Yasuda M, Erwin AL, Liu LU, et al. Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver. Mol Med. 2015;21:487-495. PMID: 26062020, PMCID: PMC4607616. Porphyrias Consortium (PC)
Acute Intermittent Porphyria (AIP) patients with intractable and frequent neurovisceral manifestations may not be responsive to the currently approved treatment of intravenous hemin infusions. Orthotopic liver transplantation (OLT) has been reported in Europe as curative of AIP, however is only considered in very severe cases. Investigators in the Porphyrias Consortium conducted the first OLT for AIP in the US and those results, as well as the first biochemical and molecular studies of the explanted AIP liver, were reported in this publication.
Othman RA, Myrie SB, Mymin D, et al. Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia. J Pediatr. Jan 2015;166(1):125-131. PMID: 25444527, PMCID: PMC4274192. Sterol and Isoprenoid Research Consortium (STAIR)
Sitosterolemia is a rare genetic disorder of plant sterol metabolism with clinical features of tendon xanthomas, thrombocytopenia and bleeding. STAIR investigators demonstrated that ezetimibe therapy has a beneficial effect to lower plant sterol accumulation and increase platelet count in sitosterolemia patients.
Finger EC, MacKinley J, Blair M, et al. Oxytocin for frontotemporal dementia: a randomized dose-finding study of safety and tolerability. Neurology. Jan 13 2015;84(2):174-181. PMID: 25503617, PMCID: PMC4336088. Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL)
This paper describes a placebo controlled clinical trial that shows that oxytocin may be a promising therapy for behavioral variant frontotemporal dementia.
Davis SD, Ferkol TW, Rosenfeld M, et al. Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med. Feb 1 2015;191(3):316-324. PMID: 25493340, PMCID: PMC4351577. Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
This multicenter, prospective study systematically evaluates clinical features of primary ciliary dyskinesia in childhood and demonstrates that those with biallelic mutations in CCDC39 and CCDC40 or associated ultrastructural defects (inner dynein arm/central apparatus/microtubular defects) have worse lung disease and poorer growth compared with those with outer dynein arm defects (defined by ultrastructural and mutations in associated genes).
DeFazio G, Hallett M, Jinnah HA, et al. Development and validation of a clinical scale for rating the severity of blepharospasm. Mov Disord. Apr 2015;30(4):525-530. PMID: 25847472. Dystonia Coalition (DC)
We developed and validated a novel scale for rating the severity of blepharospasm. This scale can be used to assess the severity of blepharospasm, which is particularly useful in natural history and pathophysiologic studies as well as in clinical trials.
Carmona FD, Mackie SL, Martin JE, et al. A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility. Am J Hum Genet. Apr 2 2015;96(4):565-580. PMID: 25817017, PMCID: PMC4385191. Vasculitis Clinical Research Consortium (VCRC)
This study discovered new and important genetic associations with giant cell arteritis and will lead to additional research on disease pathogenesis and etiology. This project utilized the VCRC Biospecimen and Clinical Data Repositories linked to our Longitudinal Studies to conduct a large study of the genetics of a rare disease (giant cell arteritis) and was a collaboration with European research partners.
Kim H, Nelson J, Krings T, et al. Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Stroke. May 2015;46(5):1362-1364. PMID: 25858236, PMCID: PMC4415515. Brain Vascular Malformation Consortium (BVMC)
Brain AVMs are present in 10% of people with Hereditary Hemorrhagic Telangiectasia, and can lead to intracranial hemorrhage. Risks of hemorrhage must be weighed against risks of preventative treatment and with this objective, we report the first predictor identified for intracranial hemorrhage in these patients.
Kwan A, Hu D, Song M, et al. Successful newborn screening for SCID in the Navajo Nation. Clin Immunol. May 2015;158(1):29-34. PMID: 25762520, PMCID: PMC4420660. Primary Immune Deficiency Treatment Consortium (PIDTC)
This was the result of a PIDTC funded pilot project and is the first report of newborn screening for Severe Combined Immunodeficiency (SCID) on the Navajo Nation. The Navajo and Apache Indians have a very high incidence of SCID due to a mutation in the DCLRE1C (Artemis) gene. It has been estimated based on family histories that the incidence is ~1:2000 live births and the newborn screening study documented the incidence at 1:1800. The availability of NBS for SCID among the Navajo is critical for long term survival of these patients and based on the results of this pilot project the Navajo Nation implemented it throughout the reservation.
Pacheco-Colon I, Washington SD, Sprouse C, Helman G, Gropman AL, VanMeter JW. Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency. PLoS ONE. Jun2015;10(6):e0129595. PMID: 26067829, PMCID: PMC4466251. Urea Cycle Disorders Consortium (UCDC)
Using 3T fMRI this study found reduced functional connectivity in patients with partial ornithine transcarbamylase deficiency (OTCD) compared to controls, most likely due to hyperammonemia-related white matter damage. Because several of the affected areas are involved in executive functioning, it is postulated that this reduced connectivity is an underlying cause of the deficits OTCD patients display in this cognitive domain.
Tarquinio DC, Hou W, Neul JL, et al. Age of diagnosis in Rett syndrome: patterns of recognition among diagnosticians and risk factors for late diagnosis. Pediatr Neurol. Jun 2015;52(6):585-591 e582. PMID: 25801175, PMCID: PMC4442062. Rett Syndrome, MECP2 Duplication, & Rett-Related Disorders Consortium (RTT)
Although earlier diagnosis of Rett syndrome has improved, further improvements are needed to ensure that specific treatments may commence at a young age. Age at diagnosis has improved among subspecialists, but not among primary care physicians where increased emphasis is necessary.
Cykowski MD, Coon EA, Powell SZ, et al. Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain. Aug 2015;138(Pt 8):2293-2309. PMID: 25981961. Autonomic Disorders Consortium (ADC)
This is a key publication establishing that neuronal inclusions including Lewy bodies are typical of MSA and that the distribution had significant selectivity. The main findings were that widespread distribution was typical of MSA. They occur in typical disease areas (striatum, nigra) but also in areas that were previously less recognized. There was also some correlation of density of inclusions and clinical features.
Fridman V, Bundy B, Reilly MM, et al. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis. J Neurol Neurosurg Psychiatry. Aug 2015;86(8):873-878. PMID: 25430934, PMCID: PMC4516002. Inherited Neuropathies Consortium (INC)
This paper is the largest collection of patients with inherited neuropathy ever assembled, all of whom have undergone deep phenotyping. This shows what can be accomplished with an international group of investigators working together and will form the baseline for longitudinal evaluations that will define the natural history of many of the distinct forms of inherited neuropathy.
Hopp K, Cogal AG, Bergstralh EJ, et al. Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. J Am Soc Nephrol. Oct 2015;26(10):2559-2570. PMID: 25644115, PMCID: PMC4587693. Rare Kidney Stone Consortium (RKSC)
Primary Hyperoxaluria (PH) is autosomal recessive disease characterized by accumulation of renal oxalate and kidney failure. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). In this paper, genotype to phenotype comparisons demonstrated differences in severity among the three PH types. Using publicly available whole exome data to calculate prevalence, PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, suggesting that PH3 (and PH2) cases are likely underdiagnosed and/or are incompletely penetrant. Together these analyses highlight a role for molecular analyses in PH for diagnostics and prognostics, and that wider analysis of the idiopathic stone forming population may be of value.
Bellur S, Jain M, Cuthbertson D, et al. Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. Genet Med. Oct 1 2015. PMID: 26426884. Brittle Bone Disorders Consortium (BBD)
Osteogenesis imperfecta (OI) is a connective tissue disorder that predisposes to recurrent fractures and bone deformities. Severe forms of OI are characterized by in utero fractures and the mode of delivery that would be safest for the fetus in such situations is not known. In a study involving 540 patients with OI, researchers of the Brittle Bone Disorders Consortium found that cesarean delivery was not associated with a decrease in the at-birth fracture rates in OI. This study provided evidence-based answers to a question relevant for the clinical care of individuals living with OI.
Berrier KL, Kazi ZB, Prater SN, et al. CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy. Genet Med. Nov 2015;17(11):912-918. PMID: 25741864, PMCID: PMC4561024. Lysosomal Disease Network (LDN)
Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross-reactive immunologic material (CRIM)–negative (CN) patients have immune responses with significant clinical decline despite continued ERT. This paper shows that immunological responses are a significant risk in CN IPD.
Saito A, Nikolaidis NM, Amlal H, et al. Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment. Sci Transl Med. Nov 11 2015;7(313):313ra181. PMID: 26560359. Rare Lung Diseases Consortium (RLDC)
Pulmonary alveolar microlithiasis (PAM) is a rare lung disease that is associated with alveolar accumulation of calcium phosphate crystals, which cause slowly progressive pulmonary fibrosis and respiratory failure. Mutations in the gene encoding the Npt2b sodium-dependent phosphate cotransporter have been reported in patients with PAM. Saito et al have developed an authentic mimic of the human disease in mice by deletion of Npt2b from the pulmonary epithelium, and have used the model to develop biomarkers and novel treatment strategies. Serum samples collected from patients in the Rare Lung Disease Consortium Clinical Network were used to validate biomarkers suggested by the PAM mouse.
Sahin M, Sur M. Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science. Nov 20 2015;350(6263). PMID: 26472761, PMCID: PMC4739545. Developmental Synaptopathies Consortium (DSC)
This paper reviews the state of research in neurodevelopmental disorders at genetic, cellular, organismal levels and proposes some recommendations for future studies, with emphasis on biomarker identification.
Ju W, Nair V, Smith S, et al. Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Sci Transl Med. Dec 2 2015;7(316):316ra193. PMID: 26631632. Nephrotic Syndrome Study Network (NEPTUNE)
This paper describes research from NEPTUNE investigators, in collaboration with investigators from three other consortia world-wide that identifies a molecular biomarker in the urine, called urinary epidermal growth factor that is linked to Chronic Kidney Disease, a condition in which damaged kidneys cannot filter blood as well as healthy kidneys. The identification of the urinary biomarker may meet an urgent clinical need for an accessible, non-invasive way to identify patients at risk for progression of kidney disease. The findings further were featured in NIH Director's blog: http://directorsblog.nih.gov/2015/12/15/pursuing-precision-medicine-for-chronic-kidney-disease/.
Kliewer KL, Venter C, Cassin AM, et al. Should wheat, barley, rye, and/or gluten be avoided in a 6-food elimination diet? J Allergy Clin. Immunol. Dec 24 2015. PMID: 26725190. Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)
Herein, CEGIR provides recommendations for the dietary treatment of eosinophilic esophagitis, focused on the risks of cross-reactivity and cross-contamination among wheat, barley, and rye proteins (including gluten). The article offer practical guidelines for the elimination diets used to treat eosinophilic esophagitis.
Benatar M, Boylan K, Jeromin A, et al. ALS biomarkers for therapy development: State of the field and future directions. Muscle Nerve. Dec 29 2015. PMID: 26574709, PMCID: PMC4718795. Clinical Research in ALS and Related Disorders for Therapeutic Development Consortium (CReATe)
Biomarkers have become the focus of intense research in the field of ALS, with the hope that they might aid therapy development efforts. This authoritative review provides a summary of the state of the field and defines a strategy for validating candidate biomarkers that might aid future clinical trials.
