Publications by authors named "Carlos R Ferreira"

89 Publications

Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies.

J Bone Miner Res 2021 Aug 5. Epub 2021 Aug 5.

Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.4418DOI Listing
August 2021

Clinical and biochemical footprints of inherited metabolic diseases. VI. Metabolic dermatoses.

Mol Genet Metab 2021 Jul 21. Epub 2021 Jul 21.

Division of Metabolism, University Children's Hospital, Zürich, Switzerland. Electronic address:

Cutaneous signs and symptoms may facilitate the diagnosis or can help in identifying complications or side effects of overtreatment of inherited metabolic diseases. The principal manifestations can be grouped into vascular lesions, ichthyosis, papular and nodular skin lesions, abnormal pigmentation, photosensitivity, skin laxity, hair shaft involvement, and nail abnormalities. We have summarized associations of these cutaneous signs and symptoms in 252 inherited metabolic diseases. This represents the sixth of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2021.07.005DOI Listing
July 2021

The low excretor phenotype of glutaric acidemia type I is a source of false negative newborn screening results and challenging diagnoses.

JIMD Rep 2021 Jul 5;60(1):67-74. Epub 2021 Apr 5.

Biochemical Genetics Laboratory, Mayo Clinic Rochester Minnesota USA.

Background: Glutaric acidemia type I (GA1) is an organic acidemia that is often unrecognized in the newborn period until patients suffer an acute encephalopathic crisis, which can be mistaken for nonaccidental trauma. Presymptomatic identification of GA1 patients is possible by newborn screening (NBS). However, the biochemical "low-excretor" (LE) phenotype with nearly normal levels of disease metabolites can be overlooked, which may result in untreated disease and irreversible neurological sequelae. The LE phenotype is also a potential source of false negative (FN) NBS results that merits further investigation.

Methods: Samples from six LE GA1 patients were analyzed by biochemical and molecular methods and newborn screen outcomes were retrospectively investigated.

Results: Five LE GA1 patients were identified that had normal NBS results and three of these presented clinically with GA1 symptoms. One additional symptomatic patient was identified who did not undergo screening. Semiquantitative urine organic acid analysis was consistent with a GA1 diagnosis in two (33%) of the six patients, while plasma glutarylcarnitine was elevated in four (67%) of the six and urine glutarylcarnitine was elevated in four (80%) of five patients. Five variants were identified in these patients; three of which have not been previously linked to the biochemical LE phenotype.

Conclusions: The data presented here raise awareness of potential FN NBS results for LE GA1 patients. The LE phenotype is not protective against adverse clinical outcomes, and the possibility of FN NBS results calls for high vigilance amongst clinicians, even in the setting of a normal NBS result.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmd2.12217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260482PMC
July 2021

Response to Stern et al.

Genet Med 2021 Oct 16;23(10):2008. Epub 2021 Jun 16.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01229-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487937PMC
October 2021

Adult diagnosis of congenital serine biosynthesis defect: A treatable cause of progressive neuropathy.

Am J Med Genet A 2021 07 4;185(7):2102-2107. Epub 2021 Jun 4.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

A woman with ichthyosis, contractures, and progressive neuropathy represents the first case of phosphoserine aminotransferase deficiency diagnosed and treated in an adult. She has novel compound heterozygous mutations in the gene PSAT1. Treatment with high dose oral L-serine completely resolved the ichthyosis. Consideration of this diagnosis is important because early treatment with L-serine repletion can halt progression of neurodegeneration and potentially improve neurological disabilities. As exome sequencing becomes more widely implemented in the diagnostic evaluation of progressive neurodegenerative phenotypes, adult neurologists and geneticists will increasingly encounter later onset manifestations of inborn errors of metabolism classically considered in infancy and early childhood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330494PMC
July 2021

Lysosomal storage disorders as an etiology of nonimmune hydrops fetalis: A systematic review.

Clin Genet 2021 Nov 16;100(5):493-503. Epub 2021 Jul 16.

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSD) in case series of nonimmune hydrops fetalis (NIHF). PubMed, Ovid, and clinicaltrials.gov were reviewed for case series evaluating the workup of NIHF diagnosed in utero or in the neonatal period in human subjects from 1979 to August 2020. Retrospective case series with at least five cases of fetal and/or neonatal NIHF with its workup mentioned were identified. Idiopathic NIHF was defined as NIHF without an apparent cause after initial standard-of-care workup. In total, 22 case series with 2678 total cases of NIHF were identified. The overall incidence of LSD was 6.6% (177/2663) in NIHF cases that were tested for any LSD, and 8.2% (177/2151) in idiopathic NIHF cases. The most common LSD identified in cases of NIHF were mucopolysaccharidosis type VII, galactosialidosis, infantile sialic acid storage disease, Gaucher disease, GM1 gangliosidosis, and sialidosis. More than 40% of the most common LSD causes of NIHF have a potential postnatal treatment. LSD testing for NIHF allows for early diagnosis, better counseling and appropriate management, planning for possible early treatment, and counseling for recurrence risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.14005DOI Listing
November 2021

Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases.

Genet Med 2021 09 26;23(9):1604-1615. Epub 2021 May 26.

Department of Dermatology, University Hospital Münster, Münster, Germany.

Purpose: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature.

Methods: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival.

Results: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old.

Conclusion: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01200-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463480PMC
September 2021

Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice.

J Bone Miner Res 2021 08 10;36(8):1548-1565. Epub 2021 May 10.

Center for Genetics of Host Defense, UT Southwestern Medical Center, Dallas, TX, USA.

Proper embryonic and postnatal skeletal development require coordination of myriad complex molecular mechanisms. Disruption of these processes, through genetic mutation, contributes to variation in skeletal development. We developed a high-throughput N-ethyl-N-nitrosourea (ENU)-induced saturation mutagenesis skeletal screening approach in mice to identify genes required for proper skeletal development. Here, we report initial results from live-animal X-ray and dual-energy X-ray absorptiometry (DXA) imaging of 27,607 G3 mice from 806 pedigrees, testing the effects of 32,198 coding/splicing mutations in 13,020 genes. A total of 39.7% of all autosomal genes were severely damaged or destroyed by mutations tested twice or more in the homozygous state. Results from our study demonstrate the feasibility of in vivo mutagenesis to identify mouse models of skeletal disease. Furthermore, our study demonstrates how ENU mutagenesis provides opportunities to create and characterize putative hypomorphic mutations in developmentally essential genes. Finally, we present a viable mouse model and case report of recessive skeletal disease caused by mutations in FAM20B. Results from this study, including engineered mouse models, are made publicly available via the online Mutagenetix database. © 2021 American Society for Bone and Mineral Research (ASBMR).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.4323DOI Listing
August 2021

Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app.

Orphanet J Rare Dis 2021 04 12;16(1):170. Epub 2021 Apr 12.

Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands.

Background: The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disability (collectively 'treatable IDs'). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identification of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation.

Methods: Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classification of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is available. Data on clinical symptoms, diagnostic testing, treatment strategies, effects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features.

Results: Our review identified 116 treatable IDs (139 genes), of which 44 newly identified, belonging to 17 ICIMD categories. The most frequent therapeutic interventions were nutritional, pharmacological and vitamin and trace element supplementation. Evidence level varied from 1 to 3 (trials, cohort studies, case-control studies) for 19% and 4-5 (case-report, expert opinion) for 81% of treatments. Reported effects included improvement of clinical deterioration in 62%, neurological manifestations in 47% and development in 37%.

Conclusion: The number of treatable IDs identified by our literature review increased by more than one-third in eight years. Although there has been much attention to gene-based and enzyme replacement therapy, the majority of effective treatments are nutritional, which are relatively affordable, widely available and (often) surprisingly effective. We present a diagnostic algorithm (adjustable to local resources and expertise) and the updated App to facilitate a swift and accurate workup, prioritizing treatable IDs. Our digital tool is freely available as Native and Web App (www.treatable-id.org) with several novel features. Our Treatable ID endeavor contributes to the Treatabolome and International Rare Diseases Research Consortium goals, enabling clinicians to deliver rapid evidence-based interventions to our rare disease patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-021-01727-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042729PMC
April 2021

Clinical and biochemical footprints of inherited metabolic disease. V. Cerebral palsy phenotypes.

Mol Genet Metab 2021 Mar 13. Epub 2021 Mar 13.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Cerebral palsy is the most common physical disability of childhood describing a heterogeneous group of neurodevelopmental disorders that cause activity limitation, but often are accompanied by disturbances of sensation, perception, cognition, communication and behavior, or by epilepsy. Inborn errors of metabolism have been reported in the literature as presenting with features of cerebral palsy. We reviewed and updated the list of metabolic disorders known to be associated with symptoms suggestive of cerebral palsy and found more than 150 relevant IEMs. This represents the fifth of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnosis according to system involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2021.03.008DOI Listing
March 2021

Inherited disorders of complex lipid metabolism: A clinical review.

J Inherit Metab Dis 2021 07 2;44(4):809-825. Epub 2021 Mar 2.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Over 80 human diseases have been attributed to defects in complex lipid metabolism. A majority of them have been reported recently in the setting of rapid advances in genomic technology and their increased use in clinical settings. Lipids are ubiquitous in human biology and play roles in many cellular and intercellular processes. While inborn errors in lipid metabolism can affect every organ system with many examples of genetic heterogeneity and pleiotropy, the clinical manifestations of many of these disorders can be explained based on the disruption of the metabolic pathway involved. In this review, we will discuss the physiological function of major pathways in complex lipid metabolism, including nonlysosomal sphingolipid metabolism, acylceramide metabolism, de novo phospholipid synthesis, phospholipid remodeling, phosphatidylinositol metabolism, mitochondrial cardiolipin synthesis and remodeling, and ether lipid metabolism as well as common clinical phenotypes associated with each.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jimd.12369DOI Listing
July 2021

(RIG-I)-related disease is associated with tissue-specific interferon pathway activation.

J Med Genet 2021 Jan 25. Epub 2021 Jan 25.

Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Background: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2.

Methods: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed.

Results: We have identified a novel variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin.

Conclusions: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2020-107447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310534PMC
January 2021

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice.

J Bone Miner Res 2021 05 18;36(5):942-955. Epub 2021 Feb 18.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1 mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1 mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1 mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1 mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.4254DOI Listing
May 2021

Clinical and biochemical footprints of inherited metabolic diseases. IV. Metabolic cardiovascular disease.

Mol Genet Metab 2021 02 25;132(2):112-118. Epub 2020 Dec 25.

Division of Metabolism, University Children's Hospital, Zürich, Switzerland. Electronic address:

Inherited metabolic diseases account for 15-20% of all cases of pediatric cardiomyopathy, with a high mortality of 15-47%. Metabolic diseases can also commonly be associated with other types of cardiovascular involvement such as arrhythmias, valvulopathy or vasculopathy. We reviewed and updated the list of known metabolic etiologies associated with cardiovascular involvement, and found 246 relevant inborn errors of metabolism. This represents the fourth of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2020.12.290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867625PMC
February 2021

An international classification of inherited metabolic disorders (ICIMD).

J Inherit Metab Dis 2021 01;44(1):164-177

Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.

Several initiatives at establishing a classification of inherited metabolic disorders have been published previously, some focusing on pathomechanisms, others on clinical manifestations, while yet another attempted a simplified approach of a comprehensive nosology. Some of these classifications suffered from shortcomings, such as lack of a mechanism for continuous update in light of a rapidly evolving field, or lack of widespread input from the metabolic community at large. Our classification-the International Classification of Inherited Metabolic Disorders, or International Classification of Inborn Metabolic Disorders (ICIMD)-includes 1450 disorders, and differs from prior approaches in that it benefited from input by a large number of experts in the field, and was endorsed by major metabolic societies around the globe. Several criteria such as pathway involvement and pathomechanisms were considered. The main purpose of the hierarchical, group-based approach of the ICIMD is an improved understanding of the interconnections between many individual conditions that may share functional, clinical, and diagnostic features. The ICIMD aims to include any primary genetic condition in which alteration of a biochemical pathway is intrinsic to specific biochemical, clinical, and/or pathophysiological features. As new disorders are discovered, we will seek the opinion of experts in the advisory board prior to inclusion in the appropriate group of the ICIMD, thus guaranteeing the continuing relevance of this classification via regular curation and expert advice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jimd.12348DOI Listing
January 2021

Skeletal dysplasias in Latin America.

Am J Med Genet C Semin Med Genet 2020 12 21;184(4):986-995. Epub 2020 Nov 21.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive character. In this article, we review the state of clinical and research SD resources available in Latin America, including three specific countries (Brazil, Argentina, and Chile), that have established multidisciplinary clinics for the care of these patients. From the epidemiological point of view, the SD prevalence of 3.2 per 10,000 births from nine South American countries included in the ECLAMC network represents the most accurate estimate not just in Latin America, but worldwide. In Brazil, there are currently five groups focused on SD. The data from one of these groups including the website www.ocd.med.br, created to assist in the diagnosis of SD, are highlighted showing that telemedicine for this purpose represents a good strategy for the region. The experience of more than 30 years of the SD multidisciplinary clinic in an Argentinian Hospital is presented, evidencing a solid experience mainly in the follow-up of the most frequent SD, especially those belonging the FGFR3 group and OI. In Chile, a group with 20 years of experience presents its work with geneticists and pediatricians, focusing on diagnostic purposes and clinical management. Altogether, although SD health-care and research activities in Latin America are in their early stages, the experience in these three countries seems promising and stimulating for the region as a whole.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31861DOI Listing
December 2020

DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature.

Mol Genet Genomic Med 2020 12 7;8(12):e1544. Epub 2020 Nov 7.

Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.

Background: DYRK1A-Related Intellectual Disability Syndrome is a rare autosomal dominant condition characterized by intellectual disability, speech and language delays, microcephaly, facial dysmorphism, and feeding difficulties. Affected individuals represent simplex cases that result from de novo heterozygous pathogenic variants in DYRK1A (OMIM 614104), or chromosomal structural rearrangements involving the DYRK1A locus. Due to the rarity of DYRK1A-Related Intellectual Disability Syndrome, the spectrum of symptoms associated with this disease has not been completely defined.

Methods And Results: We present two unrelated cases of DYRK1A-Related Intellectual Disability Syndrome resulting from variants in DYRK1A. Both probands presented to the National Institutes of Health (NIH) with multiple dysmorphic facial features, primary microcephaly, absent or minimal speech, feeding difficulties, and cognitive impairment; features that have been previously reported in individuals with DYRK1A. During NIH evaluation, additional features of enlarged cerebral subarachnoid spaces, retinal vascular tortuosity, and bilateral anomalous large optic discs with increased cup-to-disc ratio were identified in the first proband and multiple ophthalmologic abnormalities and sensorineural hearing loss were identified in the second proband.

Conclusion: We recommend that the workup of future of patients include a comprehensive eye exam. Early establishment of physical, occupational, and speech therapy may help in the management of ataxia, hypertonia, and speech impairments common in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767569PMC
December 2020

Lysinuric protein intolerance: Pearls to detect this otherwise easily missed diagnosis.

Transl Sci Rare Dis 2020 Aug 3;5(1-2):81-86. Epub 2020 Aug 3.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Lysinuric protein intolerance (LPI) is a rare autosomal recessive disorder characterized by deficient membrane transport of cationic amino acids. It is caused by pathogenic variants in SLC7A7, resulting in impairment of intestinal import and renal proximal tubule loss of the affected amino acids. LPI typically presents with gastrointestinal symptoms, such as vomiting, diarrhea, and failure to thrive.

Case Report: A 4-year-old African-American boy presented with multiple respiratory tract infections, weight loss in the setting of chronic diarrhea and worsening abdominal distention, and multiple episodes of rectal prolapse. Development was unaffected. Laboratory examination demonstrated mild anemia, hypokalemia and hypoalbuminemia, transaminitis, and normal ammonia. Initial urine amino acid analysis did not show major elevations of lysine and ornithine, often lower than expected in the setting of malnutrition. Upon initiation of total parenteral nutrition (TPN), his urine amino acids showed a characteristic profile of dibasic aminoaciduria.

Conclusions: Failure to thrive, chronic diarrhea, and hepatomegaly should raise suspicion for LPI. Urine amino acids can be normal in this condition in the setting of malnutrition, a common complication of the disease. Additionally, it has been previously shown that the plasma arginine and ornithine concentration is higher in LPI subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/TRD-190035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590902PMC
August 2020

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).

Genet Med 2021 02 2;23(2):396-407. Epub 2020 Oct 2.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion.

Methods: We performed deep phenotyping of 20 GACI survivors.

Results: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies.

Conclusion: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-00983-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867608PMC
February 2021

Fourteen-year follow-up of a child with acroscyphodysplasia with emphasis on the need for multidisciplinary management: a case report.

BMC Med Genet 2020 09 29;21(1):189. Epub 2020 Sep 29.

The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

Background: Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes.

Case Presentation: The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability.

Discussion And Conclusions: Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12881-020-01127-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526353PMC
September 2020

Mitochondrial energetic impairment in a patient with late-onset glutaric acidemia Type 2.

Am J Med Genet A 2020 10 17;182(10):2426-2431. Epub 2020 Aug 17.

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Glutaric acidemia type 2 (GA2), also called multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism resulting in excretion of multiple organic acids and glycine conjugates as well as elevation of various plasma acylcarnitine species (C4-C18). It is caused by mutations in the ETFA, ETFB, or ETFDH genes which are involved in the transfer of electrons from 11 flavin-containing dehydrogenases to Coenzyme Q (CoQ ) of the mitochondrial electron transport chain (ETC). We report a patient who was originally reported as the first case with primary myopathic CoQ deficiency when he presented at 11.5 years with exercise intolerance and myopathy that improved after treatment with ubiquinone and carnitine. At age 23, his symptoms relapsed despite increasing doses of ubiquinone and he was shown to have biallelic mutations in the ETFDH gene. Treatment with riboflavin was started and ubiquinone was changed to ubiquinol. After 4 months, the patient recovered his muscle strength with normalization of laboratory exams and exercise tolerance. Functional studies on fibroblasts revealed decreased levels of ETFDH as well as of very long-chain acyl-CoA dehydrogenase and trifunctional protein α. In addition, the mitochondrial mass was decreased, with increased formation of reactive oxygen species and oxygen consumption rate, but with a decreased spared respiratory capacity, and decreased adenosine triphosphate level. These findings of widespread dysfunction of fatty acid oxidation and ETC enzymes support the impairment of a larger mitochondrial ETC supercomplex in our patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61786DOI Listing
October 2020

Growth in individuals with Saul-Wilson syndrome.

Am J Med Genet A 2020 09 11;182(9):2110-2116. Epub 2020 Jul 11.

Division of Orthogenetics, Nemours/A.I. duPont Hospital for Children, Wilmington, Delaware, USA.

Saul-Wilson syndrome (SWS) is a rare autosomal recessive disorder characterized by microcephalic primordial dwarfism, spondyloepimetaphyseal dysplasia, characteristic facial findings, clubfoot, brachydactyly, bilateral cataracts, and hearing loss. Recently, recurrent mutations in COG4, encoding a component of the Conserved Oligomeric Golgi (COG) complex, were identified. We created detailed growth curves for stature, weight, and head circumference, as well as weight-for-length and weight velocity charts for younger children, derived from hundreds of data points obtained by retrospective chart review from 14 individuals with molecularly-confirmed SWS. In addition, we performed statistical comparisons of height-for-age model fits before and after initiation of growth hormone supplementation, and found that this therapy does not appear to influence height in individuals with SWS. We hope that these charts will represent valuable tools for clinicians, both in assessing whether SWS seems an appropriate diagnosis, as well as to monitor growth of affected individuals. In particular, we hope that our detailed growth characterization will reduce morbidity resulting from unnecessarily aggressive nutritional interventions by well-intentioned physicians trying to promote weight gain, an unrealistic goal in this genetically-determined cause of primordial dwarfism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61754DOI Listing
September 2020

Nephropathic Cystinosis: A Distinct Form of CKD-Mineral and Bone Disorder that Provides Novel Insights into the Regulation of FGF23.

J Am Soc Nephrol 2020 09 6;31(9):2184-2192. Epub 2020 Jul 6.

Skeletal Disorders and Mineral Homeostasis Section, National Institutes of Dental and Craniofacial Research, Bethesda, Maryland.

Background: The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD-mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD-mineral and bone disorder.

Methods: We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis.

Results: The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3-5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate.

Conclusions: Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2019111172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461669PMC
September 2020

Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD).

Mol Genet Metab Rep 2020 Sep 5;24:100602. Epub 2020 Jun 5.

Cyprium Therapeutics, Inc. 2 Gansevoort Street, 9th Floor, New York, NY 10014, United States.

Background: Previous estimates of the prevalence of Menkes disease, a lethal X-linked recessive disorder of copper metabolism, were based on confirmed clinical cases ascertained from specific populations and varied from 1 in 40,000 to 1 in 354,507. With newly available population-based allelic frequencies of DNA sequence variants, the expected birth prevalence of Menkes disease and other -related phenotypes can be reconsidered using Hardy-Weinberg theoretical principles.

Methods: We reviewed the canonical transcript in the current version of gnomAD (v2.1.1) to evaluate frequency of complete loss-of-function alleles in a diverse normal control population. As a comparator, we used the locus, associated with Duchenne and Becker Muscular Dystrophy, another X-linked recessive trait. We applied Hardy-Weinberg theory and PolyPhen-2 plus REVEL and CADD ensemble analyses to calculate estimated frequencies of normal and predicted deleterious alleles.

Results: We identified 1106 total variants out of 205,523 alleles in gnomAD, with missense variants most common (43.4%). Complete loss-of-function variants were found in four alleles (frequency = 0.0000194), including three frameshift/nonsense mutations and one canonical splice donor site defect. Assuming Harvey-Weinberg equilibrium, this frequency of pathogenic alleles predicts 1 in 34,810 live male births with Menkes disease or other ATP7A-related disorders each year in the US. The same analysis for loss-of-function variants predicted 1 in 7246 newborn males with Duchenne (or Becker) muscular dystrophy. We also identified nine missense variants in gnomAD predicted as deleterious by PolyPhen-2 and stringent REVEL/CADD criteria, comprising 12 more disease-causing alleles and raising the estimated birth prevalence to 1 in 8664 and predicting 225 newborns with Menkes disease or other ATP7A-related disorders per year in the US alone.

Conclusions: Assuming Harvey-Weinberg equilibrium, the allelic frequency of deleterious variants in a genomic database from a large diverse population predicts a birth prevalence of Menkes disease or ATP7A-related disorders as high as 1 in 8664 live male births. This genome-driven ascertainment of deleterious ATP7A alleles in the population implies a higher birth prevalence of Menkes disease and ATP7A-related conditions than previously appreciated. A population-based newborn screening pilot study for Menkes disease will be instrumental in confirming the prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgmr.2020.100602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283148PMC
September 2020

Pharmacokinetics of oral l-serine supplementation in a single patient.

Mol Genet Metab Rep 2020 Sep 22;24:100607. Epub 2020 May 22.

Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washinghton and Seattle Children's Hospital, Seattle, Washington, USA.

Serine, a non-essential amino acid, has attracted clinical attention because of potential benefit in certain metabolic and neurological disorders. Despite the therapeutic potential, little is known about the pharmacokinetics of l-serine metabolism in humans. Here we present pharmacokinetic data at the time of treatment initiation as well as plasma serine levels during dose escalation from a single individual taking oral l-serine as part of a treatment regimen. Our results show that plasma serine levels rise and fall rapidly after oral l-serine intake, suggesting that the optimal dosing for oral l-serine supplementation is at least three times per day.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgmr.2020.100607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256326PMC
September 2020

Lessons learned from 40 novel PIGA patients and a review of the literature.

Epilepsia 2020 06 26;61(6):1142-1155. Epub 2020 May 26.

Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

Objective: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations.

Methods: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches.

Results: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein.

Significance: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16545DOI Listing
June 2020

ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.

Hum Mutat 2020 09 24;41(9):1469-1487. Epub 2020 Jun 24.

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.24056DOI Listing
September 2020

Spondyloepimetaphyseal dysplasia with elevated plasma lysosomal enzymes caused by homozygous variant in MBTPS1.

Am J Med Genet A 2020 07 18;182(7):1796-1800. Epub 2020 May 18.

McKusick-Nathans Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Variants in MBTPS1 (membrane-bound transcription factor peptidase, site 1) encoding the protein convertase site-1 protease (S1P) were recently reported in a single individual with skeletal dysplasia and elevated plasma lysosomal enzymes. Here, we report the second individual with this newly described autosomal recessive spondyloepiphyseal dysplasia (OMIM #618392), presenting severe growth retardation, cataract and dysmorphic features, mainly retromicrognathia. Epilepsy and craniosynostosis were novel findings in our proband. She was found to be homozygous for a novel nonsense variant p.Trp983Ter in MBTPS1. In addition, she had normal levels of lysosomal enzyme activity in leukocytes but elevated levels in plasma. Our description confirms the existence of this new skeletal dysplasia and expands the phenotype and genotype of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136467PMC
July 2020
-->