities.MethodsThis was a retrospective cross-sectional cohort study. Health regions defined by the provincial governments, have, in turn, been classified into “peer groups” by Statistics Canada, on the basis of common socio-economic characteristics and socio-demographic determinants of health. To study the relationship between the distribution of the pediatric workforce and health outcomes in Canadian children, asthma admission rates within comparable peer group regions in both provinces were examined by combining multiple national and provincial health databases. We generated physician density maps for general practitioners, and general pediatricians practicing in Manitoba and Saskatchewan in 2011.ResultsAt the provincial level, Manitoba had 48.6 pediatricians/100,000 child population, compared to 23.5/100,000 in Saskatchewan. There were 3.1 pediatric asthma specialists/100,000 child population in Manitoba and 1.4/100,000 in Saskatchewan. Among peer-group A, the differences were even more striking. A significantly higher number of patients were admitted in Saskatchewan (590.3/100,000 children) compared to Manitoba (309.3/100,000, p < 0.0001).ConclusionsSaskatchewan, which has a lower pediatrician and pediatric asthma specialist supply, had a higher asthma admission rate than Manitoba. Our data suggest that there is an inverse relationship between asthma admissions and pediatrician and asthma specialist supply.