Publications by authors named "Cheryl Rockman-Greenberg"

33 Publications

Independent Registries Are Cost-Effective Tools to Provide Mandatory Postauthorization Surveillance for Orphan Medicinal Products.

Value Health 2021 Feb 19;24(2):268-273. Epub 2020 Nov 19.

Division of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Objectives: Orphan medicinal products (OMPs) often receive market authorization under conditions imposed by regulators for ongoing postauthorization surveillance (PAS) to answer questions that remain at the time of market entry. This surveillance may be provided through industry-funded registries (IFRs). Nevertheless, data in these registries may not be of sufficient quality to answer these questions and may not always be accessible for regulatory review. We propose that a mandatory independent registry is an efficient and cost-effective tool for PAS for OMPs.

Methods: Using data from the Canadian Fabry Disease Initiative, we reviewed costs per unique patient from sites participating in both the independent national registry and IFRs for Fabry disease and compared data completeness from the Canadian Fabry Disease Initiative to that in published documents from IFRs.

Results: The costs of data collection through the independent registry were 17% to 36% (depending on site) lower than costs to collect data in the IFRs, and completeness of data collected through the independent registry was higher than that through the IFRs. Data from the independent registry were reviewed annually to guide indications for publicly funded Fabry disease therapy. Even when enrollment ceased to be a requirement to receive therapy, 77% of patients continued to enroll in the registry, suggesting the structure was acceptable to patients.

Conclusions: Independent registries are cost-effective and efficient tools and should be mandated by regulatory agencies as the preferred tool for PAS for OMPs. Countries with publicly funded health systems should consider investment in registry infrastructure for OMPs.
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http://dx.doi.org/10.1016/j.jval.2020.10.006DOI Listing
February 2021

The Influence of Prenatal Vitamin D Supplementation on Dental Caries in Infants.

J Can Dent Assoc 2020 Nov;86:k13

Objectives: Early childhood caries (ECC) originates prenatally. This study investigated whether a relation exists between levels of vitamin D in the umbilical cord and caries in offspring.

Methods: A prospective cohort of expectant mothers was selected from a high-risk urban population receiving prenatal care in Winnipeg, Canada. Participants self-selected into 1 of 2 groups. The intervention group received 2 oral prenatal doses of 50 000 international units (IU) of vitamin D in addition to routine prenatal care. The control group received routine prenatal care. A prenatal questionnaire was completed at the first visit. Umbilical cord blood was analyzed for 25 hydroxyvitamin D (25(OH)D). At the time of their infant's first birthday, participants returned for a follow-up questionnaire and a dental examination of the infant. A p value ≤ 0.05 was significant.

Results: In all, 283 women were recruited (mean age 23.4 ± 5.6 years), 141 in the intervention group and 142 in the control group. The mean cord 25(OH)D level was 49.6 ± 24.3 nmol/L and did not differ between the groups. For the follow-up visit, 175 women returned. Overall, 26.3% of infants had ECC, and the mean decayed tooth (dt) score was 0.94 ± 2.16 teeth (range 0-16). There was no significant difference in prevalence of ECC between the intervention and control groups (p = 0.21). Poisson regression determined an inverse relation between 25(OH)D levels and dt scores (p = 0.001). Socioeconomic factor index (SEFI), age and enamel hypoplasia, but not vitamin D supplementation were significantly and independently associated with dt. Multiple logistic regression models also revealed that higher SEFI score, age and enamel hypoplasia were associated with ECC.

Conclusion: No relation was found between the 2 groups and prevalence of ECC. However, significance was seen in an inverse relation between 25(OH)D levels and the number of decayed primary teeth. Further studies with higher levels of vitamin D supplementation are needed.
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November 2020

Multigenerational case examples of hypophosphatasia: Challenges in genetic counseling and disease management.

Mol Genet Metab Rep 2020 Dec 21;25:100661. Epub 2020 Oct 21.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

Hypophosphatasia (HPP) is an inherited metabolic condition caused by pathogenic mutations in the gene. This leads to deficiency of tissue non-specific alkaline phosphatase (TNSALP), resulting in decreased mineralization of the bones and/or teeth and multi-systemic complications. Inheritance may be autosomal dominant or recessive, and the phenotypic spectrum, including age of onset, varies widely. We present four families demonstrating both modes of inheritance of HPP and phenotypic variability and discuss the resultant challenges in disease management, genetic counseling, and risk assessment. Failure to consider different modes of inheritance in a family with HPP may lead to an inaccurate risk assessment upon which medical and reproductive decisions may be made. We highlight the essential role of high-quality genetic counseling and meaningful biochemical and molecular testing strategies in the evaluation and management of families with HPP.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578550PMC
December 2020

Induced pluripotent stem cell line UOMi002-A from a patient with Leigh syndrome with compound heterozygous mutations in the NDUFV1 gene.

Stem Cell Res 2020 10 27;48:101964. Epub 2020 Aug 27.

Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Regenerative Medicine Program, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Canada. Electronic address:

Within the umbrella of mitochondrial disorders, Leigh's disease is characterised as a rarer form with more than 80 genetic and mitochondrial DNA aberration variants. Here we report establishment of an induced pluripotent stem cell (iPSC) line from a 2.5 years old deceased female child, harbouring mutations in the NDUFV1 gene. One of the variants reported here is novel. The establishment of iPSC line allows development of a stable disease model for the specific variations, as there are no other cell/animal disease models for the same.
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http://dx.doi.org/10.1016/j.scr.2020.101964DOI Listing
October 2020

Establishment of variant free-iPSC (UOMi003-A) line from patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes.

Stem Cell Res 2020 10 3;48:101935. Epub 2020 Aug 3.

Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Regenerative Medicine Program, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. Electronic address:

Heteroplasmy in patients affected with Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) offers a chance to harvest specific cells which might have a very low or no mutation load of the mitochondrial DNA. Here we demonstrate establishment of induced pluripotent stem cells (iPSC) cell lines (with normal mitochondrial DNA copies), from unaffected tissues of a male patient with MELAS harbouring m.3243A > G mutations. This platform allowed us to compare specific pathway differences between the cells of the affected tissues of the patients and their isogenic counterparts derived from iPSCs, which do not harbour the mutations.
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http://dx.doi.org/10.1016/j.scr.2020.101935DOI Listing
October 2020

Generation of human induced pluripotent stem cell (hiPSC) line UOMi001-A from a patient with Leigh-like syndrome harbouring compound heterozygous variants in ECHS1 gene.

Stem Cell Res 2020 10 3;48:101934. Epub 2020 Aug 3.

Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Regenerative Medicine Program, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Canada. Electronic address:

Leigh syndrome is a rare multi-organ system disorder that affects less than 1 in 5000 births. In cases where clinical heterogeneity makes some presentations difficult to categorize as Leigh syndrome, but are highly suggestive, those are referred to as Leigh-like syndrome. It may present with delay after birth and can be slightly milder than classic Leigh. We have created an iPSC line for the novel variants in the ECHS1 gene that was reported in our patient. This cellular model is being used to determine prospective treatment opportunities for the patient.
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http://dx.doi.org/10.1016/j.scr.2020.101934DOI Listing
October 2020

Burden of Illness in Adults With Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry.

J Bone Miner Res 2020 11 10;35(11):2171-2178. Epub 2020 Aug 10.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by deficient tissue non-specific alkaline phosphatase activity. This study aims to assess patient-reported pain, disability and health-related quality of life (HRQoL) in a real-world cohort of adults with HPP who were not receiving asfotase alfa during the analysis. Adults (≥18 years old) with HPP (confirmed by ALPL gene mutation and/or low serum alkaline phosphatase activity for age/sex) were identified from the Global HPP Registry (NCT02306720). Demographics, clinical characteristics, and data on patient-reported pain, disability, and HRQoL (assessed by Brief Pain Inventory Short Form [BPI-SF], Health Assessment Questionnaire Disability Index [HAQ-DI], and 36-Item Short-Form Health Survey version 2 [SF-36v2], respectively) were stratified by pediatric- and adult-onset HPP and summarized descriptively. Of the 304 adults included (median [min, max] age 48.6 [18.8, 79.8] years; 74% women), 45% had adult-onset HPP and 33% had pediatric-onset HPP (unknown age of onset, 22%). Of those with data, 38% had experienced ≥5 HPP manifestations and 62% had a history of ≥1 fracture/pseudofracture. Median (Q1, Q3) BPI-SF scores were 3.5 (1.5, 5.3) for pain severity and 3.3 (0.9, 6.2) for pain interference. Median (Q1, Q3) disability on the HAQ-DI was 0.3 (0.0, 0.7). Median (Q1, Q3) physical and mental component summary scores on the SF-36v2 were 42.4 (32.7, 49.9) and 45.3 (36.3, 54.8), respectively. Greater numbers of HPP manifestations experienced/body systems affected correlated significantly with poorer scores on the BPI-SF, HAQ-DI, and SF-36v2 (all p < 0.05). No significant differences between adults with pediatric- and adult-onset HPP were observed for patient-reported outcomes, except for disability and the BPI-SF question "pain at its worst," which were significantly higher among adults with pediatric- versus adult-onset HPP (p = 0.03 and 0.04, respectively). These data from the Global HPP Registry show that adults with HPP have a substantial burden of illness that is associated with reduced patient-reported HRQoL, regardless of age of disease onset. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4130DOI Listing
November 2020

Therapeutic challenges in two adolescent male patients with Fabry disease and high antibody titres.

Mol Genet Metab Rep 2020 Sep 24;24:100618. Epub 2020 Jun 24.

Department of Pediatrics and Child Health, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Enzyme replacement therapy (ERT) has been shown to stabilize certain aspects of Fabry disease (FD). However, in some patients on ERT, high antibody titres have been documented, with limited clinical improvement in systemic manifestations and often with significant adverse drug reactions. We present two related adolescent males with a 4.5 kb deletion, not amenable to chaperone therapy, leading to profound reduction in α-galactosidase A (α-gal A) enzyme activity. Over a 3-year period of ERT, increasing IgG antibody titres against α-gal A were noted. After starting ERT serial urine globotriaosylceramide (Gb) measurements showed an upward trend from 333 to 2260 μg/mmol creatinine for patient 1 and 1165 to 2260 μg/mmol creatinine for patient 2. Markedly increased levels of urine and plasma globotriaosylsphingosine (Lyso-Gb analogues were also found. The patients experienced recurrent infusion-associated reactions necessitating premedication and prolonged infusion times. Over the 3-year period of ERT, the patients experienced continued malaise, gastrointestinal symptoms and neuropathic pain. In addition, they had increasing anxiety related to their disease and apparent lack of response to ERT which led to a decision to ultimately stop ERT. No other approved treatment options are currently available for these patients. It is possible that the rapid development of the high antidrug neutralizing antibody (ADA) titres is related to the large deletion leading to virtually absent enzyme activity. It remains unclear if their symptomatology during the period of receiving ERT is related to lack of its efficacy, the rising ADA titres, or both. These two patients highlight the need for further research into the management of antidrug antibodies and additional therapeutic approaches for FD.

Synopsis: The development of very high antidrug antibody titres in response to ERT in two related adolescent males with FD highlight the need for other therapeutic options for patients in whom ERT or other currently approved therapies does not meet their treatment needs.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322173PMC
September 2020

Mass Spectrometry Evaluation of Biomarkers in the Vitreous Fluid in Gaucher Disease Type 3 with Disease Progression Despite Long-Term Treatment.

Diagnostics (Basel) 2020 Jan 26;10(2). Epub 2020 Jan 26.

Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3T2N2, Canada.

Intraocular lesions have been infrequently reported in patients with Gaucher disease type 3 (GD3). We previously reported siblings with GD3 who responded well to the combination of enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Here we report progressive bilateral vitreous and preretinal deposits with declining visual acuity requiring bilateral vitrectomies in one of these siblings. These ocular manifestations had progressed despite combined ERT and SRT with improvement in visual acuity after vitrectomies. Vitrectomy fluid analysis performed for the first time by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) identified a high concentration of glucosylceramide (GluCer) in the patient (262.842 nM) compared to a sample (0.428 nM from a patient without a lysosomal storage or known hereditary metabolic disorder). The GluCer detected in our patient was resolved into 12 different isoforms including two methylated ones. No evidence of galactosylceramide (GalCer) was detected. The development of these intraocular manifestations and their characterization by UPLC-MS/MS indicate a need for ongoing ophthalmologic evaluation of all GD patients and for new therapies that can cross the blood-retinal and blood-brain barriers for patients with GD and other neuropathic lysosomal storage disorders.
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http://dx.doi.org/10.3390/diagnostics10020069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168891PMC
January 2020

Correction to: Does specialist physician supply affect pediatric asthma health outcomes?

BMC Health Serv Res 2019 Nov 27;19(1):896. Epub 2019 Nov 27.

Department of Pediatrics, University Laval, Faculty of Medicine, Quebec City, Quebec, Canada.

In the original publication of this article [1], the institutional author's name needs to be revised from The Paediatric Chairs of Canada Mark Bernstein to The Paediatric Chairs of Canada.
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http://dx.doi.org/10.1186/s12913-019-4752-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880490PMC
November 2019

Health Care for Mitochondrial Disorders in Canada: A Survey of Physicians.

Can J Neurol Sci 2019 11;46(6):717-726

School of Epidemiology & Public Health, University of Ottawa, Ottawa, Ontario, Canada.

Background: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care.

Methods: We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities.

Results: We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend "mitochondrial cocktails" for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority.

Conclusions: While Canadian physicians' views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols.
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http://dx.doi.org/10.1017/cjn.2019.240DOI Listing
November 2019

Letter to the Editor: "Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: A Phase 2 Open-Label Study".

J Clin Endocrinol Metab 2019 08;104(8):3146-3147

University of Manitoba, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.

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http://dx.doi.org/10.1210/jc.2018-02413DOI Listing
August 2019

Health services use among children diagnosed with medium-chain acyl-CoA dehydrogenase deficiency through newborn screening: a cohort study in Ontario, Canada.

Orphanet J Rare Dis 2019 03 22;14(1):70. Epub 2019 Mar 22.

School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, 600 Peter Morand Cr, Ottawa, ON, K1G 5Z3, Canada.

Background: We describe early health services utilization for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency through newborn screening in Ontario, Canada, relative to a screen negative comparison cohort.

Methods: Eligible children were identified via newborn screening between April 1, 2006 and March 31, 2010. Age-stratified rates of physician encounters, emergency department (ED) visits and inpatient hospitalizations to March 31, 2012 were compared using incidence rate ratios (IRR) and incidence rate differences (IRD). We used negative binomial regression to adjust IRRs for sex, gestational age, birth weight, socioeconomic status and rural/urban residence.

Results: Throughout the first few years of life, children with MCAD deficiency (n = 40) experienced statistically significantly higher rates of physician encounters, ED visits, and hospital stays compared with the screen negative cohort. The highest rates of ED visits and hospitalizations in the MCAD deficiency cohort occurred from 6 months to 2 years of age (ED use: 2.1-2.5 visits per child per year; hospitalization: 0.5-0.6 visits per child per year), after which rates gradually declined.

Conclusions: This study confirms that young children with MCAD deficiency use health services more frequently than the general population throughout the first few years of life. Rates of service use in this population gradually diminish after 24 months of age.
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http://dx.doi.org/10.1186/s13023-019-1001-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431026PMC
March 2019

Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: A Phase 2 Open-Label Study.

J Clin Endocrinol Metab 2019 07;104(7):2735-2747

Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.

Context: Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited.

Objective: To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years.

Design: Phase 2 open-label study (July 2010 to September 2016).

Setting: Twenty-two sites; 12 countries.

Participants: Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months.

Intervention: Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously.

Main Outcome Measures: Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2).

Results: During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment.

Conclusions: Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.
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http://dx.doi.org/10.1210/jc.2018-02335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530655PMC
July 2019

Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry.

BMC Musculoskelet Disord 2019 Feb 14;20(1):80. Epub 2019 Feb 14.

Department of Pediatrics, Duke University Medical Center, 2301 Erwin Rd, Durham, NC, 27710, USA.

Background: Hypophosphatasia (HPP) is a rare, systemic disease caused by mutation(s) within the ALPL gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP has a heterogeneous presentation, which coupled with its rarity, often leads to missed/delayed diagnosis and an incomplete understanding of its natural history. To better understand the epidemiology and clinical course of HPP, including timing of diagnosis after first reported manifestation, we present baseline data for patients enrolled in the Global HPP Registry.

Methods: Data were analyzed from patients with an HPP diagnosis confirmed by low serum ALP activity and/or an ALPL pathogenic variant, regardless of prior or current treatment, according to age at enrollment (children: < 18 y; adult: ≥18 y). All analyses were descriptive.

Results: Of 269 patients from 11 countries enrolled January 2015-September 2017, 121 (45.0%) were children and 148 (55.0%) were adults. The majority of children and adults were female (61.2 and 73.0%, respectively) and white (57.7 and 90.0%, respectively). Children had a median (min, max) age at earliest reported HPP manifestation of 7.2 months (- 2.3 mo, 16.0 y), which was > 12 months before diagnosis at age 20.4 months (- 0.2 mo, 16.0 y). In adults, the earliest reported manifestation occurred at a median (min, max) age of 37.6 years (0.2 y, 75.2 y), which preceded age at diagnosis (47.5 years [0.2 y, 75.2 y]) by ~ 10 years. Premature loss of deciduous teeth (48.2%, age ≥ 6 mo), bone deformity (32.5%), and failure to thrive (26.7%) were most commonly reported in the HPP-related disease history of children. Pain (74.5%), orthopedic procedures and therapies (44.6%), and recurrent and poorly healing fractures (36.5%) were most commonly reported in the HPP-related disease history of adults.

Conclusions: The Global HPP Registry represents the largest observational study of patients with HPP, capturing real world data. This analysis shows that diagnostic delay is common, reflecting limited awareness of HPP, and that HPP is associated with systemic manifestations across all ages. Many patients diagnosed in adulthood had HPP manifestations in childhood, highlighting the importance of taking thorough medical histories to ensure timely diagnosis.

Trial Registration: Clinicaltrials.gov : NCT02306720 , December 2014; ENCePP.eu: EUPAS13526 , May 2016 (retrospectively registered).
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http://dx.doi.org/10.1186/s12891-019-2420-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376686PMC
February 2019

ALPL mutations in adults with rheumatologic disorders and low serum alkaline phosphatase activity.

J Bone Miner Metab 2019 Sep 4;37(5):893-899. Epub 2019 Feb 4.

Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada.

Tissue-nonspecific alkaline phosphatase (ALP), encoded by ALPL, is important for bone homeostasis and interacts with collagen type I. In the present study, we sequenced ALPL and a panel of collagen type I-related genes in 24 adults (age 22-80 years; 20 female) with persistently low serum ALP (< 40 U/L) and a range of rheumatologic symptoms. We found heterozygous pathogenic or likely pathogenic variants in ALPL in 14 (58%) of these individuals. In addition, 7 study participants had potentially damaging heterozygous variants of uncertain significance in genes related to collagen type I. Patients who were positive for ALPL variants had similar age and serum ALP levels to patients in whom no ALPL variants were detected, but had higher serum pyridoxal-5-phosphate concentrations (median 214 nmol/L vs. 64 nmol/L; p = 0.02; U test). In summary, heterozygous ALPL variants are frequent in individuals with rheumatologic symptoms and low ALP serum activity. It is possible that variants in genes that are involved in collagen type I production have a modifying effect on the clinical consequences of such ALPL variants.
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http://dx.doi.org/10.1007/s00774-019-00991-4DOI Listing
September 2019

Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia.

Bone 2019 04 18;121:149-162. Epub 2018 Dec 18.

Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA. Electronic address:

Hypophosphatasia (HPP) features low tissue-nonspecific alkaline phosphatase (TNSALP) isoenzyme activity resulting in extracellular accumulation of its substrates including pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B6, and inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Asfotase alfa is an enzyme replacement therapy developed to treat HPP. This multinational, randomized, open-label study (NCT01163149; EudraCT 2010-019850-42) evaluated the efficacy and safety of asfotase alfa in adults and adolescents 13-66 years of age with HPP. The study comprised a 6-month primary treatment period and a 4.5-year extension phase. In the primary treatment period, 19 patients were randomized to receive asfotase alfa 0.3 mg/kg/d subcutaneously (SC; n = 7), asfotase alfa 0.5 mg/kg/d SC (n = 6), or no treatment (control; n = 6) for 6 months. In the extension phase, patients received asfotase alfa (0.5 mg/kg/d for 6 mo-1 y, then 1 mg/kg/d 6 d/wk). During the primary treatment period, changes from Baseline to Month 6 in plasma PLP and PPi concentrations (coprimary efficacy measure) were greater in the combined asfotase alfa group compared with the control group, reaching statistical significance for PLP (P = 0.0285) but not for PPi (P = 0.0715). However, for the total cohort, the within subject changes in both PLP and PPi after 6 months and over 5 years of treatment with asfotase alfa were significant (P < 0.05). Secondary efficacy measures included transiliac crest histomorphometry, dual-energy X-ray absorptiometry (DXA), and the 6-Minute Walk Test (6MWT). A significant decrease from Baseline in mineralization lag time was observed in the combined asfotase alfa group at Year 1. There were no significant differences between treated and control patients in DXA mean bone mineral density results at 6 months; Z-scores and T-scores were within the expected range for age at Baseline and remained so over 5 years of treatment. On the 6MWT, median (min, max) distance walked increased from 355 (10, 620; n = 19) meters before treatment to 450 (280, 707; n = 13) meters at 5 years (P < 0.05). Results for the exploratory outcome measures suggested improvements in gross motor function, muscle strength, and patient-reported functional disability over 5 years of treatment. There were no deaths during this study. Asfotase alfa was generally well tolerated; the most common adverse events were mild to moderate injection site reactions. This study suggests that in adults and adolescents with pediatric-onset HPP, treatment with asfotase alfa is associated with normalization of circulating TNSALP substrate levels and improved functional abilities.
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http://dx.doi.org/10.1016/j.bone.2018.12.011DOI Listing
April 2019

Newborn Screening for IKBKB Deficiency in Manitoba, Using Genetic Mutation Analysis.

J Clin Immunol 2018 10 4;38(7):742-744. Epub 2018 Oct 4.

Department of Pediatrics & Child Health, University of Manitoba, 840 Sherbrook Street, Winnipeg, Manitoba, R3A 1S1, Canada.

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http://dx.doi.org/10.1007/s10875-018-0555-2DOI Listing
October 2018

Does specialist physician supply affect pediatric asthma health outcomes?

BMC Health Serv Res 2018 04 5;18(1):247. Epub 2018 Apr 5.

Department of Pediatrics, University Laval, Faculty of Medicine, Quebec City, Quebec, Canada.

Background: Pediatrician 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.

Methods: This 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.

Results: At 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).

Conclusions: Saskatchewan, 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.
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http://dx.doi.org/10.1186/s12913-018-3084-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887258PMC
April 2018

Caffeine is a risk factor for osteopenia of prematurity in preterm infants: a cohort study.

BMC Pediatr 2018 01 22;18(1). Epub 2018 Jan 22.

Community Health Sciences Department, Faculty of Health Sciences, University of Manitoba, MS361K, 820 Sherbrook St, Winnipeg, MB, R3A 1R9, Canada.

Background: Caffeine, the most commonly used medication in Neonatal Intensive Care Units, has calciuric and osteoclastogenic effects.

Methods: To examine the association between the cumulative dose and duration of therapy of caffeine and osteopenia of prematurity, a retrospective cohort study was conducted including premature infants less than 31 weeks and birth weight less than 1500 g. Osteopenia of prematurity was evaluated using chest X-rays on a biweekly basis over 12 weeks of hospitalization.

Results: The cohort included 109 infants. 51% had osteopenia of prematurity and 8% had spontaneous rib fractures. Using the generalized linear mixed model, caffeine dose and duration of caffeine therapy showed a strong association with osteopenia of prematurity. Steroids and vitamin D were also significantly correlated with osteopenia of prematurity while diuretic use did not show a statistically significant effect.

Conclusion: The cumulative dose and duration of therapy of caffeine, as well as steroid are associated with osteopenia of prematurity in this cohort. Future studies are needed to confirm these findings and determine the lowest dose of caffeine needed to treat effectively apnea of prematurity.
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http://dx.doi.org/10.1186/s12887-017-0978-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776771PMC
January 2018

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

Mol Genet Metab Rep 2018 Mar 7;14:22-26. Epub 2017 Nov 7.

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.

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 centre's 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.
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http://dx.doi.org/10.1016/j.ymgmr.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681336PMC
March 2018

Asfotase alfa therapy for children with hypophosphatasia.

JCI Insight 2016 06 16;1(9):e85971. Epub 2016 Jun 16.

The University of Manitoba, Faculty of Health Sciences, Department of Pediatrics and Child Health, Winnipeg, Manitoba, Canada.

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. 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. 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. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826). Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.
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http://dx.doi.org/10.1172/jci.insight.85971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033855PMC
June 2016

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

Orphanet J Rare Dis 2016 Feb 3;11:12. Epub 2016 Feb 3.

School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, ON, K1H 8 M5, Canada.

Background: There 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.

Methods: The 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.

Results: We 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.

Conclusions: The 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.
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http://dx.doi.org/10.1186/s13023-016-0391-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741015PMC
February 2016

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

JAMA Neurol 2016 Jan;73(1):111-6

Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York.

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.
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http://dx.doi.org/10.1001/jamaneurol.2015.3537DOI Listing
January 2016

Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia.

J Clin Endocrinol Metab 2016 Jan 3;101(1):334-42. Epub 2015 Nov 3.

Shriners Hospital for Children (M.P.W.) and Division of Bone and Mineral Diseases at Washington University School of Medicine (M.P.W.), St Louis, Missouri 63110; University of Manitoba and Children's Hospital Research Institute of Manitoba (C.R.-G.), Winnipeg, MB R3T 2N2 Canada; Graduate School of Medicine (K.O.), Osaka University, Osaka, 565-0871 Japan; Alexion Pharmaceuticals, Inc. (R.R., S.M., A.M., D.D.T.), Cheshire, Connecticut 06410; Department of Human Metabolism (N.B.), University of Sheffield, Sheffield, S10 2TN United Kingdom; Sheffield Children's Hospital (N.B.), Sheffield, S10 2TH United Kingdom; University Children's Hospital (C.H.), University of Würzburg, Würzburg, D-97080 Germany.

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.
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http://dx.doi.org/10.1210/jc.2015-3462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701846PMC
January 2016

A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature.

BMC Med Genet 2015 Apr 30;16:28. Epub 2015 Apr 30.

Department of Pediatrics and Child Health, University of Manitoba, FE229 Community Services Bldg, 685 William Ave, Winnipeg, MB, R3E 0Z2, Canada.

Background: Mutations in CCBE1 have been found to be responsible for a subset of families with autosomal recessive Hennekam syndrome. Hennekam syndrome is defined as the combination of generalized lymphatic dysplasia (ie. lymphedema and lymphangiectasia), variable intellectual disability and characteristic dysmorphic features. The patient we describe here has a lymphatic dysplasia without intellectual disability or dysmorphism caused by mutation in CCBE1, highlighting the phenotypic variability that can be seen with abnormalities in this gene.

Case Presentation: Our patient is a 5 week old child of Pakistani descent who presented to our center with generalized edema, ascites, and hypoalbuminemia. She was diagnosed with a protein losing enteropathy secondary to segmental primary intestinal lymphangiectasia. As the generalized edema resolved, it became clear that she had mild persistent lymphedema in her hands and feet. No other abnormalities were noted on examination and development was unremarkable at 27 months of age. Given the suspected genetic etiology and the consanguinity in the family, we used a combination of SNP genotyping and exome sequencing to identify the underlying cause of her disease. We identified several large stretches of homozygosity in the patient that allowed us to sort the variants found in the patient's exome to identify p.C98W in CCBE1 as the likely pathogenic variant.

Conclusions: CCBE1 mutation analysis should be considered in all patients with unexplained lymphatic dysplasia even without the other features of classic Hennekam syndrome.
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http://dx.doi.org/10.1186/s12881-015-0175-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630843PMC
April 2015

Metabolic Clinic Atlas: Organization of Care for Children with Inherited Metabolic Disease in Canada.

JIMD Rep 2015 26;21:15-22. Epub 2015 Feb 26.

Children's Hospital of Eastern Ontario, Ottawa, ON, Canada, K1H 8L1.

Introduction: Nearly all children in Canada with an inherited metabolic disease (IMD) are treated at one of the country's Hereditary Metabolic Disease Treatment Centres. We sought to understand the system of care for paediatric IMD patients in Canada in order to identify sources of variation and inform future research priorities.

Methods: Treatment centres were contacted by email and invited to complete a web-based survey. The questionnaire addressed, for each centre, the population size served and scope of practice, available human resources and clinic services and research capacity. Survey responses were analyzed descriptively.

Results: We received responses from 13 of the 14 treatment centres invited to participate. These centres represent at least 85% of the Canadian population, with over half of the centres located in southern Ontario and Quebec. All centres reported paediatric patients with IMDs as their main patient population. A variety of dedicated staff was identified; every centre reported having at least one physician and one dietician. The most common ancillary services available included telehealth (11/12 respondents) and biochemical genetic laboratory testing (10/12), with a high variability of access to on-site laboratory tests. A majority of centres indicated access to additional off-site services, but barriers to these were reported. All but one centre indicated previous experience with research.

Conclusions: The variation we identified in the organization of care highlights the need to investigate the association between practice differences and health outcomes for paediatric IMD patients to inform policies that establish equitable access to services that are beneficial.
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http://dx.doi.org/10.1007/8904_2014_347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470950PMC
June 2015

Tremor in Spinocerebellar Ataxia Type 12.

Mov Disord Clin Pract 2014 Apr 10;1(1):76-78. Epub 2014 Apr 10.

Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease Toronto Western Hospital University Health Network Toronto Ontario Canada.

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http://dx.doi.org/10.1002/mdc3.12015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6183183PMC
April 2014

Hypophosphatasia.

Pediatr Endocrinol Rev 2013 Jun;10 Suppl 2:380-8

Department of Pediatrics and Child Health, University of Manitoba, Child Health Programme, Winnipeg Regional Health Authority, Winnipeg, MB.

Hypophosphatasia (HPP) is a rare, inherited, potentially life-threatening metabolic disorder that arises from loss-of-function mutations in the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). As a result of these mutations (as many as 260 genetic mutations have been associated with HPP), patients have disordered bone mineralization leading to rickets, osteomalacia, fractures and other skeletal abnormalities as well as other systemic complications such as seizures, respiratory compromise, dental anomalies, nephrocalcinosis and/or weakness and chronic pain. HPP may appear across the age spectrum, from in utero, to infancy, childhood, adolescence and/or adulthood. More severe cases tend to be seen in utero and infancy, and in these instances, mortality may be as high as 50%. In surviving or older patients, disability and poor quality of life may be seen. Based on clinical presentation, HPP can be mistakenly diagnosed as other skeletal diseases, but a low alkaline phosphatase is an important, distinguishing sign of this condition. While patients with HPP may benefit from supportive measures, at the present time, there is no approved specific therapy for HPP.
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June 2013