Assuntos
Mutação , Piruvato Desidrogenase (Lipoamida) , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Acidente Vascular Cerebral , Feminino , Humanos , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Acidente Vascular Cerebral/genética , CriançaRESUMO
BACKGROUND: the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. METHODS: we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. RESULTS: molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. CONCLUSIONS: our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.
Assuntos
Homocistinúria , Metilenotetra-Hidrofolato Redutase (NADPH2) , Humanos , Recém-Nascido , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Homocistinúria/diagnóstico , Homocistinúria/genética , Testes Genéticos , Diagnóstico PrecoceAssuntos
Epilepsia , Deficiência Intelectual , Criança , Epilepsia/diagnóstico , Epilepsia/genética , GTP Fosfo-Hidrolases/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Convulsões , Deleção de SequênciaRESUMO
Multiple Sulfatase Deficiency (MSD) is an inborn error of metabolism caused by pathogenic variants in the SUMF1 gene encoding the formylglycine-generating enzyme (FGE) that activates all known sulfatases. FGE deficiency results in widespread tissue accumulation of multiple sulphated substrates. Through a systematic analysis of published cases, we retrieved 80 MSD cases and reviewed the disease clinical, biochemical, and genetic findings. Leukodystrophy, neurosensorial hearing loss, and ichthyosis were the most frequent findings at diagnosis. Of 51 reported pathogenic variants, 20 were likely gene disruptive and the remaining were missense variants. No correlations between class of variants and clinical severity or degree of enzyme deficiency were detected. However, cases harboring variants located at N-terminal always had severe neonatal presentations. Moreover, cases with neonatal onset showed the lowest overall survival rate compared to late-infantile and juvenile onsets. Using GnomAD, carrier frequency for pathogenic SUMF1 variants was estimated to be ~1/700 and the disease prevalence was approximately 1/2,000,000. In summary, MSD is an ultra-rare multisystem disorder with mainly neurologic, hearing and skin involvements. Although the collected data were retrospective and heterogenous, the quantitative data inform the disease natural history and are important for both counseling and design of future interventional studies.
Assuntos
Doença da Deficiência de Múltiplas Sulfatases/diagnóstico , Mutação , Sulfatases/deficiência , Sulfatases/genética , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Doença da Deficiência de Múltiplas Sulfatases/enzimologia , Doença da Deficiência de Múltiplas Sulfatases/genética , Prognóstico , Taxa de Sobrevida , Revisões Sistemáticas como AssuntoRESUMO
Biallelic variants in nuclear gene NDUFA2 have been reported so far in only three children with variable presentations including Leigh syndrome or leukoencephalopathy. Herein, we report a further female child affected by NDUFA2-related disorder presenting with cavitating and tigroid-like pattern of leukodystrophy and without systemic biochemical abnormalities of mitochondrial disorders.
RESUMO
Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties. Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left-convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss-of-function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra- and extra-dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi-cystic kidney disease.
Assuntos
Anormalidades Múltiplas/genética , Cardiopatias Congênitas/genética , Meningocele/genética , Receptor Notch3/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Éxons/genética , Feminino , Predisposição Genética para Doença , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Meningocele/diagnóstico por imagem , Meningocele/fisiopatologia , Fenótipo , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologia , Sequenciamento do ExomaRESUMO
Interstitial deletions of 16q chromosome including 16q12.1q21 region are very rare, with only three cases reported to date. Main clinical features include dysmorphisms, short stature, microcephaly, eye abnormalities, epilepsy, development delay, intellectual disability, and autism spectrum disorder. We report two independent subjects with 16q12.1q21 deletion syndrome presenting with dysmorphic facial features, developmental delay, strabismus, and aggressive behavior. A minimal region of overlap spanning 1.7 Mb on chromosome 16, including IRX5, GNAO1, and NUDT21 genes was shared among these two cases and those previously reported. This minimal region of overlap suggests the potential pathogenic role of these genes, previously implicated in diseases of the central nervous system.
Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 16/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Criança , Transtornos Cromossômicos/patologia , Fator de Especificidade de Clivagem e Poliadenilação/genética , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Proteínas de Homeodomínio/genética , Humanos , Masculino , Síndrome , Fatores de Transcrição/genéticaRESUMO
We identified a 14q21.2 microdeletion in a 16-year-old boy with autism spectrum disorder (ASD), IQ in the lower part of normal range but high-functioning memory skills. The deletion affects a gene desert, and the non-deleted gene closest to the microdeletion boundaries is LRFN5, which encodes a protein involved in synaptic plasticity and implicated in neuro-psychiatric disorders. LRFN5 expression was significantly decreased in the proband's skin fibroblasts. The deleted region includes the pseudogene chr14.232.a, which is transcribed into a long non-coding RNA (lncLRFN5-10), whose levels were also significantly reduced in the proband's fibroblasts compared to controls. Transfection of the patient's fibroblasts with a plasmid expressing chr14.232.a significantly increased LRFN5 expression, while siRNA targeting chr14.232.a-derived lncLRFN5-10 reduced LRFN5 levels. In summary, we report on an individual with ASD carrying a microdeletion encompassing the pseudogene chr14.232.a encoding for lncLRFN5-10, which was found to affect the expression levels of the nearby, non-deleted LRFN5. This case illustrates the potential role of long non-coding RNAs in regulating expression of neighbouring genes with a functional role in ASD pathogenesis.
Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Deleção Cromossômica , Cromossomos Humanos Par 14 , Expressão Gênica , Glicoproteínas de Membrana/genética , Pseudogenes , Adolescente , Fibroblastos/metabolismo , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Pele/citologia , Sequenciamento do ExomaAssuntos
Transtornos do Neurodesenvolvimento/epidemiologia , Síndrome de Rett/diagnóstico , Síndrome de Rett/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Inquéritos e Questionários , Adolescente , Adulto , Distribuição por Idade , Análise de Variância , Criança , Pré-Escolar , Comorbidade , Feminino , Hospitais Universitários , Humanos , Incidência , Itália , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Dor/diagnóstico , Dor/epidemiologia , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Transtornos do Sono-Vigília/diagnóstico , Estatísticas não Paramétricas , Adulto JovemRESUMO
Myhre syndrome is a rare autosomal dominant disorder caused by a narrow spectrum of missense mutations in the SMAD4 gene. Typical features of this disorder are distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, short hands and feet, compact build, joint stiffness, and skeletal anomalies. The clinical features generally appear during childhood and become more evident in older patients. Therefore, the diagnosis of this syndrome in the first years of life is challenging. We report a 2-year-old girl diagnosed with Myhre syndrome by whole exome sequencing (WES) that revealed the recurrent p.Ile500Val mutation in the SMAD4 gene. Our patient presented with growth deficiency, dysmorphic features, tetralogy of Fallot, and corectopia (also known as ectopia pupillae). The girl we described is the youngest patient with Myhre syndrome. Moreover, corectopia and tetralogy of Fallot have not been previously reported in this disorder.
Assuntos
Criptorquidismo/genética , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Distúrbios Pupilares/genética , Proteína Smad4/genética , Tetralogia de Fallot/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Pré-Escolar , Criptorquidismo/complicações , Criptorquidismo/fisiopatologia , Fácies , Feminino , Transtornos do Crescimento/complicações , Transtornos do Crescimento/fisiopatologia , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Mutação , Fenótipo , Distúrbios Pupilares/fisiopatologia , Tetralogia de Fallot/complicações , Tetralogia de Fallot/fisiopatologia , Sequenciamento do ExomaRESUMO
Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.
Assuntos
Biomarcadores/metabolismo , Dieta Cetogênica , Proteínas de Transporte de Monossacarídeos/deficiência , Erros Inatos do Metabolismo dos Carboidratos , Metabolismo Energético , Ácidos Graxos/metabolismo , Humanos , Metabolômica , Proteínas de Transporte de Monossacarídeos/química , FenótipoRESUMO
Post-zygotic activating mutations in PIK3CA and other genes encoding members of PI3K-AKT-mTOR pathway have been found in various overgrowth syndromes that have been grouped together as PIK3CA-related overgrowth spectrum (PROS). We report a female patient with gait disturbance, leg pain, isolated macrodactyly of the foot, and mild intellectual disability. Imaging of the lower limb showed a lipoblastoma of the right thigh. A mosaic gain-of-function mutation in the catalytic domain of PIK3CA (c.3140 A > G; p.His1047Arg) was detected in the adipose tissue and in skin cultured fibroblasts from the macrodactyly but not in blood. The leg pain and the severe walking disturbance improved slightly over time and serial MRI of the lower limbs suggested that the size of the lipoblastoma relative to the lower limb muscles or to the whole lower limb was unchanged as consequence of limb growth. This case report illustrates that pain and gait disturbance can be features of PROS and highlights the need of better knowledge about the natural history of the disease.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Dedos/anormalidades , Marcha , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Lipoblastoma/genética , Extremidade Inferior/patologia , Células Cultivadas , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Fibroblastos/metabolismo , Mutação com Ganho de Função , Humanos , Deficiência Intelectual/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Lipoblastoma/diagnóstico , Extremidade Inferior/diagnóstico por imagem , SíndromeRESUMO
The gene DST encodes for the large protein BPAG1 involved in hemidesmosomes. Its alternative splicing gives rise to tissue-enriched isoforms in brain, muscle, and skin. The few patients described so far with bi-allelic mutations in the DST gene have either a skin phenotype of epidermolysis bullosa simplex or a neurological phenotype. Here, we report a 17-year-old female individual presenting with a more complex phenotype consisting of both skin and neuronal involvement, in addition to several previously unreported findings, such as iris heterochromia, cataract, hearing impairment, syringomyelia, behavioral, and gastrointestinal issues, osteoporosis, and growth hormone deficiency. Family-trio whole exome sequencing revealed that she was a compound heterozygous for two variants in the DST gene with highly-predicted functional impact, c.3886A>G (p.R1296X) in exon 29 and c.806C>T (p.H269R) in exon 7. Interestingly, exon 7 is included in the neuronal isoform whereas exon 29 is expressed in both skin and neuronal isoforms. The patient we described is the first case with a mutation affecting an exon expressed in both the neuronal and skin isoforms that can explain the more complex phenotype compared to previously reported cases.