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1.
Am J Hum Genet ; 108(7): 1231-1238, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089648

RESUMO

Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear.


Assuntos
Estado Terminal/terapia , Medicina de Precisão , Sequenciamento Completo do Genoma , California , Estudos de Coortes , Efeitos Psicossociais da Doença , Cuidados Críticos , Feminino , Hospitais Pediátricos , Humanos , Lactente , Recém-Nascido , Masculino , Medicaid , Estudos Prospectivos , Resultado do Tratamento , Estados Unidos
2.
Am J Med Genet A ; 191(4): 930-940, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36651673

RESUMO

Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder.


Assuntos
Anormalidades Múltiplas , Doenças Hematológicas , Doenças Vestibulares , Gravidez , Feminino , Humanos , Lactente , Anormalidades Múltiplas/genética , Face/anormalidades , Doenças Hematológicas/genética , Doenças Vestibulares/genética , Fenótipo , Histona Desmetilases/genética
3.
Genet Med ; 24(7): 1567-1582, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35482014

RESUMO

PURPOSE: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). METHODS: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. RESULTS: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. CONCLUSION: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.


Assuntos
Metiltransferases , Transtornos do Neurodesenvolvimento , Difosfato de Adenosina/metabolismo , Animais , Histidina/análogos & derivados , Histidina/metabolismo , Humanos , Metiltransferases/genética , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Síndrome
4.
Mol Genet Metab ; 135(2): 122-132, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35012890

RESUMO

OBJECTIVE: To assess our hypothesis that brain macrostructure is different in individuals with mucopolysaccharidosis type I (MPS I) and healthy controls (HC), we conducted a comprehensive multicenter study using a uniform quantitative magnetic resonance imaging (qMRI) protocol, with analyses that account for the effects of disease phenotype, age, and cognition. METHODS: Brain MRIs in 23 individuals with attenuated (MPS IA) and 38 with severe MPS I (MPS IH), aged 4-25 years, enrolled under the study protocol NCT01870375, were compared to 98 healthy controls. RESULTS: Cortical and subcortical gray matter, white matter, corpus callosum, ventricular and choroid plexus volumes in MPS I significantly differed from HC. Thicker cortex, lower white matter and corpus callosum volumes were already present at the youngest MPS I participants aged 4-5 years. Age-related differences were observed in both MPS I groups, but most markedly in MPS IH, particularly in cortical gray matter metrics. IQ scores were inversely associated with ventricular volume in both MPS I groups and were positively associated with cortical thickness only in MPS IA. CONCLUSIONS: Quantitatively-derived MRI measures distinguished MPS I participants from HC as well as severe from attenuated forms. Age-related neurodevelopmental trajectories in both MPS I forms differed from HC. The extent to which brain structure is altered by disease, potentially spared by treatment, and how it relates to neurocognitive dysfunction needs further exploration.


Assuntos
Mucopolissacaridose I , Substância Branca , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética , Mucopolissacaridose I/patologia , Neuroimagem , Substância Branca/patologia
5.
Am J Med Genet A ; 188(6): 1915-1927, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35266292

RESUMO

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.


Assuntos
Síndrome de Costello , Síndrome de Noonan , Síndrome de Costello/genética , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Síndrome de Noonan/genética , Transdução de Sinais , Proteínas ras/genética , Proteínas ras/metabolismo
6.
Genet Med ; 23(10): 1807-1817, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34140662

RESUMO

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and 30% of all cases of CRC are believed to have a familial component and up to one-third of these (10%) are hereditary. Pathogenic germline variants in multiple genes have been associated with predisposition to hereditary CRC or polyposis. Lynch syndrome (LS) is the most common hereditary CRC syndrome, caused by variants in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 and is inherited in a dominant manner. Heritable conditions associated with colonic polyposis include familial adenomatous polyposis (FAP) associated with APC pathogenic variants, MUTYH-associated polyposis (MAP) caused by biallelic MUTYH pathogenic variants, and polymerase proofreading-associated polyposis (PPAP) caused by POLE or POLD1 pathogenic variants. Given the overlapping phenotypes of the cancer syndromes along with the limited sensitivity of using clinical criteria alone, a multigene panel testing approach to diagnose these conditions using next-generation sequencing (NGS) is effective and efficient. This technical standard is not recommended for use in the clinic for patient evaluation. Please refer to National Comprehensive Cancer Network (NCCN) clinical practice guidelines to determine an appropriate testing strategy and guide medical screening and management. This 2021 edition of the American College of Medical Genetics and Genomics (ACMG) technical standard supersedes the 2013 edition on this topic.


Assuntos
Neoplasias Colorretais , Genética Médica , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Testes Genéticos , Genômica , Mutação em Linhagem Germinativa/genética , Humanos , Estados Unidos
7.
Am J Hematol ; 96(9): 1156-1165, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34161616

RESUMO

Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat-treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9-month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open-label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3-6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal [MN], n = 13), mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n = 13), mean hemoglobin increased 1.4 g/dl (from 11.9 to 13.4 g/dl, n = 12), mean platelet count increased by 87% (from 67.6 to 122.6 × 109 /L, n = 12), median chitotriosidase decreased by 82% (from 13 394 to 2312 nmol/h/ml, n = 11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 µg/ml, n = 11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/ml, n = 10), and mean spine T-score increased from -1.07 (osteopenia) to -0.53 (normal) (n = 9). The magnitude of improvement in Gaucher disease manifestations and biomarkers over time was similar among the full trial cohort. Eliglustat was well-tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Doença de Gaucher/tratamento farmacológico , Pirrolidinas/uso terapêutico , Adulto , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Feminino , Doença de Gaucher/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Efeito Placebo , Pirrolidinas/efeitos adversos , Baço/efeitos dos fármacos , Baço/patologia , Resultado do Tratamento , Adulto Jovem
8.
Mol Genet Metab ; 131(1-2): 219-228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33012654

RESUMO

Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001-012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16-74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Terapia de Reposição de Enzimas , Doença de Fabry/tratamento farmacológico , Rim/efeitos dos fármacos , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/efeitos adversos , Adolescente , Adulto , Idoso , Biomarcadores Farmacológicos/metabolismo , Doença de Fabry/patologia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/diagnóstico , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Adulto Jovem , alfa-Galactosidase/genética
9.
N Engl J Med ; 375(6): 545-55, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27509102

RESUMO

BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).


Assuntos
1-Desoxinojirimicina/análogos & derivados , Doença de Fabry/tratamento farmacológico , Rim/química , Triexosilceramidas/análise , alfa-Galactosidase/antagonistas & inibidores , 1-Desoxinojirimicina/efeitos adversos , 1-Desoxinojirimicina/uso terapêutico , Adolescente , Adulto , Idoso , Diarreia/tratamento farmacológico , Diarreia/etiologia , Método Duplo-Cego , Doença de Fabry/complicações , Feminino , Taxa de Filtração Glomerular , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Triexosilceramidas/urina , Ultrassonografia , Adulto Jovem , alfa-Galactosidase/genética
10.
Mol Genet Metab ; 127(1): 86-94, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30987917

RESUMO

BACKGROUND: Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients. METHODS: In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5-18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE). RESULTS: The mean age was 11.6 (range: 5-18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-agalsidase beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (-26.3%; P = .0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their agalsidase beta dose increased. CONCLUSIONS: Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5 years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved agalsidase beta dose of 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.


Assuntos
Terapia de Reposição de Enzimas/estatística & dados numéricos , Doença de Fabry/tratamento farmacológico , Isoenzimas/uso terapêutico , alfa-Galactosidase/uso terapêutico , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Humanos , Masculino , Pele/química , Pele/patologia , Resultado do Tratamento , Triexosilceramidas/análise
11.
Am J Med Genet A ; 179(9): 1725-1744, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31222966

RESUMO

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.


Assuntos
Anormalidades Múltiplas/genética , Síndrome de Costello/genética , Coração/fisiopatologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/fisiopatologia , Síndrome de Costello/fisiopatologia , Síndrome de Costello/terapia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Gerenciamento Clínico , Face/anormalidades , Regulação da Expressão Gênica/genética , Genótipo , Mutação em Linhagem Germinativa/genética , Guias como Assunto , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Humanos , Fenótipo
12.
Am J Med Genet A ; 179(6): 1091-1097, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30908877

RESUMO

The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas Quinases Ativadas por Mitógeno/genética , Neurofibromatoses/etiologia , Proteínas ras/genética , Biomarcadores , Gerenciamento Clínico , Estudos de Associação Genética/métodos , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Neurofibromatoses/diagnóstico , Neurofibromatoses/terapia , Transdução de Sinais , Pesquisa Translacional Biomédica , Proteínas ras/metabolismo
13.
Pediatr Blood Cancer ; 66(8): e27788, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31038288

RESUMO

Growing teratoma syndrome (GTS) is a condition in which mature teratoma with negative tumor markers arises at the site of a treated malignant germ cell tumor. Pathogenic variants in PTEN have been reported to cause autosomal dominant cancer predisposition syndromes and are associated with germ cell tumors. We report the association of a novel heterozygous pathogenic variant in PTEN and very early onset ovarian germ cell tumor complicated by GTS as well as overgrowth syndrome. This marks the youngest reported patient to have developed GTS following treatment of her primary malignant ovarian germ cell tumor.


Assuntos
Heterozigoto , Mutação , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , PTEN Fosfo-Hidrolase/genética , Teratoma/complicações , Pré-Escolar , Feminino , Humanos , Neoplasias Embrionárias de Células Germinativas/etiologia , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/genética , Prognóstico , Síndrome , Teratoma/genética
14.
Blood Cells Mol Dis ; 68: 226-231, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-27839985

RESUMO

Gaucher disease (GD) may worsen during pregnancy, leading to the discussion of continuing treatment during pregnancy. We examined fetal outcomes of pregnancies reported in the Gaucher Outcome Survey, an international GD-specific registry established in 2010. A total of 453 pregnancies were reported. Most pregnancies (336/453, 74.2%) were in women who did not receive GD-specific treatment during pregnancy, while enzyme replacement therapy (ERT) was received during 117/453 (25.8%) pregnancies. No pregnancies exposed to substrate reduction therapy were reported. The percentage of normal outcomes (live birth delivered at term with no congenital abnormalities) was similar in untreated and treated pregnancies (92.9% vs. 91.4%). The percentage of spontaneous abortions in untreated pregnancies was 3.6% (95% CI, 1.9%- 6.2%) compared with 6.9% (95% CI, 3.0%-13.1%) in treated pregnancies (p=0.1866). In women who received velaglucerase alfa <1month prior to conception and/or during pregnancy, 34/36 (94.4%) pregnancies had normal outcomes and 2 (5.6%) ended in spontaneous abortion. Normal outcomes were observed in the 20 pregnancies with velaglucerase alfa exposure starting <1month prior to conception and continuing through all trimesters. These observations, in addition to information in the literature, suggest that continuation of ERT during pregnancy may be appropriate for GD patients.


Assuntos
Terapia de Reposição de Enzimas , Doença de Gaucher/complicações , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Complicações na Gravidez/tratamento farmacológico , Adolescente , Adulto , Criança , Terapia de Reposição de Enzimas/métodos , Feminino , Doença de Gaucher/epidemiologia , Humanos , Gravidez , Complicações na Gravidez/epidemiologia , Resultado da Gravidez , Sistema de Registros , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
15.
Am J Med Genet A ; 176(8): 1778-1783, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30055036

RESUMO

Wagner syndrome and erosive vitreoretinopathy together constitute the phenotypic continuum of an autosomal dominant vitreoretinopathy, with clinical findings typically isolated to the eye. The disease is caused by pathogenic variants in the VCAN gene and all such variants reported to date are those that plausibly result in haploinsufficiency of exon 8 containing vcan transcripts. Here, we report the molecular findings and long-term follow-up of a 16-year-old female with a history of retinal detachments and pigmentary retinal changes. Next-generation sequencing and microarray analysis of 141 genes established a diagnosis of Wagner syndrome in this individual, by detection of an 11.7 kilobase (kb) deletion encompassing exon 8 of VCAN. In light of the emerging functions and roles of versican protein in human disease, we discuss how variants within exon 8 of the VCAN gene can be compared to those in exon 2 of the COL2A1 gene that cause atypical Stickler syndrome and propose that variants in other regions of the gene can be expected to present with a more systemic disease. The distinctive facial features and atypical gastrointestinal symptoms observed in this long-term follow-up study support the possibility that individuals with VCAN-related vitreoretinopathy may have extra-ocular clinical features.


Assuntos
Degeneração Retiniana/genética , Descolamento Retiniano/genética , Retinose Pigmentar/genética , Versicanas/deficiência , Adolescente , Colágeno Tipo II/genética , Éxons/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Linhagem , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/fisiopatologia , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/fisiopatologia , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/fisiopatologia , Deleção de Sequência/genética , Versicanas/genética
16.
Am J Med Genet A ; 176(12): 2924-2929, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30302932

RESUMO

This report summarizes and highlights the fifth International RASopathies Symposium: When Development and Cancer Intersect, held in Orlando, Florida in July 2017. The RASopathies comprise a recognizable pattern of malformation syndromes that are caused by germ line mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Because of their common underlying pathogenetic etiology, there is significant overlap in their phenotypic features, which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, gastrointestinal and ocular abnormalities, neurological and neurocognitive issues, and a predisposition to cancer. The RAS pathway is a well-known oncogenic pathway that is commonly found to be activated in somatic malignancies. As in somatic cancers, the RASopathies can be caused by various pathogenetic mechanisms that ultimately impact or alter the normal function and regulation of the MAPK pathway. As such, the RASopathies represent an excellent model of study to explore the intersection of the effects of dysregulation and its consequence in both development and oncogenesis.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas ras/genética , Animais , Regulação da Expressão Gênica , Estudos de Associação Genética/métodos , Desenvolvimento Humano , Humanos , Modelos Biológicos , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Organogênese/genética , Transdução de Sinais , Síndrome , Proteínas ras/metabolismo
17.
J Med Genet ; 54(4): 288-296, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27834756

RESUMO

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking. METHODS: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. RESULTS: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. CONCLUSIONS: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations. TRIAL REGISTRATION NUMBER: NCT00925301; Pre-results.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Doença de Fabry/tratamento farmacológico , Chaperonas Moleculares/administração & dosagem , alfa-Galactosidase/genética , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/efeitos adversos , Administração Oral , Adolescente , Adulto , Idoso , Terapia de Reposição de Enzimas/efeitos adversos , Doença de Fabry/metabolismo , Doença de Fabry/fisiopatologia , Feminino , Humanos , Lisossomos/genética , Lisossomos/patologia , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/efeitos adversos , Resultado do Tratamento
19.
Am J Hematol ; 92(11): 1170-1176, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28762527

RESUMO

Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18-month outcomes of patients who entered the trial extension period, in which all patients received eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to eliglustat in the double-blind period, continuing treatment with eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double-blind period, eliglustat treatment during the 9-month, open-label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received eliglustat in the double-blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of eliglustat in treatment-naïve patients. Eliglustat was well-tolerated, and there were no new safety concerns with longer-term exposure.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Terapia de Reposição de Enzimas , Doença de Gaucher/tratamento farmacológico , Pirrolidinas/uso terapêutico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Seguimentos , Doença de Gaucher/diagnóstico , Doença de Gaucher/enzimologia , Glucosilceramidase/antagonistas & inibidores , Humanos , Fígado/patologia , Tamanho do Órgão , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Baço/patologia , Resultado do Tratamento
20.
Mol Genet Metab ; 117(2): 164-71, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26043810

RESUMO

BACKGROUND: Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). METHODS: Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30-60U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. RESULTS: The study included 24 pediatric patients. Fifteen patients were naïve to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for >30months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naïve patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. CONCLUSION: The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults.


Assuntos
Terapia de Reposição de Enzimas , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Adolescente , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Humanos , Masculino , Maturidade Sexual , Resultado do Tratamento
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