RESUMEN
BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood-brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles. METHODS: Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. RESULTS: No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist-C when subjects were taking simvastatin. CONCLUSION: This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol-to-total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS.Genet Med 19 3, 297-305.
Asunto(s)
Simvastatina/uso terapéutico , Síndrome de Smith-Lemli-Opitz/tratamiento farmacológico , Adolescente , Alelos , Niño , Preescolar , Colesterol , Estudios Cruzados , Deshidrocolesteroles/sangre , Método Doble Ciego , Femenino , Humanos , Masculino , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/líquido cefalorraquídeo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Placebos , Simvastatina/efectos adversos , Síndrome de Smith-Lemli-Opitz/sangre , Síndrome de Smith-Lemli-Opitz/líquido cefalorraquídeo , Síndrome de Smith-Lemli-Opitz/genéticaRESUMEN
We previously reported a mutation in the cholesterol biosynthesis gene, hydroxysteroid (17-beta) dehydrogenase 7 (Hsd17b7(rudolph)), that results in striking embryonic forebrain dysgenesis. Here we describe abnormal patterns of neuroprogenitor proliferation in the mutant forebrain, namely, a decrease in mitotic cells within the ventricular zone (VZ) and an increase through the remainder of the cortex by E11.5. Further evidence suggests mutant cells undergo abnormal interkinetic nuclear migration (IKNM). Furthermore, intermediate progenitors are increased at the expense of apical progenitors by E12.5, and post-mitotic neurons are expanded by E14.5. In vitro primary neuron culture further supports our model of accelerated cortical differentiation in the mutant. Combined administration of a statin and dietary cholesterol in utero achieved partial reversal of multiple developmental abnormalities in the Hsd17b7(rudolph) embryo, including the forebrain. These results suggest that abnormally increased levels of specific cholesterol precursors in the Hsd17b7(rudolph) embryo cause cortical dysgenesis by altering patterns of neurogenesis.
Asunto(s)
Colesterol/biosíntesis , Neurogénesis/fisiología , Neuronas/metabolismo , Prosencéfalo/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Embrión de Mamíferos/metabolismo , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis/genética , Prosencéfalo/crecimiento & desarrolloRESUMEN
Mutations of both nuclear and mitochondrial DNA (mtDNA)-encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.523delC, p.Q175RfsX38), which codes for the heart-muscle isoform of the adenine nucleotide translocator-1. Ten homozygous null (adenine nucleotide translocator-1(-/-)) patients monitored over a median of 6 years had a phenotype of progressive myocardial thickening, hyperalaninemia, lactic acidosis, exercise intolerance, and persistent adrenergic activation. Electrocardiography and echocardiography with velocity vector imaging revealed abnormal contractile mechanics, myocardial repolarization abnormalities, and impaired left ventricular relaxation. End-stage heart disease was characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. Substantial variability in the progression and severity of heart disease segregated with maternal lineage, and sequencing of mtDNA from five maternal lineages revealed two major European haplogroups, U and H. Patients with the haplogroup U mtDNAs had more rapid and severe cardiomyopathy than those with haplogroup H.
Asunto(s)
Translocador 1 del Nucleótido Adenina/deficiencia , Translocador 1 del Nucleótido Adenina/genética , Cardiomiopatías/genética , Cardiomiopatías/patología , ADN Mitocondrial/genética , Haplotipos/genética , Adolescente , Cardiomiopatías/fisiopatología , Progresión de la Enfermedad , Femenino , Homocigoto , Humanos , Masculino , Mutación , Miocardio/patología , Miocardio/ultraestructura , LinajeRESUMEN
Ubiquitination plays a crucial role in neurodevelopment as exemplified by Angelman syndrome, which is caused by genetic alterations of the ubiquitin ligase-encoding UBE3A gene. Although the function of UBE3A has been widely studied, little is known about its paralog UBE3B. By using exome and capillary sequencing, we here identify biallelic UBE3B mutations in four patients from three unrelated families presenting an autosomal-recessive blepharophimosis-ptosis-intellectual-disability syndrome characterized by developmental delay, growth retardation with a small head circumference, facial dysmorphisms, and low cholesterol levels. UBE3B encodes an uncharacterized E3 ubiquitin ligase. The identified UBE3B variants include one frameshift and two splice-site mutations as well as a missense substitution affecting the highly conserved HECT domain. Disruption of mouse Ube3b leads to reduced viability and recapitulates key aspects of the human disorder, such as reduced weight and brain size and a downregulation of cholesterol synthesis. We establish that the probable Caenorhabditis elegans ortholog of UBE3B, oxi-1, functions in the ubiquitin/proteasome system in vivo and is especially required under oxidative stress conditions. Our data reveal the pleiotropic effects of UBE3B deficiency and reinforce the physiological importance of ubiquitination in neuronal development and function in mammals.
Asunto(s)
Blefarofimosis/genética , Blefaroptosis/genética , Discapacidad Intelectual/genética , Ubiquitina-Proteína Ligasas/genética , Alelos , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Blefarofimosis/diagnóstico , Blefaroptosis/diagnóstico , Encéfalo/patología , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Sistema Nervioso Central , Niño , Preescolar , Exoma , Facies , Femenino , Genotipo , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Noqueados , Mutación , Estrés Oxidativo , Síndrome , Ubiquitina-Proteína Ligasas/deficienciaRESUMEN
Barth Syndrome is a rare X-linked disorder characterized principally by dilated cardiomyopathy, skeletal myopathy and neutropenia and caused by defects in tafazzin, an enzyme responsible for modifying the acyl chain moieties of cardiolipin. While several comprehensive clinical studies of Barth Syndrome have been published detailing cardiac and hematologic features, descriptions of its biochemical characteristics are limited. To gain a better understanding of the clinical biochemistry of this rare disease, we measured hematologic and biochemical values in a cohort of Barth Syndrome patients. We characterized multiple biochemical parameters, including plasma amino acids, plasma 3-methylglutaconic acid, cholesterol, cholesterol synthetic intermediates, and red blood cell membrane fatty acid profiles in 28 individuals with Barth Syndrome from ages 10 months to 30 years. We describe a unique biochemical profile for these patients, including decreased plasma arginine levels. We further studied the plasma amino acid profiles, cholesterol, cholesterol synthetic intermediates, and plasma 3-methylglutaconic acid levels in 8 female carriers and showed that they do not share any of the distinct, Barth Syndrome-specific biochemical laboratory abnormalities. Our studies augment and expand the biochemical profiles of individuals with Barth Syndrome, describe a unique biochemical profile for these patients, and provide insight into the possible underlying biochemical pathology in this disorder.
Asunto(s)
Arginina/sangre , Síndrome de Barth/sangre , Síndrome de Barth/fisiopatología , Biomarcadores/sangre , Adolescente , Adulto , Síndrome de Barth/patología , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
We describe the rudolph mouse, a mutant with striking defects in both central nervous system and skeletal development. Rudolph is an allele of the cholesterol biosynthetic enzyme, hydroxysteroid (17-beta) dehydrogenase 7, which is an intriguing finding given the recent implication of oxysterols in mediating intracellular Hedgehog (Hh) signaling. We see an abnormal sterol profile and decreased Hh target gene induction in the rudolph mutant, both in vivo and in vitro. Reduced Hh signaling has been proposed to contribute to the phenotypes of congenital diseases of cholesterol metabolism. Recent in vitro and pharmacological data also indicate a requirement for intracellular cholesterol synthesis for proper regulation of Hh activity via Smoothened. The data presented here are the first in vivo genetic evidence supporting both of these hypotheses, revealing a role for embryonic cholesterol metabolism in both CNS development and normal Hh signaling.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , Colesterol/metabolismo , Proteínas Hedgehog/metabolismo , Prosencéfalo/anomalías , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Desarrollo Óseo/genética , Colesterol/genética , Etilnitrosourea/farmacología , Ratones , Ratones Mutantes , Mutagénesis , Mutación , Prosencéfalo/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Receptor SmoothenedRESUMEN
INTRODUCTION: Gulf War illness (GWI) is an environmentally-triggered chronic multisymptom illness typified by protean symptoms, in which mitochondrial impairment is evident. It has been likened to accelerated aging. Nuclear genetics of detoxification have been linked to GWI. OBJECTIVE: To see whether mitochondrial (mt) haplogroup U - a heritable profile of mitochondrial DNA that has been tied to aging-related conditions - significantly predicts greater GWI severity; and to assess whether GWI severity is influenced by mitochondrial as well as nuclear genetics. 54 consenting Gulf War veterans gave information on GWI severity, of whom 52 had nuclear DNA assessment; and 45 had both nuclear and mitochondrial DNA assessments. Regression with robust standard errors assessed prediction of GWI severity as a function of nuclear genetics (butyrylcholinesterase variants), mitochondrial genetics (haplogroup U, previously tied to aging-related conditions); or both. RESULTS: BChE "adverse" variants significantly predicted GWI severity (ß(SE) = 23.4(11.4), p = 0.046), as did mt haplogroup U (ß(SE) = 36.4(13.6), p = 0.010). In a model including both, BChE was no longer significant, but mt haplogroup U retained significance (ß(SE) = 36.7(13.0), p = 0.007). This is the first study to show that mitochondrial genetics are tied to GWI severity in Gulf-deployed veterans. Other data affirm a tie to nuclear genetics, making GWI indeed a "tale of two genomes."
Asunto(s)
ADN Mitocondrial , Síndrome del Golfo Pérsico , Veteranos , Humanos , Síndrome del Golfo Pérsico/genética , Persona de Mediana Edad , Masculino , ADN Mitocondrial/genética , Femenino , Haplotipos , Butirilcolinesterasa/genética , Adulto , Anciano , Índice de Severidad de la EnfermedadRESUMEN
CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development.
Asunto(s)
3-Hidroxiesteroide Deshidrogenasas/genética , Anomalías Múltiples/genética , Alelos , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Temperatura , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Exones , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Linaje , Homología de Secuencia de Aminoácido , Adulto JovenRESUMEN
Costeff Syndrome, which is caused by mutations in the OPTIC ATROPHY 3 (OPA3) gene, is an early-onset syndrome characterized by urinary excretion of 3-methylglutaconic acid (MGC), optic atrophy and movement disorders, including ataxia and extrapyramidal dysfunction. The OPA3 protein is enriched in the inner mitochondrial membrane and has mitochondrial targeting signals, but a requirement for mitochondrial localization has not been demonstrated. We find zebrafish opa3 mRNA to be expressed in the optic nerve and retinal layers, the counterparts of which in humans have high mitochondrial activity. Transcripts of zebrafish opa3 are also expressed in the embryonic brain, inner ear, heart, liver, intestine and swim bladder. We isolated a zebrafish opa3 null allele for which homozygous mutants display increased MGC levels, optic nerve deficits, ataxia and an extrapyramidal movement disorder. This correspondence of metabolic, ophthalmologic and movement abnormalities between humans and zebrafish demonstrates a phylogenetic conservation of OPA3 function. We also find that delivery of exogenous Opa3 can reduce increased MGC levels in opa3 mutants, and this reduction requires the mitochondrial localization signals of Opa3. By manipulating MGC precursor availability, we infer that elevated MGC in opa3 mutants derives from extra-mitochondrial HMG-CoA through a non-canonical pathway. The opa3 mutants have normal mitochondrial oxidative phosphorylation profiles, but are nonetheless sensitive to inhibitors of the electron transport chain, which supports clinical recommendations that individuals with Costeff Syndrome avoid mitochondria-damaging agents. In summary, this paper introduces a faithful Costeff Syndrome model and demonstrates a requirement for mitochondrial OPA3 to limit HMG-CoA-derived MGC and protect the electron transport chain against inhibitory compounds.
Asunto(s)
Glutaratos/metabolismo , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Proteínas/genética , Proteínas de Pez Cebra/genética , Acilcoenzima A/metabolismo , Alelos , Errores Innatos del Metabolismo de los Aminoácidos/genética , Animales , Modelos Animales de Enfermedad , Transporte de Electrón , Proteínas de la Membrana/genética , Mitocondrias/genética , Modelos Biológicos , Modelos Genéticos , Atrofia Óptica/genética , Fosforilación , Pez Cebra , Proteínas de Pez Cebra/metabolismoRESUMEN
UNLABELLED: Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n = 13) and G3 (n = 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P(adj) = 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P(adj) = 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [Δ55.2 mg/dL; P(adj) = 0.0015], 7DHC [Δ0.0075 mg/dL; P(adj) = 0.0026], lathosterol [Δ0.0430 mg/dL P(adj) = 0.0405]). In contrast, lanosterol was unchanged after SVR (P = 0.9515). CONCLUSION: HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms.
Asunto(s)
Albúminas/uso terapéutico , Colesterol/genética , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/genética , Interferón-alfa/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Anciano , Antivirales/uso terapéutico , Colesterol/metabolismo , Cromatografía de Gases , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/patología , Humanos , Lanosterol/genética , Lanosterol/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Estrés Oxidativo/genética , Proyectos Piloto , Pronóstico , Medición de Riesgo , Índice de Severidad de la Enfermedad , Transducción de Señal/genética , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
Smith-Lemli-Opitz syndrome (SLOS), desmosterolosis and lathosterolosis are human syndromes caused by defects in the final stages of cholesterol biosynthesis. Many of the developmental malformations in these syndromes occur in tissues and structures whose embryonic patterning depends on signaling by the Hedgehog (Hh) family of secreted proteins. Here we report that response to the Hh signal is compromised in mutant cells from mouse models of SLOS and lathosterolosis and in normal cells pharmacologically depleted of sterols. We show that decreasing levels of cellular sterols correlate with diminishing responsiveness to the Hh signal. This diminished response occurs at sterol levels sufficient for normal autoprocessing of Hh protein, which requires cholesterol as cofactor and covalent adduct. We further find that sterol depletion affects the activity of Smoothened (Smo), an essential component of the Hh signal transduction apparatus.
Asunto(s)
Colesterol/biosíntesis , Lovastatina/análogos & derivados , Receptores Acoplados a Proteínas G , Transactivadores/genética , Transactivadores/fisiología , Células 3T3 , Animales , Anticolesterolemiantes/farmacología , Células Cultivadas , Embrión de Pollo , Ciclodextrinas/farmacología , Relación Dosis-Respuesta a Droga , Proteínas Hedgehog , Humanos , Lovastatina/farmacología , Ratones , Modelos Biológicos , Pruebas de Precipitina , Receptores de Superficie Celular/genética , Transducción de Señal , Síndrome de Smith-Lemli-Opitz/genética , Receptor Smoothened , Factores de Tiempo , TransfecciónRESUMEN
The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth.
Asunto(s)
Proteínas Portadoras/genética , Desoxirribonucleótidos/metabolismo , Proteínas de Transporte de Membrana , Microcefalia/genética , Proteínas Portadoras/metabolismo , Cristianismo , Cromosomas Humanos Par 17 , Clonación Molecular , Escherichia coli , Etnicidad , Femenino , Marcadores Genéticos , Haplotipos , Humanos , Escala de Lod , Masculino , Proteínas de Transporte de Membrana Mitocondrial , Mutación , Linaje , Mapeo Físico de Cromosoma , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
We studied a unique phenotype of cognitive delay, autistic behavior, and gait instability segregating in three separate sibships. We initiated genome-wide mapping in two sibships using Affymetrix 10K SNP Mapping Arrays and identified a homozygous 8.2 Mb region on chromosome 15 common to five affected children. We used exome sequencing of two affected children to assess coding sequence variants within the mapped interval. Four novel homozygous exome variants were shared between the two patients; however, only two variants localized to the mapped interval on chromosome 15. A third sibship in an Ohio Amish deme narrowed the mapped interval to 2.6 Mb and excluded one of the two novel homozygous exome variants. The remaining variant, a missense change in HERC2 (c.1781C>T, p.Pro594Leu), occurs in a highly conserved proline residue within an RCC1-like functional domain. Functional studies of truncated HERC2 in adherent retinal pigment epithelium cells suggest that the p.Pro594Leu variant induces protein aggregation and leads to decreased HERC2 abundance. The phenotypic correlation with the mouse Herc1 and Herc2 mutants as well as the phenotypic overlap with Angelman syndrome provide further evidence that pathogenic changes in HERC2 are associated with nonsyndromic intellectual disability, autism, and gait disturbance. Hum Mutat 33:1639-1646, 2012. © 2012 Wiley Periodicals, Inc.
Asunto(s)
Anomalías Múltiples/genética , Trastornos Generalizados del Desarrollo Infantil/genética , Discapacidades del Desarrollo/genética , Factores de Intercambio de Guanina Nucleótido/genética , Mutación Missense , Adolescente , Adulto , Secuencia de Bases , Línea Celular , Niño , Preescolar , Mapeo Cromosómico , Femenino , Trastornos Neurológicos de la Marcha/genética , Estudios de Asociación Genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Homocigoto , Humanos , Masculino , Fenotipo , Transporte de Proteínas , Análisis de Secuencia de ADN , Ubiquitina-Proteína Ligasas , Adulto JovenRESUMEN
Desmosterolosis, a rare disorder of cholesterol biosynthesis, is caused by mutations in DHCR24, the gene encoding the enzyme 24-dehydrocholesterol reductase (DHCR24). To date, desmosterolosis has been described in only two patients. Here we report on a third patient with desmosterolosis who presented after delivery with relative macrocephaly, mild arthrogryposis, and dysmorphic facial features. Brain MRI revealed hydrocephalus, thickening of the tectum and massa intermedia, mildly effaced gyral pattern, underopercularization, and a thin corpus callosum. The diagnosis of desmosterolosis was established by detection of significant elevation of plasma desmosterol levels and reduced enzyme activity of DHCR24 upon expression of the patient's DHCR24 cDNA in yeast. The patient was found to be a compound heterozygote for c.281G>A (p.R94H) and c.1438G>A (p.E480K) mutations. Structural and evolutionary analyses showed that residue R94 resides at the flavin adenine dinucleotide (FAD) binding site and is strictly conserved throughout evolution, while residue E480 is less conserved, but the charge shift substitution is accompanied by drastic changes in the local protein environment of that residue. We compare the phenotype of our patient with previously reported cases.
Asunto(s)
Desmosterol/metabolismo , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Fenotipo , Determinación de la Edad por el Esqueleto , Encéfalo/patología , Desmosterol/sangre , Exones/genética , Femenino , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/sangre , Imagen por Resonancia Magnética , Simulación de Dinámica Molecular , Mutación/genética , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/química , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Conformación Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genéticaRESUMEN
OBJECTIVES: To describe the metabolic and endocrine features of a patient with Barth syndrome who showed evidence of growth hormone resistance. CASE PRESENTATION: A male proband deteriorated rapidly with lactic acidosis after a circumcision at age three weeks and was found to have severe dilated cardiomyopathy. A cardiomyopathy gene panel led to the diagnosis of TAZ-deficiency Barth syndrome. He subsequently experienced hypotonia and gross motor delay, feeding difficulties for the first four years, constitutional growth delay and one episode of ketotic hypoglycaemia. Cardiomyopathy resolved on oral anti-failure therapy by age three years. He had a hormonal pattern of growth hormone resistance, and growth hormone treatment was considered, however height velocity improved spontaneously after age 3½ years. He also had biochemical primary hypothyroidism. CONCLUSIONS: With careful metabolic management with l-arginine supplementation, overnight corn starch, and a prescribed exercise program, our patient's strength, endurance, level of physical activity and body composition improved significantly by age six years.
Asunto(s)
Síndrome de Barth/complicaciones , Cardiomiopatía Dilatada/etiología , Hormona del Crecimiento/farmacología , Arginina/administración & dosificación , Estatura , Niño , Humanos , MasculinoRESUMEN
Impaired bioenergetics have been reported in veterans with Gulf War illness (VGWIs), including prolonged post-exercise recovery of phosphocreatine (PCr-R) assessed with 31Phosphorus magnetic resonance spectroscopy. The citric acid cycle (CAC) is considered the most important metabolic pathway for supplying energy, with relationships among CAC markers reported to shift in some but not all impaired bioenergetic settings. We sought to assess relations of CAC markers to one another and to PCr-R. Participants were 33 VGWIs and 33 healthy controls 1:1 matched on age-sex-ethnicity. We assessed seven CAC intermediates, and evaluated PCr-R in a subset of matched case-control pairs (N = 14). CAC markers did not significantly differ between cases and controls. Relationships of alpha-ketoglutarate to malate, isocitrate, and succinate were strongly significant in cases with materially weaker relationships in controls, suggesting possible shifts in these markers in concert in VGWIs. PCr-R correlated strongly with five of seven CAC markers in controls (succinate, malate, fumarate, citrate, isocitrate, range r = -0.74 to -0.88), but bore no relationship in VGWIs. In summary, PCr-R related significantly to CAC markers in healthy controls, but not VGWIs. In contrast, relations of CAC markers to one another appeared to shift (often strengthen) in VGWIs.
Asunto(s)
Ciclo del Ácido Cítrico , Guerra del Golfo , Metabolismo Energético , Humanos , Fosfocreatina , Proyectos PilotoRESUMEN
Here we present a 24-week fetus with Smith-Lemli-Opitz syndrome (SLOS), alobar holoprosencephaly (HPE) and cyclopia (synophthalmia). Following birth, we suspected SLOS in this fetus due to the additional findings of ambiguous genitalia and bilateral 2-3 toe syndactyly. The diagnosis of SLOS was confirmed by finding an elevated amniotic fluid 7-dehydrocholesterol level (9,890 ng/ml; normal range = 3-9 ng/ml), and molecularly by detecting two different mutations in the DHCR7 gene, the gene causing SLOS. The first mutation was an IVS8-1G>T change and the second was a deletion of exons 3 and 4; this latter mutation has not been reported previously. The mother carries the deletion, while the father carries the splice-site mutation. Also of note, the father has an abnormally low total plasma cholesterol level (104-109 mg/dl). This is the most severe case of HPE described in any patient with SLOS. We postulate that the HPE in this case resulted from severe impairment of Sonic Hedgehog signaling secondary to abnormal cholesterol metabolism; however, the unique combination of mutations in the fetus functionally appears to be no different from other homozygous null mutations reported in DHCR7. Therefore, there must be other yet to be identified factors that contributed to the severity of HPE in SLOS.
Asunto(s)
Holoprosencefalia/diagnóstico , Síndrome de Smith-Lemli-Opitz/diagnóstico , Feto Abortado/anomalías , Adolescente , Femenino , Holoprosencefalia/complicaciones , Humanos , EmbarazoRESUMEN
OBJECTIVES: We sought to identify characteristic lipid abnormalities in patients with Barth syndrome (BTHS) and to correlate the lipid profile to phenotype and genotype. BACKGROUND: Barth syndrome typically includes cardiomyopathy, skeletal myopathy, neutropenia, growth retardation, and 3-methylglutaconic aciduria, and it is commonly associated with mutations in the tafazzin (TAZ) gene, whose products are homologous to phospholipid acyltransferases. However, clinical features of BTHS have also been found in patients with normal TAZ gene. METHODS: We analyzed molecular species of phospholipids in left and right ventricle, skeletal muscle, platelets, lymphoblasts, and fibroblasts from 19 children with BTHS (positive TAZ mutation), 6 children with BTHS-like syndromes (wild-type TAZ), 4 children with isolated cardiomyopathy (wild-type TAZ), and various controls. RESULTS: Cardiolipin, the specific lipid found only in mitochondria, was decreased in all tissues from BTHS patients, whereas concentrations of other phospholipids were normal. The molecular composition of cardiolipin was altered in all tissues from BTHS patients. The molecular compositions of phosphatidylcholine and phosphatidylethanolamine were altered in the heart. Cardiolipin abnormalities were only found in children with true BTHS, not in children with BTHS-like disease or with isolated cardiomyopathy. The degree of cardiolipin deficiency was tissue-specific but did not correlate with severity or specific phenotypic expression of BTHS. CONCLUSIONS: Abnormal cardiolipin is a specific diagnostic marker of cardiomyopathies caused by TAZ mutations. These mutations lead to alterations in the fatty acid composition of several phospholipids, supporting the idea that TAZ encodes a human acyltransferase.
Asunto(s)
Cardiomiopatías/metabolismo , Enfermedades Musculares/metabolismo , Fosfolípidos/análisis , Factores de Transcripción , Aciltransferasas , Plaquetas/química , Cardiolipinas/análisis , Fibroblastos/química , Glutaratos/orina , Trastornos del Crecimiento/metabolismo , Ventrículos Cardíacos/metabolismo , Linfocitos/química , Músculo Esquelético/metabolismo , Mutación , Miocardio/química , Neutropenia/metabolismo , Proteínas/genética , SíndromeRESUMEN
Hyperimmunoglobulinemia D (hyper-IgD) and periodic fever syndrome, a hereditary autoinflammatory syndrome, is characterized by lifelong recurrent episodes of fever and inflammation. No effective treatment is known. It is caused by a defect of mevalonate kinase, an enzyme that follows 3'-hydroxy-3'-methylglutaryl-coenzyme A (HMG-CoA) reductase in the isoprenoid pathway. We wanted to test the hypothesis that inhibition of HMG-CoA reductase would ameliorate the inflammatory attacks. Six patients with hyper-IgD syndrome and proven mevalonate kinase deficiency were followed up for 2 treatment periods with either simvastatin, 80 mg/d, or placebo for 24 weeks, separated by a 4-week washout period in a double-blind fashion. Simvastatin resulted in a drop in urinary mevalonic acid concentration in all patients and decreased the number of febrile days in 5 of 6 patients. No side effects were observed. These data offer preliminary evidence for the hypothesis that simvastatin may improve inflammatory attacks in the hyper-IgD syndrome. This highlights the anti-inflammatory properties of HMG-CoA reductase inhibition.
Asunto(s)
Fiebre Mediterránea Familiar/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipergammaglobulinemia/tratamiento farmacológico , Simvastatina/uso terapéutico , Adolescente , Adulto , Método Doble Ciego , Fiebre Mediterránea Familiar/patología , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hipergammaglobulinemia/patología , Masculino , Ácido Mevalónico/orina , Persona de Mediana Edad , Simvastatina/administración & dosificación , Síndrome , Resultado del TratamientoRESUMEN
A new metabolic disorder characterized by severe congenital microcephaly, death within the first year, and severe 2-ketoglutaric aciduria has been found among the Old-Order Amish of Lancaster County, Pennsylvania. Amish lethal microcephaly segregates as an autosomal recessive disorder and has an unusually high incidence of at least 1 in 500 births. When the infants are well, the urine organic acid profiles show isolated, extreme elevations of 2-ketoglutaric acid. However, during otherwise simple viral illnesses, the infants often develop a metabolic acidosis, which may follow a lethal course. Cranial magnetic resonance imaging of a single patient showed a smooth, immature brain similar to that of a 20-week fetus except for a moderate degree of cerebellar vermal hypoplasia. Assay of 2-ketoglutarate dehydrogenase in cultured lymphoblasts of one patient showed normal activity. Amish lethal microcephaly maps to 17q25 and may be caused by a defect in a mitochondrial inner membrane protein functioning as a 2-ketoglutarate transporter.