RESUMO
BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid disorder. Affected patients often remain undiagnosed until the age of 20-30 years, when they have already developed significant neurologic disease that may not be reversible. An elevated plasma cholestanol concentration has been accepted as a diagnostic criterion for CTX for decades. OBJECTIVE: Full biochemical characterization was performed for three genetically and clinically confirmed atypical CTX cases with normal plasma cholestanol levels. METHODS: Clinical assessment and genetic/biochemical testing for patients with CTX was performed by their physician providing routine standard of care. RESULTS: We report three new atypical CTX cases with large extensor tendon xanthomas but normal plasma cholestanol levels. All three cases had marked elevations of bile acid precursors and bile alcohols in plasma and urine that decreased on treatment with chenodeoxycholic acid. We also review eight published cases of atypical CTX with normal/near normal circulating cholestanol levels. CONCLUSION: The atypical biochemical presentation of these cases provides a diagnostic challenge for CTX, a disorder for which cholestanol has been believed to be a sensitive biomarker. These cases demonstrate measurements of plasma cholestanol alone are insufficient to exclude a diagnosis of CTX. The data presented is consistent with the concept that bile acid precursors and bile alcohols are sensitive biomarkers for atypical CTX with normal cholestanol, and that such testing is indicated, along with CYP27A1 gene analyses, in patients presenting with significant tendon and/or tuberous xanthomas and/or neurologic disease in early adulthood despite normal or near normal cholesterol and cholestanol levels.
Assuntos
Ácidos e Sais Biliares , Colestanol , Xantomatose Cerebrotendinosa , Humanos , Xantomatose Cerebrotendinosa/genética , Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/sangue , Colestanol/sangue , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/metabolismo , Masculino , Adulto , Feminino , Ácido Quenodesoxicólico/uso terapêutico , Adulto Jovem , Colestanóis/sangueRESUMO
The NFIX gene encodes a DNA-binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall-Smith syndrome (MIM 602535), which are clinically distinct due to different disease-causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N-terminal DNA binding and dimerization domain or are protein-truncating variants that trigger nonsense-mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall-Smith syndrome are protein-truncating and are clustered between exons 6 and 10, including a recurrent Alu-mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall-Smith syndrome is likely due to a dominant-negative effect of these protein-truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon-level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.
Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Anormalidades Craniofaciais , Deficiência Intelectual , Megalencefalia , Displasia Septo-Óptica , Síndrome de Sotos , Criança , Humanos , Fatores de Transcrição NFI/genética , Síndrome de Sotos/genética , Éxons/genética , Megalencefalia/genética , Deficiência Intelectual/genética , Análise de Sequência de RNARESUMO
In this article, patients with cerebrotendinous xanthomatosis (CTX) and caregivers detail their experience with lifelong symptoms, diagnosis, treatment and efficacy, and ongoing disease management. One patient and four caregivers describe the challenges associated with pursuing a correct diagnosis for years before testing confirmed a CTX diagnosis. They also detail their ongoing struggles and desire for greater access to physicians with CTX knowledge and to reliable online resources to continue their education about the disease and strategies for symptom management. The expert perspective is a direct response by three CTX researchers, including physicians who are treating patients with CTX in the United States and experts whose laboratories provide genetic and biochemical testing for CTX. They respond to many of the patient and caregiver concerns, including steps that are being taken to identify CTX earlier and provide access to confirmatory diagnostic testing sooner, and suggest the best online resources for CTX-related information and access to webinars and support groups. While the expert perspective is a direct response to the patient and caregiver authors' CTX journeys, it should be beneficial to any patient with CTX or their caregivers.
Assuntos
Xantomatose Cerebrotendinosa , Humanos , Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/complicações , Xantomatose Cerebrotendinosa/genética , Cuidadores , Colestanotriol 26-Mono-Oxigenase/genéticaRESUMO
Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient's primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis.
Assuntos
Cirrose Hepática , Proteínas Supressoras de Tumor , Adulto , Animais , Criança , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Síndrome , Proteínas Supressoras de Tumor/genética , Peixe-Zebra/genéticaRESUMO
Heterozygous de novo missense pathogenic variants in PTDSS1 that result in gain-of-function of phosphatidylserine synthase 1 are associated with Lenz-Majewski hyperostotic dwarfism (LMHD). We identified the novel heterozygous de novo variant p.(Leu137Phe) in PTDSS1 in a child with mild-to-moderate developmental delay. Skeletal survey revealed no evidence of LMHD in this patient. Functional assessment of the p.Leu137Phe variant was performed by overexpressing the mutant protein into HEK293 cells. Following C14 -serine labeling and TLC analysis of lipids, we observed that the p.(Leu137Phe) variant displayed no catalytic activity compared to the wild-type enzyme. We conclude that p.(Leu137Phe) variant has decreased enzymatic activity and that is likely to be the etiology of the patient's symptoms given the gene's constraint in the population. This is the first report of the clinical phenotype seen in an individual with a heterozygous loss-of-function variant in PTDSS1. This phenotype is distinct from LMHD, which results from gain-of-function pathogenic variants in the same gene. Evaluation of the neurodevelopmental phenotype of additional individuals with loss-of-function variants in PTDSS1 is indicated to determine the spectrum of associated phenotypes.
Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Células HEK293 , Humanos , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , FenótipoRESUMO
De novo pathogenic variants in CHAMP1 (chromosome alignment maintaining phosphoprotein 1), which encodes kinetochore-microtubule associated protein on 13q34, cause a rare neurodevelopmental disorder. We enrolled 14 individuals with pathogenic variants in CHAMP1 that were documented by exome sequencing or gene panel sequencing. Medical history interviews, seizure surveys, Vineland Adapted Behavior Scales Second Edition, and other behavioral surveys were completed by primary caregivers of available participants in Simons Searchlight. Clinicians extracted clinical data from the medical record for two participants. We report on clinical features of 14 individuals (ages 2-26) with de novo predicted loss-of-function variants in CHAMP1 and compare them with previously reported cases (total n = 32). At least two individuals have the same de novo variant: p.(Ser181Cysfs*5), p.(Trp348*), p.(Arg398*), p.(Arg497*), or p.(Tyr709*). Common phenotypes include intellectual disability/developmental delay, language impairment, congenital and acquired microcephaly, behavioral problems including autism spectrum disorder, seizures, hypotonia, gastrointestinal issues of reflux and constipation, and ophthalmologic issues. Other rarely observed phenotypes include leukemia, failure to thrive, and high pain tolerance. Pathogenic variants in CHAMP1 are associated with a variable clinical phenotype of developmental delay/intellectual disability and seizures.
Assuntos
Proteínas Cromossômicas não Histona/genética , Mutação com Perda de Função , Transtornos do Neurodesenvolvimento/genética , Fosfoproteínas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Leucemia/genética , Masculino , Transtornos do Neurodesenvolvimento/fisiopatologia , Testes Neuropsicológicos , Fenótipo , Adulto JovemRESUMO
INTRODUCTION: Mucolipidosis type II (MLII) is a lysosomal storage disease causing systemic deposition of mucopolysaccharides. We describe imaging and bronchoscopy findings not previously reported in the literature in a child with MLII. CASE: A 9-year-old with MLII s/p hematopoietic stem-cell transplant (HSCT), bronchiectasis, and aspiration presented with recurrent respiratory illnesses. Bronchoscopy and chest computed tomography were performed, showing a saber-sheath trachea with fixed narrowing and curvature. DISCUSSION: This case describes potentially life-threatening airway distortion in MLII despite HSCT that cannot be ameliorated with tracheostomy. Etiology is unknown but likely due to abnormal deposition causing an immobile, stenotic airway and restricted thorax.
Assuntos
Bronquiectasia/diagnóstico por imagem , Mucolipidoses/diagnóstico por imagem , Traqueia/diagnóstico por imagem , Broncoscopia , Criança , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Mucolipidoses/terapia , Tomografia Computadorizada por Raios XRESUMO
Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging. She died shortly after. Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.
Assuntos
Sulfeto de Hidrogênio/metabolismo , Doença de Leigh/enzimologia , Mitocôndrias/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Quinona Redutases/fisiologia , Acidose Láctica/patologia , Encefalopatias/patologia , Pré-Escolar , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Família , Feminino , Homozigoto , Humanos , Sulfeto de Hidrogênio/química , Cinética , Doença de Leigh/metabolismo , Imageamento por Ressonância Magnética , Masculino , Oxirredução , Quinona Redutases/químicaRESUMO
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal disorder characterized by progressive gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, skeletal myopathy, ophthalmoparesis, and ptosis. MNGIE stems from deficient thymidine phosphorylase activity (TP) leading to toxic elevations of plasma thymidine. Hematopoietic stem cell transplant (HSCT) restores TP activity and halts disease progression but has high transplant-related morbidity and mortality. Liver transplant (LT) was reported to restore TP activity in two adult MNGIE patients. We report successful LT in four additional MNGIE patients, including a pediatric patient. Our patients were diagnosed between ages 14 months and 36 years with elevated thymidine levels and biallelic pathogenic variants in TYMP. Two patients presented with progressive gastrointestinal dysmotility, and three demonstrated progressive peripheral neuropathy with two suffering limitations in ambulation. Two patients, including the child, had liver dysfunction and cirrhosis. Following LT, thymidine levels nearly normalized in all four patients and remained low for the duration of follow-up. Disease symptoms stabilized in all patients, with some manifesting improvements, including intestinal function. No patient died, and LT appeared to have a more favorable safety profile than HSCT, especially when liver disease is present. Follow-up studies will need to document the long-term impact of this new approach on disease outcome. Take Home Message: Liver transplantation is effective in stabilizing symptoms and nearly normalizing thymidine levels in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and may have an improved safety profile over hematopoietic stem cell transplant.
Assuntos
Transplante de Fígado/métodos , Mitocôndrias/metabolismo , Encefalomiopatias Mitocondriais/terapia , Timidina Fosforilase/genética , Adolescente , Adulto , Transtornos da Motilidade Esofágica/genética , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Transplante de Fígado/mortalidade , Imageamento por Ressonância Magnética , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Encefalomiopatias Mitocondriais/diagnóstico por imagem , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/fisiopatologia , Doenças do Sistema Nervoso Periférico/genética , Timidina/sangue , Sequenciamento do ExomaRESUMO
LONP1 is an ATP-dependent protease and chaperone that plays multiple vital roles in mitochondria. LONP1 is essential for mitochondrial homeostasis due to its role in maintenance of the mitochondrial genome and its central role in regulating mitochondrial processes such as oxidative phosphorylation, mitophagy, and heme biosynthesis. Bi-allelic LONP1 mutations have been reported to cause a constellation of clinical presentations. We report a patient heterozygous for a de novo mutation in LONP1: c.901C>T,p.R301W presenting as a neonate with seizures, encephalopathy, pachygyria and microcephaly. Assays of respiratory chain activity in muscle showed complex II-III function at 8% of control. Functional studies in patient fibroblasts showed a signature of dysfunction that included significant decreases in known proteolytic targets of LONP1 (TFAM, PINK1, phospho-PDH E1α) as well as loss of mitochondrial ribosome subunits MRPL44 and MRPL11 with concomitant decreased activity and level of protein subunits of oxidative phosphorylation complexes I and IV. These results indicate excessive LONP1 proteolytic activity and a loss of LONP1 chaperone activity. Further, we demonstrate that the LONP1 N-terminal domain is involved in hexamer stability of LONP1 and that the ability to make conformational changes is necessary for LONP1 to regulate proper functioning of both its proteolytic and chaperone activities.
Assuntos
Proteases Dependentes de ATP/genética , Mitocôndrias/patologia , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Chaperonas Moleculares/genética , Proteólise , Transporte de Elétrons/genética , Transporte de Elétrons/fisiologia , Feminino , Heme/biossíntese , Humanos , Recém-Nascido , Mitocôndrias/genética , Mitofagia/genética , Fosforilação Oxidativa , Convulsões/genéticaRESUMO
Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).
Assuntos
Proteínas de Membrana Transportadoras/genética , Mutagênese Insercional , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética , Oligonucleotídeos Antissenso/uso terapêutico , Medicina de Precisão , Doenças Raras/tratamento farmacológico , Biópsia , Criança , Desenvolvimento Infantil , Descoberta de Drogas , Drogas em Investigação/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Testes Neuropsicológicos , RNA Mensageiro , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Pele/patologia , Sequenciamento Completo do GenomaRESUMO
Proteoglycans are among the most abundant and structurally complex biomacromolecules and play critical roles in connective tissues. They are composed of a core protein onto which glycosaminoglycan (GAG) side chains are attached via a linker region. Biallelic mutations in B3GALT6, encoding one of the linker region glycosyltransferases, are known to cause either spondyloepimetaphyseal dysplasia (SEMD) or a severe pleiotropic form of Ehlers-Danlos syndromes (EDS). This study provides clinical, molecular and biochemical data on 12 patients with biallelic B3GALT6 mutations. Notably, all patients have features of both EDS and SEMD. In addition, some patients have severe and potential life-threatening complications such as aortic dilatation and aneurysm, cervical spine instability and respiratory insufficiency. Whole-exome sequencing, next generation panel sequencing and direct sequencing identified biallelic B3GALT6 mutations in all patients. We show that these mutations reduce the amount of ß3GalT6 protein and lead to a complete loss of galactosyltransferase activity. In turn, this leads to deficient GAG synthesis, and ultrastructural abnormalities in collagen fibril organization. In conclusion, this study redefines the phenotype associated with B3GALT6 mutations on the basis of clinical, molecular and biochemical data in 12 patients, and provides an in-depth assessment of ß3GalT6 activity and GAG synthesis to better understand this rare condition.
Assuntos
Síndrome de Ehlers-Danlos/genética , Sequenciamento do Exoma , Galactosiltransferases/genética , Mutação , Fenótipo , Adulto , Criança , Pré-Escolar , Síndrome de Ehlers-Danlos/enzimologia , Síndrome de Ehlers-Danlos/patologia , Ensaios Enzimáticos , Feminino , Galactosiltransferases/metabolismo , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , MasculinoRESUMO
BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.
Assuntos
Alquil e Aril Transferases/genética , Ataxia/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Síndrome Nefrótica/terapia , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Ataxia/complicações , Ataxia/diagnóstico , Ataxia/genética , Biópsia , Criança , Pré-Escolar , Testes Genéticos , Humanos , Rim/patologia , Transplante de Rim , Masculino , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Debilidade Muscular/complicações , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Síndrome Nefrótica/sangue , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologia , Resultado do Tratamento , Ubiquinona/administração & dosagem , Ubiquinona/genéticaRESUMO
Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.
Assuntos
Domínio Catalítico/genética , Metaloendopeptidases/genética , Mutação/genética , Degeneração Neural/genética , Criança , Pré-Escolar , Derme/patologia , Transporte de Elétrons , Feminino , Fibroblastos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas Ferro-Enxofre/genética , Imageamento por Ressonância Magnética , Masculino , Mitocôndrias/metabolismo , Linhagem , Proto-Oncogene Mas , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Peptidase de Processamento MitocondrialRESUMO
Cerebrotendinous xanthomatosis (CTX) is an inborn error of metabolism leading to progressive multisystem disease. Symptoms often begin in the first decade of life with chronic diarrhea, cataracts, developmental delay, intellectual disability, and cerebellar or pyramidal dysfunction. Later manifestations include tendon xanthomas, polyneuropathy, and abnormal neuroimaging. Pathogenic biallelic variants in CYP27A1 leading to compromised function of sterol 27-hydroxylase result in accumulation of detectable toxic intermediates of bile acid synthesis rendering both genetic and biochemical testing effective diagnostic tools. Effective treatment with chenodeoxycholic acid is available, making early diagnosis critical for patient care. Here we report a new patient with CTX and describe the early signs of disease in this patient. Initial symptoms included infantile spasms, which have not previously been reported in CTX. Developmental delay, mild intellectual disability with measured cognitive decline in childhood, was also observed. These clinical signs do not traditionally compel testing for CTX, and we highlight the need to consider this rare but treatable disorder among the differential diagnosis of children with similar clinical presentation. Increased awareness of early signs of CTX is important for improving time to diagnosis for this patient population.
RESUMO
In recent decades, dozens of genes that cause isolated and combined pituitary hormone deficiencies have been discovered. We will review the clinically relevant genes known to cause isolated and combined pituitary hormone deficiencies in humans. This review will address genetic causes of adrenocorticotropic hormone deficiency, thyroid stimulating hormone deficiency, growth hormone deficiency, hypogonadotropic hypogonadism, and diabetes insipidus. Additionally, we will discuss genetic causes of combined pituitary hormone deficiency, septo-optic dysplasia, holoprosencephaly, and multisystemic syndromes in which hypopituitarism is a significant component. With the widespread clinical availability of next generation sequencing and ongoing identification of new disease causing genes, genetic diagnoses are determined for increasing numbers of patients. With new insights into mechanisms of disease resulting from multiple gene interactions, an increasingly nuanced understanding of the underlying genetic etiology of pituitary hormone deficiencies is possible.
Assuntos
Hipopituitarismo/genética , Insuficiência Adrenal/genética , Diabetes Insípido/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Holoprosencefalia/genética , Hormônio do Crescimento Humano/deficiência , Humanos , Hipogonadismo/genética , Masculino , Mutação , Fenótipo , Tireotropina/deficiênciaRESUMO
Topical anesthetics are commonly used in many health care settings and for many clinical conditions. However, there are a number of potential adverse effects associated with their use. Their widespread administration can convey a false sense of security and failure to appreciate possible complications. We present the case of an infant with extensive vascular malformations treated with EMLA cream who developed seizures and methemoglobinemia from lidocaine and prilocaine toxicity. We describe the pathophysiology of these morbidities, the use of pulse oximetry in this setting, and the clinical presentation and treatment of methemoglobinemia.