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

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

Generalized arterial calcification (AC) of infancy (GACI) is the autosomal recessive disorder caused by deactivating mutations within the gene for ectonucleotide pyrophosphatase phosphodiesterase-1 (ENPP1). ENPP1 on osteoblasts, chondrocytes, and vascular smooth muscle cells hydrolyzes nucleotide triphosphates to nucleotide monophosphates and inorganic pyrophosphate (PPi). PPi potently inhibits mineralization. In GACI, low extracellular levels of PPi promote hydroxyapatite crystal deposition in elastic fibers of arteries. Untreated, ~ 85% of patients die by age six months from cardiac ischemia and congestive heart failure. Etidronate (EHDP), the bisphosphonate (BP), inhibits bone resorption but can mimic PPi blocking mineralization. During EHDP treatment for GACI, AC can resolve and does not recur with cessation of treatment. Skeletal disease is not a feature of GACI, although rickets can develop from EHDP therapy. We report a 7-year-old boy with GACI referred for profound, acquired, skeletal disease. AC resolved during infancy after five months of EHDP therapy, but joint calcifications, seen in GACI, had progressed. He was receiving 200 mg/day of EHDP and had odynodysphagia, opioid-controlled body pain, facial asymmetry, plagiocephaly, proptosis, joint calcifications and contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal although serum osteocalcin was low and he had markedly elevated serum levels of creatine kinase (brain isoform) and TRAP-5b consistent with osteopetrosis (OPT). Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, widened physes with metaphyseal osteosclerosis, “tongues” of radiolucency, along with cupping and fraying, and long-bone bowing. Radiographic features of BP-induced OPT included femoral Erlenmeyer flask deformity and osteosclerosis (lumbar spine DXA z-score +5.7). ENPP1 mutation analysis revealed a missense mutation (c.653A\u3eT, p.Asp218Val) that reduced catalytic efficiency to 17% of normal. After stopping EHDP, he improved quickly with remarkable healing of his rachitic skeleton and decreased joint calcifications. Our patient with GACI had profound, but rapidly reversible, inhibition of skeletal mineralization along with paradoxical calcifications near joints from high-dose EHDP therapy. Although EHDP is life-saving in GACI, surveillance for toxicity is important. doi: 10.1002/jbmr.175

Mitogenomics reveals low variation within a trigeneric complex of black corals from the North Pacific Ocean

A 2013 study revealed that three morphologically distinct antipatharian genera (Dendrobathypathes, Lillipathes, Parantipathes) from the eastern North Pacific (ENP) are genetically indistinguishable using three mitochondrial and four nuclear markers (7,203 bp). To investigate whether this lack of molecular variability extends beyond three mitochondrial genes, we sequenced the complete mitogenome of a single representative within each genus. Dendrobathypathes was the only specimen from the 2013 study containing high molecular weight (HMW) DNA. In terms of geographic proximity to the ENP, the closest Lillipathes and Parantipathes yielding HMW DNA were from the central North Pacific near Hawai'i. Based on cox3-IGR-cox1, Lillipathes and Parantipathes each contained two variable sites and thus were not equivalent substitutes for specimens from the ENP. Nonetheless, variation was extremely low when comparing the mitogenomes, with 32 variable positions across 17,687 bp. Pairwise comparisons revealed 18 (Dendrobathypathes and Parantipathes) and 23 (Lillipathes and Parantipathes;Lillipathes and Dendrobathypathes) variable sites. An ML-based phylogenetic reconstruction using 13 protein-coding genes and two rRNAs revealed that the three North Pacific genera grouped in a clade with Atlantic Dendrobathypathes, while Atlantic Parantipathes spp. formed a sister clade. Previous research hypothesized that hybridization with subsequent introgression was responsible for the lack of variability among genera. Due to uniparental inheritance and lack of recombination, mtDNA cannot identify hybrids; however, finding Pacific Parantipathes grouping with Dendrobathypathes and Lillipathes rather than Atlantic Parantipathes suggests that the trigeneric complex has a unique evolutionary history. If high-resolution nuclear markers support hybridization, it will be important to elucidate the molecular mechanism that maintains three distinct morphological forms occurring in sympatry

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers