RESUMEN
Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect â¼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.
Asunto(s)
Codón/genética , Estudios de Asociación Genética , Mutación Missense/genética , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Adolescente , Secuencia de Aminoácidos , Niño , Estudios de Cohortes , Simulación por Computador , Demografía , Femenino , Heterocigoto , Humanos , Masculino , Neurofibromina 1/química , Fenotipo , Adulto JovenRESUMEN
INTRODUCTION: Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited metabolic disorder that impairs the synthesis of creatine (CRE). Lack of CRE in the brain can cause intellectual disability, autistic-like behavior, seizures, and movement disorders. Identification at birth and immediate therapy can prevent intellectual disability and seizures. Here we report the first two cases of GAMT deficiency identified at birth by newborn screening (NBS) in Utah and New York. METHODS: NBS dried blood spots were analyzed by tandem mass spectrometry (MS/MS) using either derivatized or non-derivatized assays to detect guanidinoacetate (GUAC) and CRE. For any positive samples, a second-tier test using a more selective method, ultra-performance liquid chromatography (UPLC) combined with MS/MS, was performed to separate GUAC from potential isobaric interferences. RESULTS: NBS for GAMT deficiency began in Utah on June 1, 2015 using a derivatized method for the detection of GUAC and CRE. In May 2019, the laboratory and method transitioned to a non-derivatized method. GAMT screening was added to the New York State NBS panel on October 1, 2018 using a derivatized method. In New York, a total of 537,408 babies were screened, 23 infants were referred and one newborn was identified with GAMT deficiency. In Utah, a total of 273,902 infants were screened (195,425 with the derivatized method, 78,477 with the non-derivatized method), three infants referred and one was identified with GAMT deficiency. Mean levels of GUAC and CRE were similar between methods (Utah derivatized: GUAC = 1.20 ± 0.43 µmol/L, CRE = 238 ± 96 µmol/L; Utah non-derivatized: GUAC = 1.23 ± 0.61 µmol/L, CRE = 344 ± 150 µmol/L, New York derivatized: GUAC = 1.34 ± 0.57 µmol/L, CRE = 569 ± 155 µmol/L). With either Utah method, similar concentrations of GUAC are observed in first (collected around 1 day of age) and the second NBS specimens (routinely collected at 7-16 days of age), while CRE concentrations decreased in the second NBS specimens. Both infants identified with GAMT deficiency started therapy by 2 weeks of age and are growing and developing normally at 7 (Utah) and 4 (New York) months of age. CONCLUSIONS: Newborn screening allows for the prospective identification of GAMT deficiency utilizing elevated GUAC concentration as a marker. First-tier screening may be incorporated into existing methods for amino acids and acylcarnitines without the need for new equipment or staff. Newborn screening performed by either derivatized or non-derivatized methods and coupled with second-tier testing, has a very low false positive rate and can prospectively identify affected children. SummaryCerebral creatine deficiency syndromes caused by defects in creatine synthesis can result in intellectual disability, and are preventable if therapy is initiated early in life. This manuscript reports the identification of two infants with GAMT deficiency (one of the cerebral creatine deficiency syndromes) by newborn screening and demonstrates NBS feasibility using a variety of methods.
Asunto(s)
Guanidinoacetato N-Metiltransferasa/deficiencia , Trastornos del Desarrollo del Lenguaje/diagnóstico , Trastornos del Movimiento/congénito , Tamizaje Neonatal/métodos , Tamizaje Neonatal/normas , Cromatografía Liquida , Creatina/metabolismo , Pruebas con Sangre Seca/métodos , Humanos , Recién Nacido , Trastornos del Desarrollo del Lenguaje/complicaciones , Trastornos del Movimiento/complicaciones , Trastornos del Movimiento/diagnóstico , New York , Estudios Prospectivos , UtahRESUMEN
Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity. Whole-exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70%-90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity.
Asunto(s)
Alanina-ARNt Ligasa/genética , Síndrome de Lennox-Gastaut/genética , Microcefalia/genética , Espasmos Infantiles/genética , Paraplejía Espástica Hereditaria/genética , Secuencia de Aminoácidos/genética , Aminoacilación/genética , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Preescolar , Electroencefalografía , Femenino , Humanos , Lactante , Síndrome de Lennox-Gastaut/complicaciones , Síndrome de Lennox-Gastaut/diagnóstico , Síndrome de Lennox-Gastaut/patología , Microcefalia/diagnóstico por imagen , Microcefalia/patología , Mutación/genética , Biosíntesis de Proteínas/genética , Hermanos , Espasmos Infantiles/complicaciones , Espasmos Infantiles/diagnóstico por imagen , Espasmos Infantiles/patología , Paraplejía Espástica Hereditaria/complicaciones , Paraplejía Espástica Hereditaria/patología , Secuenciación del ExomaRESUMEN
PURPOSE: Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006. METHODS: Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination. RESULTS: Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease. CONCLUSIONS: The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.
Asunto(s)
Galactosilceramidasa/genética , Galactosilceramidasa/metabolismo , Leucodistrofia de Células Globoides/diagnóstico , Tamizaje Neonatal/métodos , Polimorfismo de Nucleótido Simple , Algoritmos , Pruebas con Sangre Seca , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Recién Nacido , Leucodistrofia de Células Globoides/enzimología , Leucodistrofia de Células Globoides/terapia , Espectrometría de Masas , New York , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
BACKGROUND: Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006. METHODS: Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT. RESULTS: Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease. CONCLUSIONS: These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.
Asunto(s)
Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/terapia , Tamizaje Masivo , Tamizaje Neonatal , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Recién Nacido , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/mortalidad , New York , Factores de RiesgoRESUMEN
Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.
Asunto(s)
Sustitución de Aminoácidos , Codón , Mutación Missense , Neurofibromina 1/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Enanismo/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neurofibromina 1/química , Adulto JovenRESUMEN
INTRODUCTION: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome. METHOD: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms. RESULTS: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 micromol/L in the asymptomatic vs. 19.1 micromol/L in the symptomatic, p<0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p<0.012). Four infants had initial C8 level >30 micromol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians. DISCUSSION: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.
Asunto(s)
Acil-CoA Deshidrogenasas/deficiencia , Acil-CoA Deshidrogenasas/genética , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/fisiopatología , Tamizaje Neonatal/métodos , Carnitina/análogos & derivados , Carnitina/sangre , Ácidos Grasos/metabolismo , Femenino , Genotipo , Humanos , Recién Nacido , Masculino , Errores Innatos del Metabolismo/genética , Mutación , New York , Fenotipo , PronósticoRESUMEN
Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.
Asunto(s)
Leucodistrofia de Células Globoides/diagnóstico , Tamizaje Neonatal/organización & administración , Tamizaje Neonatal/normas , Análisis Mutacional de ADN , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Potenciales Evocados Visuales/fisiología , Estudios de Seguimiento , Galactosilceramidasa/análisis , Galactosilceramidasa/metabolismo , Trasplante de Células Madre Hematopoyéticas , Humanos , Recién Nacido , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/terapia , Imagen por Resonancia Magnética , Modelos Organizacionales , Conducción Nerviosa/fisiología , Examen Neurológico , New York , Derivación y Consulta , Medición de Riesgo , Resultado del TratamientoRESUMEN
Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of á-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1, POMT2, FCMD and FKRP, many of which were novel alleles, but no mutations in POMGNT1 or LARGE. Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation.
Asunto(s)
Anomalías Múltiples/genética , Proteínas de la Membrana/genética , Mutación , Anomalías Múltiples/etnología , Niño , Lisencefalia de Cobblestone/etnología , Lisencefalia de Cobblestone/genética , Análisis Mutacional de ADN , Anomalías del Ojo/etnología , Anomalías del Ojo/genética , Femenino , Genoma Humano , Genotipo , Humanos , Masculino , Medio Oriente , Distrofias Musculares/etnología , Distrofias Musculares/genética , Linaje , Fenotipo , SíndromeRESUMEN
While the 'original' bronchopulmonary dysplasia (BPD) was attributed to the iatrogenic effects of oxygen and barotrauma on the preterm lung, analyses of the 'new' BPD suggests that these environmental effects may contribute to arrested pulmonary development, and that there may also be genetic foundations for the susceptibility to BPD. Twinning, family and population studies implicate heritable factors in the evolution of BPD. The candidate genes examined for their potential role in BPD include surfactant apoprotein and inflammatory genes. With the identification and mapping of single nucleotide polymorphisms (SNPs), an explosion of testing for these genetic components that may contribute to a number of complex, multigenic disease conditions-including BPD-have been initiated. Sophisticated multiplex analyses are now available to link candidate SNPs to conditions such as BPD. However, there continues to be wide variation in the expression of BPD throughout neonatal units. Differentiating the effects caused by environmental and environmental-genetic interactions from isolated genetic etiologies is still problematic and will require carefully designed genetic analyses of preterm infant groups and their families.
Asunto(s)
Displasia Broncopulmonar/genética , Predisposición Genética a la Enfermedad , Alelos , Apoproteínas/metabolismo , Enfermedades en Gemelos , Evolución Molecular , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro , Inflamación , Desequilibrio de Ligamiento , Pulmón/patología , Modelos Biológicos , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Riesgo , Tensoactivos/químicaRESUMEN
Werner's syndrome is an autosomal recessive disorder resulting in premature aging. Most patients die in their fifth decade from malignancies or heart disease. The gene for Werner's syndrome (WRN) encodes a recQ helicase. Cells from patients with Werner's syndrome have increased sensitivity to DNA-damaging drugs in vitro. Here we present a patient with Werner's syndrome who developed severe chemotherapy-induced toxicity during treatment for acute myelogenous leukemia. We propose that lack of WRN resulted in increased sensitivity of the patient's cells to the toxicity of chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndrome de Werner/tratamiento farmacológico , Adulto , Citarabina/administración & dosificación , ADN Helicasas/genética , Etopósido/administración & dosificación , Exodesoxirribonucleasas , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/enzimología , Masculino , Mitoxantrona/administración & dosificación , RecQ Helicasas , Síndrome de Werner/complicaciones , Síndrome de Werner/enzimología , Helicasa del Síndrome de WernerRESUMEN
We describe a 12-year-old boy with mosaic variegated aneuploidy (MVA), subnormal response to growth hormone (GH) stimulation testing, and short stature. In addition to features more commonly described in MVA such as microcephaly, cognitive deficits, and certain facial features, he also has features not commonly reported in MVA, including short limb segments, epidermoid cysts, ventricular septal defect, and subaortic stenosis. Chromosomal analysis revealed hyperdiploid chromosome numbers ranging from 47 to 70; modal number 50, in 24% of the metaphases. This case demonstrates that although the phenotype of MVA almost always includes growth failure, microcephaly, and mental retardation, additional features may vary greatly across individuals. His clinical features and course suggest that in addition to GH deficiency, he may have an intrinsic inability of the growth plate to respond to growth hormone.
Asunto(s)
Anomalías Múltiples/genética , Aneuploidia , Cardiopatías Congénitas/patología , Hormona de Crecimiento Humana/deficiencia , Anomalías Múltiples/patología , Niño , Femenino , Trastornos del Crecimiento/patología , Humanos , Masculino , Microcefalia/patología , MosaicismoRESUMEN
BACKGROUND: Failure-to-thrive (FTT) has been described in patients with organic acidemias treated with low protein diets. OBJECTIVE: To determine if patients with methylmalonic (MMA) or propionic acidemia (PA) can achieve normal growth and nutrition status. METHODS: A 6-month multicenter outpatient study was conducted with infants and toddlers treated with Propimex-1 Amino Acid-Modified Medical Food With Iron (Ross Products Division, Abbott Laboratories, Columbus, OH). Main outcome measures were anthropometrics, protein status indices, plasma retinol, and alpha-tocopherol. RESULTS: Sixteen patients completed the study. Mean baseline age was 0.54 +/- 0.02 years (range 0.03-3.00 years). By study end, mean National Center for Health Statistics (NCHS) weight centile increased from 26 to 49%; mean crown-heel length centile from 25 to 33%; and mean head circumference centile from 43 to 54%. Mean (+/- SE) protein and energy intakes by <6-month-old, 6<12-month-old, and 1<4-year-old patients were 15.3 +/- 0.9 g and 645 +/- 10 kcal; 18.3 +/- 1.1 g and 741 +/- 92 kcal; and 25.1 +/- 2.46 g and 1062 +/- 100 kcal, respectively. Plasma glycine concentrations were significantly and negatively correlated with energy intake (r=-0.77, p<0.0005). No correlation was found between dietary protein intakes and plasma ammonia concentrations. Protein status indices, retinol and alpha-tocopherol concentrations were within reference ranges at study end. CONCLUSIONS: Propimex-1 improved growth and nutrition status in patients with MMA or PA in just 6 months when fed in sufficient amounts. Providing energy and protein for patients with FTT at intakes recommended for catch-up growth may have resulted in even better growth.