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A deficiency of 3-hydroxyisobutyric acid dehydrogenase (HIBADH) has been recently identified as a cause of primary 3-hydroxyisobutyric aciduria in two siblings; the only previously recognized primary cause had been a deficiency of methylmalonic semialdehyde dehydrogenase, the enzyme that is immediately downstream of HIBADH in the valine catabolic pathway and is encoded by the ALDH6A1 gene. Here we report on three additional patients from two unrelated families who present with marked and persistent elevations of urine L-3-hydroxyisobutyric acid (L-3HIBA) and a range of clinical findings. Molecular genetic analyses revealed novel, homozygous variants in the HIBADH gene that are private within each family. Evidence for pathogenicity of the identified variants is presented, including enzymatic deficiency of HIBADH in patient fibroblasts. This report describes new variants in HIBADH as an underlying cause of primary 3-hydroxyisobutyric aciduria and expands the clinical spectrum of this recently identified inborn error of valine metabolism. Additionally, we describe a quantitative method for the measurement of D- and L-3HIBA in plasma and urine and present the results of a valine restriction therapy in one of the patients.
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Erros Inatos do Metabolismo dos Aminoácidos , Espectrometria de Massas em Tandem , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Cromatografia Líquida , Humanos , Hidroxibutiratos/urina , Oxirredutases , ValinaRESUMO
The original article contains an unintended omission of a statement of competing interests. As such, the authors would like to declare the following complete statement of competing interests.
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BACKGROUND: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset. METHODS: We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays. FINDINGS: In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing. INTERPRETATION: c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. FUND: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17-32) and Metakids (2016-063).
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Genes Modificadores , Estudos de Associação Genética , Predisposição Genética para Doença , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , Fenótipo , Adolescente , Adulto , Idade de Início , Alelos , Criança , Pré-Escolar , Frequência do Gene , Genótipo , Doença de Depósito de Glicogênio Tipo II/metabolismo , Humanos , Lactente , Íntrons , Pessoa de Meia-Idade , Mutação , Splicing de RNA , Avaliação de Sintomas , Adulto Jovem , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismoRESUMO
BACKGROUND: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like (MELAS) syndrome is a rare condition with heterogeneous clinical presentation. Cardiac involvement commonly develops during adulthood, comprising both structural and conduction/arrhythmic abnormalities; early paediatric onset has rarely been reported. We describe the clinical profile, outcome and clinical implication of MELAS-associated cardiomyopathy at a tertiary referral centre. METHODS: From 2000 to 2016 we enrolled 21 patients affected by genetically-proven MELAS. Patients were followed-up at least annually over a mean of 8.5â¯years. RESULTS: All patients carried the MT-TL1 3243A>G mutation. Cardiac involvement was documented in 8 (38%) patients (three <18â¯years; five ≥18â¯years), including 6 (75%) with hypertrophic cardiomyopathy, 1 (12.5%) with dilated cardiomyopathy, and 1 (12.5%) with persistent pulmonary hypertension. During follow-up, 3 patients died, all with cardiac onset <18â¯years. The cause of death, however, was non-cardiac (infections, respiratory failure, stroke). Neither events nor cardiac progression were recorded among patients with onset ≥18â¯years. Adult cardiologists were responsible for 5/8 of referrals, even in patients with long-standing extra-cardiac involvement. CONCLUSIONS: Cardiac involvement was found in over 1/3 of patients with MELAS syndrome, and exhibited a bimodal age-related distribution with distinct final outcomes. Paediatric-onset cardiomyopathy represented a hallmark of systemic disease severity, without being the main determinant of outcome. Conversely, adult-onset cardiomyopathy appeared to represent a mild and non-progressive mid-term manifestation. Adult cardiologists played an important role in the diagnostic process, triggering suspicion of MELAS in most of patients diagnosis >18â¯years.
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Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Síndrome MELAS/diagnóstico por imagem , Síndrome MELAS/fisiopatologia , Adolescente , Adulto , Fatores Etários , Cardiomiopatias/genética , Criança , Feminino , Seguimentos , Humanos , Síndrome MELAS/genética , Masculino , Mitocôndrias/genética , Mutação/genética , Estudos RetrospectivosRESUMO
Newborn screening (NBS) methods and therapeutic options have become increasingly available for mucopolysaccharidoses (MPS), and there is a clear evidence that early intervention significantly improves the outcome. It is recommended that mucopolysaccharidosis type I (MPS I) is included in the US newborn screening panel, and this is currently underway in some NBS programs in the world. The key factors in recommending MPS I for inclusion in NBS are the strongly improved efficacy of early-onset therapy and the improved performance of screening tests. Two studies on MPS I screening have been conducted in Italy. In the Tuscany-Umbria pilot NBS, eight infants were confirmed positive, and alpha-L-iduronidase (IDUA) gene molecular analysis showed that seven had either homozygosity or compound heterozygosity for pseudodeficiency alleles. p.Ala79Thr and p.His82Gln changes were demonstrated in four and three infants, respectively, six of which were of African origin. Only one infant had transitory elevation of urine glycosaminoglycans (GAGs) (by quantitative analysis) and she is in follow-up at the time of writing. In the North East Italy experience, there was one affected newborn for 66,491 screened. In this patient treatment started at 1 month of age. In the North East Italy experience the incidence of pseudodeficiency was very high (1:6044), with a high incidence of pseudodeficiency from patients of African origin.A significant problem that is encountered in the follow-up of infants with abnormal NBS and variants of unknown significance (VUS) on molecular analysis results relates to those who cannot be positively identified as either affected or unaffected. Long-term follow-up of these infants, and of those detected with late-onset disorders, will be essential to document the true risks and benefits of NBS. The availability of treatments in MPS II, IVA, VI, and VII with a better clinical outcome when started early in life, and the availability of a combined multiple assay for MPS, may be a prerequisite for new pilot NBS studies in the near future.
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Mucopolissacaridose I/diagnóstico , Triagem Neonatal , Humanos , Recém-Nascido , Valor Preditivo dos TestesRESUMO
N-acetylglutamate synthase deficiency (NAGSD) is an extremely rare urea cycle disorder (UCD) with few adult cases so far described. Diagnosis of late-onset presentations is difficult and delayed treatment may increase the risk of severe hyperammonemia. We describe a 52-year-old woman with recurrent headaches who experienced an acute onset of NAGSD. As very few papers focus on headaches in UCDs, we also report a literature review of types and pathophysiologic mechanisms of UCD-related headaches. In our case, headaches had been present since puberty (3-4 days a week) and were often accompanied by nausea, vomiting, or behavioural changes. Despite three previous episodes of altered consciousness, ammonia was measured for the first time at 52 years and levels were increased. Identification of the new homozygous c.344C>T (p.Ala115Val) NAGS variant allowed the definite diagnosis of NAGSD. Bioinformatic analysis suggested that an order/disorder alteration of the mutated form could affect the arginine-binding site, resulting in poor enzyme activation and late-onset presentation. After optimized treatment for NAGSD, ammonia and amino acid levels were constantly normal and prevented other headache bouts. The manuscript underlies that headache may be the presenting symptom of UCDs and provides clues for the rapid diagnosis and treatment of late-onset NAGSD.
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Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Idade de Início , Aminoácido N-Acetiltransferase/metabolismo , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Eletroencefalografia , Feminino , Glutamatos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Avaliação de Sintomas , Resultado do Tratamento , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/patologia , Distúrbios Congênitos do Ciclo da Ureia/terapiaRESUMO
PURPOSE: To describe the retinal structure of a group of patients affected by methylmalonic aciduria with homocystinuria cblC type, caused by mutations in the MMACHC gene, using spectral domain optical coherence tomography (SD-OCT). METHODS: Young patients (n = 11, age 0-74 months) with cblC disease, detected by newborn screening or clinically diagnosed within 40 days of life, underwent molecular analysis and complete ophthalmic examination, including fundus photography and SD-OCT. In one case, we also performed fluorescein angiography (FA) and standard electroretinography (ERG). RESULTS: Molecular analysis of the MMACHC gene fully confirmed cblC disease in nine of 11 patients. Two patients harboured only a single heterozygous pathogenic MMACHC mutation and large unbalanced rearrangements were excluded by array-CGH analysis in both. All patients except two showed a bilateral maculopathy. In general, retinal changes were first observed before one year of age and progressed to a well-established maculopathy. Measurable visual acuities ranged from normal vision, in keeping with age, to bilateral, severe impairment of central vision. Nystagmus was present in six patients. Spectral domain optical coherence tomography (SD-OCT) showed macular thinning with severe alterations in outer, and partial sparing of inner, retinal layers. CONCLUSION: Patients affected by cblC disease may frequently show an early onset maculopathy with variable ophthalmoscopic appearance. Spectral domain optical coherence tomography (SD-OCT) broadens the knowledge of subtle retinal alterations during the disease's progression and helps to shed light on the pathological mechanism of maculopathy development.
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DNA/genética , Homocistinúria/complicações , Macula Lutea/patologia , Ácido Metilmalônico/urina , Mutação , Proteínas Proto-Oncogênicas c-cbl/genética , Doenças Retinianas/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Homocistinúria/genética , Homocistinúria/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Oftalmoscopia , Oxirredutases , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Doenças Retinianas/diagnóstico , Doenças Retinianas/etiologia , Tomografia de Coerência ÓpticaAssuntos
Canais de Cloreto/genética , Miotonia Congênita/genética , Miotonia Congênita/patologia , Adulto , Família , Feminino , Genótipo , Humanos , Itália , Masculino , Linhagem , FenótipoRESUMO
BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.
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Metilação/efeitos dos fármacos , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Proteínas Proto-Oncogênicas c-cbl/deficiência , Vitamina B 12/farmacologia , Vitamina B 12/uso terapêutico , Animais , Homocisteína/genética , Humanos , Metionina/genéticaRESUMO
Short-chain acyl-coA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation caused by ACADS gene alterations. SCADD is a heterogeneous condition, sometimes considered to be solely a biochemical condition given that it has been associated with variable clinical phenotypes ranging from no symptoms or signs to metabolic decompensation occurring early in life. A reason for this variability is due to SCAD alterations, such as the common p.Gly209Ser, that confer a disease susceptibility state but require a complex multifactorial/polygenic condition to manifest clinically. Our study focuses on 12 SCADD patients carrying 11 new ACADS variants, with the purpose of defining genotype-phenotype correlations based on clinical data, metabolite evaluation, molecular analyses, and in silico functional analyses. Interestingly, we identified a synonymous variant, c.765G > T (p.Gly255Gly) that influences ACADS mRNA splicing accuracy. mRNA characterisation demonstrated that this variant leads to an aberrant splicing product, harbouring a premature stop codon. Molecular analysis and in silico tools are able to characterise ACADS variants, identifying the severe mutations and consequently indicating which patients could benefit from a long term follow- up. We also emphasise that synonymous mutations can be relevant features and potentially associated with SCADD.
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Abstract The isodecyl neopentanoate is an ingredient used in the cosmetic industry to prepare a nipple fissure balm. We report on 12 newborns that showed elevated C5-acylcarnitine levels upon newborn screening following treatment with balm. The first 3 neonates were immediately recalled for confirmatory tests and resulted negative for both isovaleric acidemia and short/branched chain acyl-CoA dehydrogenase deficiency. In the other 9 cases, the immediate recall was avoided by applying a new second-tier test able to confirm the presence of pivaloylcarnitine. The concentration of C5-acylcarnitine was measured in the days following the suspension of balm application. Abnormal concentrations of C5-acylcarnitine did not seem to be associated with free carnitine deficiency, probably due to the short time of exposure. A direct correlation between balm ingestion and the elevation in pivaloylcarnitine has been demonstrated in 10 adult volunteers. The commercial balm containing a pivalic acid derivative is causal of false-positive results during newborn screening, and it could have the potential to cause secondary carnitine deficiency when used chronically.
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AIM: We aimed to identify specific polymorphisms of genes encoding for vascular endothelial growth factor A (VEGFA), endothelial nitric oxide synthase (eNOS), renin-angiotensin system (angiotensinogen gene [AGT], angiotensinogen type 1 receptor [AGTR1], angiotensin-converting enzyme [ACE]), and heme oxygenase-1 (HMOX-1) in a cohort of preterm infants and correlate their presence with the development of respiratory distress syndrome (RDS) requiring mechanical ventilation (MV), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) and retinopathy of prematurity (ROP). STUDY DESIGN: We carried out a retrospective study to evaluate the allele frequency and genotype distribution of polymorphisms of VEGFA, eNOS, AGT, AGTR1, ACE, and HMOX-1 in a population of preterm neonates (n=342) with a gestational age ≤28 weeks according to the presence or absence of RDS requiring MV, BPD, IVH, or ROP. Moreover, we evaluated through the haplotype reconstruction analysis whether combinations of the selected polymorphisms are related to the occurrence of RDS, BPD, IVH and ROP. RESULTS: In our population 157 infants developed RDS requiring MV, 71 BPD, 70 IVH, and 43 ROP. We found that TC+CC rs2070744 eNOS (41.7 vs. 25.4%, p=0.01) and GT+TT rs1799983 eNOS (51.8 vs. 35.2%, p=0.01) polymorphisms are independent risk factors for BPD. Haplotype reconstruction showed that haplotypes in VEGF and eNOS are significantly associated with different effects on RDS, BPD, IVH, and ROP in our population. CONCLUSIONS: We found that TC+CC rs2070744 eNOS and GT+TT rs1799983 eNOS polymorphisms are independent predictors of an increased risk of developing BPD. Haplotypes of VEGFA and eNOS may be independent protective or risk markers for prematurity complications.
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Polimorfismo de Nucleotídeo Único , Nascimento Prematuro/genética , Angiotensinogênio/genética , Displasia Broncopulmonar/complicações , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Heme Oxigenase-1/genética , Humanos , Recém-Nascido , Hemorragias Intracranianas/complicações , Masculino , Óxido Nítrico Sintase Tipo III/genética , Peptidil Dipeptidase A/genética , Gravidez , Nascimento Prematuro/enzimologia , Nascimento Prematuro/terapia , Receptor Tipo 1 de Angiotensina/genética , Respiração Artificial , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Retinopatia da Prematuridade/complicações , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Sepiapterin reductase deficiency (SRD) causes depletion of biogenic amines in the brain, early onset motor disorder, and intellectual disability. The diagnostic marker for this rare disease is increased sepiapterin and biopterin in CSF. Through a new analytic methodology we demonstrated accumulation of sepiapterin in urine of four SRD patients several times greater than that found in healthy controls and carriers, regardless of age or treatment. Our findings suggest a new interpretation of current theories of peripheral pterin metabolism and provide a new noninvasive diagnostic tool for children with early onset cryptogenetic developmental delay and/or movement disorder.
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Distonia/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Transtornos Psicomotores/diagnóstico , Pterinas/urina , Biomarcadores/urina , Distonia/urina , Humanos , Lactente , Erros Inatos do Metabolismo/urina , Prognóstico , Transtornos Psicomotores/urinaRESUMO
Newborn screening (NBS) is justified if early intervention is effective in a disorder generally not detected early in life on a clinical basis, and if sensitive and specific biochemical markers exist. Experience with NBS for homocystinurias and methylation disorders is limited. However, there is robust evidence for the success of early treatment with diet, betaine and/or pyridoxine for CBS deficiency and good evidence for the success of early betaine treatment in severe MTHFR deficiency. These conditions can be screened in dried blood spots by determining methionine (Met), methionine-to-phenylanine (Met/Phe) ratio, and total homocysteine (tHcy) as a second tier marker. Therefore, we recommend NBS for cystathionine beta-synthase and severe MTHFR deficiency. Weaker evidence is available for the disorders of intracellular cobalamin metabolism. Early treatment is clearly of advantage for patients with the late-onset cblC defect. In the early-onset type, survival and non-neurological symptoms improve but the effect on neurocognitive development is uncertain. The cblC defect can be screened by measuring propionylcarnitine, propionylcarnitine-to-acetylcarnitine ratio combined with the second tier markers methylmalonic acid and tHcy. For the cblE and cblG defects, evidence for the benefit of early treatment is weaker; and data on performance of Met, Met/Phe and tHcy even more limited. Individuals homozygous or compound heterozygous for MAT1A mutations may benefit from detection by NBS using Met, which on the other hand also detects asymptomatic heterozygotes. Clinical and laboratory data is insufficient to develop any recommendation on NBS for the cblD, cblF, cblJ defects, glycineN-methyltransferase-, S-adenosylhomocysteinehydrolase- and adenosine kinase deficiency.
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Homocistinúria/diagnóstico , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Triagem Neonatal , Acetilcarnitina/sangue , Betaína/uso terapêutico , Carnitina/análogos & derivados , Carnitina/sangue , Humanos , Recém-Nascido , Metionina/sangue , Metilação , Metilenotetra-Hidrofolato Redutase (NADPH2)/efeitos dos fármacos , Ácido Metilmalônico/sangue , Guias de Prática Clínica como AssuntoRESUMO
Biotinidase deficiency (BD), which is caused by BTD genetic lesions, if untreated, can result in neurological and cutaneous manifestations. Biotin supplementation can improve or prevent symptoms. We herewith present a family, which we studied at biochemical and molecular level, after identifying the proband through a newborn screening programme. BTD gene molecular analysis showed the proband to be compound heterozygous for the c.1330G>C p.(Asp444His) mild known variant, and for the c.1475 C>T p.(Thr492Ile) new variant. Bioinformatic analysis allowed us to confirm the pathogenic role of the newly identified variant. The proband's father, who exhibited low biotinidase (BTD) enzyme activity, was homozygous for the mild variant, whereas the proband's mother, who exhibited borderline BTD values, the BTD mutation carrier status could not be detected. This is the first description of a patient with BD harbouring a variant whose origin is either de novo or the consequence of gonadal mosaicism. BTD molecular analysis and bioinformatic tools for the evaluation of pathogenicity of newly identified variants are necessary for diagnostic purposes (i.e., clarifying borderline enzyme assays and the carrier status of parents), and for genetic counselling.
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Deficiência de Biotinidase/diagnóstico , Deficiência de Biotinidase/genética , Biotinidase/genética , Mosaicismo , Mutação , Adulto , Sequência de Aminoácidos , Sequência de Bases , Deficiência de Biotinidase/patologia , Feminino , Aconselhamento Genético , Heterozigoto , Homozigoto , Humanos , Recém-Nascido , Masculino , Dados de Sequência Molecular , Triagem Neonatal , PaisRESUMO
ATP synthase or complex V (cV) of the oxidative phosphorylation system is responsible for the production of ATP, dissipating the electrochemical gradient generated by the mitochondrial respiratory chain. In addition to maternally transmitted cV dysfunction caused by mutations in mtDNA genes (MT-ATP6 or MT-ATP8), encoding cV subunits, recessive mutations in the nuclear TMEM70 are the most frequent cause of ATP synthase deficiency.We report on a cohort of ten Italian patients presenting with neonatal lactic acidosis, respiratory distress, hypotonia, cardiomyopathy and psychomotor delay and harbouring mutations in TMEM70, including the common splice mutation and four novel variants. TMEM70 protein was virtually absent in all tested TMEM70 patients' specimens.The exact function of TMEM70 is not known, but it is considered to impact on cV assembly since TMEM70 mutations have been associated with isolated cV activity reduction. We detected a clear cV biochemical defect in TMEM70 patients' fibroblasts, whereas the assay was not reliable in frozen muscle. Nevertheless, the evaluation of the amount of holocomplexes in patients with TMEM70 mutations showed a nearly absent cV in muscles and a strong decrease of cV with accumulation of sub-assembly species in fibroblasts. In our cohort we found not only cV deficiencies but also impairment of other OXPHOS complexes. By ultrastructural analysis of muscle tissue from one patient with isolated cV deficiency, we found a severely impaired mitochondrial morphology with loss of the cristae. These findings indicate that cV impairment could indirectly alter other respiratory chain complex activities by disrupting the mitochondrial cristae structure.
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BACKGROUND: X-linked Ornithine Transcarbamylase deficiency (OTCD) is often unrecognized in adults, as clinical manifestations are non-specific, often episodic and unmasked by precipitants, and laboratory findings can be normal outside the acute phase. It may thus be associated with significant mortality if not promptly recognized and treated. The aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations. METHODS: We carried out a clinical, biochemical and molecular study on five unrelated adult patients (one female and four males) with late onset OTCD, who presented to the Emergency Department (ED) with initial fatal encephalopathy. The molecular study consisted of OTC gene sequencing in the probands and family members and in silico characterization of the newly detected mutations. RESULTS: We identified two new, c.119G>T (p.Arg40Leu) and c.314G>A (p.Gly105Glu), and three known OTC mutations. Both new mutations were predicted to cause a structural destabilization, correlating with late onset OTCD. We also identified, among the family members, 8 heterozygous females and 2 hemizygous asymptomatic males. Patients' histories revealed potential environmental triggering factors, including steroid treatment, chemotherapy, diet changes and hormone therapy for in vitro fertilization. CONCLUSIONS: This report raises awareness of the ED medical staff in considering OTCD in the differential diagnosis of sudden neurological and behavioural disorders associated with hyperammonemia at any age and in both genders. It also widens the knowledge about combined effect of genetic and environmental factors in determining the phenotypic expression of OTCD.
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Mutação , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Ornitina Carbamoiltransferase/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Doença da Deficiência de Ornitina Carbomoiltransferase/terapiaRESUMO
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disorder of fatty acid oxidation characterized by hypoglycemic crisis under fasting or during stress conditions, leading to lethargy, seizures, brain damage, or even death. Biochemical acylcarnitines data obtained through newborn screening by liquid chromatography-tandem mass spectrometry (LC-MS/MS) were confirmed by molecular analysis of the medium-chain acyl-CoA dehydrogenase (ACADM) gene. Out of 324.000 newborns screened, we identified 14 MCADD patients, in whom, by molecular analysis, we found a new nonsense c.823G>T (p.Gly275∗) and two new missense mutations: c.253G>C (p.Gly85Arg) and c.356T>A (p.Val119Asp). Bioinformatics predictions based on both phylogenetic conservation and functional/structural software were used to characterize the new identified variants. Our findings confirm the rising incidence of MCADD whose existence is increasingly recognized due to the efficacy of an expanded newborn screening panel by LC-MS/MS making possible early specific therapies that can prevent possible crises in at-risk infants. We noticed that the "common" p.Lys329Glu mutation only accounted for 32% of the defective alleles, while, in clinically diagnosed patients, this mutation accounted for 90% of defective alleles. Unclassified variants (UVs or VUSs) are especially critical when considering screening programs. The functional and pathogenic characterization of genetic variants presented here is required to predict their medical consequences in newborns.
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Acil-CoA Desidrogenase/deficiência , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Testes Genéticos/estatística & dados numéricos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Triagem Neonatal/métodos , Modelos de Riscos Proporcionais , Acil-CoA Desidrogenase/genética , Feminino , Humanos , Incidência , Recém-Nascido , Itália/epidemiologia , Erros Inatos do Metabolismo Lipídico/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Oxidative stress (OS) is significantly involved in the development of several complications associated with preterm birth, such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) and intraventricular hemorrhage (IVH). Evidence is growing about the associations between single nucleotide polymorphisms (SNPs) in genes involved in OS or antioxidant response and the occurrence of neonatal morbidities. AIM OF THE STUDY: To assess whether SNPs in genes of superoxide dismutase (SOD) and catalase (CAT), involved in antioxidant pathways, correlate with the occurrence of RDS, BPD, IVH and ROP in preterm neonates. METHODS: We performed a retrospective study involving neonates <28 weeks of gestational age. RESULTS: We demonstrated that rs8192287 SOD3 polymorphism is an independent protective factor for IVH, while rs4880 and rs5746136 SOD2 polymorphisms are associated with lower gestational age and birth weight. Haplotypes reconstruction showed that SOD1 (GG) decreased the risk of RDS, IVH and ROP; SOD2 (GT) increased the risk of BPD and decreased the risk of RDS, IVH, and ROP; SOD3 (TGC) decreased the risk of BPD and IVH; and CAT (CTC) decreased the risk of RDS. CONCLUSIONS: The study of SNPs or haplotypes reconstruction in genes involved in OS or scavenging activity may be helpful in identifying preterm newborns with a particularly high risk of morbidities, who may benefit from specific prevention strategies.
Assuntos
Antioxidantes , Enzimas/genética , Recém-Nascido Prematuro , Polimorfismo Genético , Nascimento Prematuro/genética , Adulto , Antioxidantes/metabolismo , Catalase/genética , Catalase/metabolismo , Enzimas/metabolismo , Humanos , Recém-Nascido , Recém-Nascido Prematuro/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Polimorfismo Genético/fisiologia , Nascimento Prematuro/enzimologia , Nascimento Prematuro/metabolismo , Estudos Retrospectivos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1RESUMO
We aimed to identify specific polymorphisms of genes encoding for superoxide dismutase (SOD) 1 (cytoplasmic Cu/ZnSOD), SOD2 (mitochondrial MnSOD), SOD3 (extracellular Cu/ZnSOD) and CAT in a cohort of preterm infants and correlate their presence to the development of respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH) and retinopathy of prematurity (ROP). We carried out a retrospective study to evaluate the allele frequency and the genotype distribution of polymorphisms of SODs and CAT in a population of preterm neonates (n = 152) with a gestational age ≤ 28 weeks according to the presence or absence of RDS, BPD, IVH and ROP. Moreover, we evaluated through the haplotype reconstruction analysis whether combinations of the selected polymorphisms are related to the occurrence of RDS, BPD, IVH and ROP. We found that rs8192287 SOD3 polymorphism is an independent protective factor for all grade IVH, while rs4880 and rs5746136 SOD2 polymorphisms are associated with a lower gestational age (rs4880, rs5746136) and birth weight (rs4880). Haplotypes reconstruction showed that SOD1 (GG) decreased the risk of RDS, IVH and ROP; SOD2 (GT) increased the risk of BPD and decreased the risk of RDS, IVH and ROP; SOD3 (TGC) decreased the risk of BPD and IVH; and 4) CAT (CTC) decreased the risk of RDS. The rs8192287 SOD3 polymorphism is per se an independent predictor of a decreased risk of developing IVH. Different SOD2 polymorphisms are associated per se with a lower gestational age and/or birth weight, and haplotypes of SOD1, SOD3 and CAT genes may be independent protecting or risk markers for prematurity complications.