ABSTRACT
Nitrogen removal is an important process for wastewater ponds prior to effluent release. Bacteria and archaea can drive nitrogen removal if they possess the genes required to metabolize nitrogen. In the tropical savanna of northern Australia, we identified the previously unresolved microbial communities responsible for nitrogen cycling in a multi-pond wastewater stabilization system by measuring genomic DNA and cDNA for the following: nifH (nitrogen fixation); nosZ (denitrification); hzsA (anammox); archaeal AamoA and bacterial BamoA (ammonia oxidation); nxrB (nitrite oxidation); and nrfA (dissimilatory NO3 reduction to NH3). By collecting 160 DNA and 40 cDNA wastewater samples and measuring nitrogen (N)-cycling genes using a functional gene array, we found that genes from all steps of the N cycle were present and, except for nxrB, were also expressed. As expected, N-cycling communities showed daily, seasonal, and yearly shifts. However, contrary to our prediction, probes from most functional groups, excluding nosZ and AamoA, were different between ponds. Further, different genes that perform the same N-cycling role sometimes had different trends over space and time, resulting in only weak correlations between the different functional communities. Although N-cycling communities were correlated with wastewater nitrogen levels and physico-chemistry, the relationship was not strong enough to reliably predict the presence or diversity of N-cycling microbes. The complex and dynamic response of these genes to other functional groups and the changing physico-chemical environment provides insight into why altering wastewater pond conditions can result an abundance of some gene variants while others are lost.
Subject(s)
Nitrogen , Ponds , Archaea/genetics , Denitrification , Genes, Microbial , Nitrogen/analysis , Nitrogen Cycle , Oxidation-Reduction , WastewaterABSTRACT
This study aims to evaluate the etiology of pediatric sensorineural hearing loss (SNHL). A total of 423 children with SNHL were evaluated, with the focus on the determination of causative genetic and acquired etiologies of uni- and bilateral SNHL in relation to age at diagnosis and severity of the hearing loss. We found that a stepwise diagnostic approach comprising of imaging, genetic, and/or pediatric evaluation identified a cause for SNHL in 67% of the children. The most common causative finding in children with bilateral SNHL was causative gene variants (26%), and in children with unilateral SNHL, a structural anomaly of the temporal bone (27%). The probability of finding an etiologic diagnosis is significantly higher in children under the age of 1 year and children with profound SNHL.Conclusions: With our stepwise diagnostic approach, we found a diagnostic yield of 67%. Bilateral SNHL often has a genetic cause, whereas in unilateral SNHL structural abnormalities of the labyrinth are the dominant etiologic factor. The diagnostic yield is associated with the age at detection and severity of hearing loss: the highest proportion of causative abnormalities is found in children with a young age at detection or a profound hearing loss. What is Known: ⢠Congenital sensorineural hearing loss is one of the most common congenital disorders ⢠Determination of the cause is important for adequate management and prognosis and may include radiology, serology, and DNA analysis What is New: ⢠Using a stepwise diagnostic approach, causative abnormalities are found in 67% both in uni- and bilateral SNHL, with the highest diagnostic yield in very young children and those suffering from profound hearing loss ⢠Bilateral SNHL often has a genetic cause, whereas in unilateral SNHL structural abnormalities of the labyrinth are the dominant etiologic factor.
Subject(s)
Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/etiology , Adolescent , Audiometry , Child , Child, Preschool , Female , Genetic Markers , Genetic Testing , Hearing Loss, Bilateral/diagnosis , Hearing Loss, Bilateral/etiology , Hearing Loss, Unilateral/diagnosis , Hearing Loss, Unilateral/etiology , Humans , Infant , Infant, Newborn , Magnetic Resonance Imaging , Male , Retrospective Studies , Severity of Illness Index , Tomography, X-Ray ComputedABSTRACT
This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.
Subject(s)
Carrier Proteins/genetics , Fuchs' Endothelial Dystrophy/genetics , Genetic Predisposition to Disease , Hearing Loss, Sensorineural/genetics , Adolescent , Adult , Audiometry , Child , Child, Preschool , Female , Fuchs' Endothelial Dystrophy/physiopathology , Genetic Association Studies , Genotype , Hearing Loss, Sensorineural/physiopathology , Heterozygote , Humans , Male , Middle Aged , Mutation, Missense , Pedigree , PhenotypeABSTRACT
OBJECTIVE: To evaluate the clinically relevant abnormalities as visualized on CT and MR imaging in children with symmetric and asymmetric bilateral sensorineural hearing loss (SNHL), in relation to age and the severity of hearing loss. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral otology and audiology center. PATIENTS AND DIAGNOSTIC INTERVENTIONS: From January 2006 until January 2016, a total of 207 children diagnosed with symmetric and asymmetric bilateral SNHL were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss. MAIN OUTCOME MEASURES: Radiologic abnormalities associated with SNHL. RESULTS: 302 scans were performed in 207 children (median age of 0.8 years old) with bilateral SNHL. The most frequently identified cause of bilateral SNHL was a malformation of the labyrinth. The combined diagnostic yield of CT and MR imaging was 32%. The diagnostic yield of MR (34%) was considerably higher than that of CT (20%). We found a higher rate of abnormalities in children with profound hearing loss (41%) compared to milder hearing loss (8-29%), and in asymmetric SNHL (52%) compared to symmetric SNHL (30%). CONCLUSION: Imaging is essential in the etiologic evaluation of children with bilateral SNHL. The highest diagnostic yield is found in children with bilateral asymmetric SNHL or profound SNHL. Based on our findings, MR is the primary imaging modality of choice in the etiological evaluation of children with bilateral SNHL because of its high diagnostic yield.
Subject(s)
Hearing Loss, Bilateral/diagnostic imaging , Hearing Loss, Sensorineural/diagnostic imaging , Magnetic Resonance Imaging/methods , Tomography, X-Ray Computed/methods , Adolescent , Child , Child, Preschool , Cohort Studies , Ear, Inner/abnormalities , Female , Hearing Loss, Bilateral/etiology , Hearing Loss, Sensorineural/etiology , Humans , Infant , Male , Retrospective StudiesABSTRACT
BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.
Subject(s)
Ectopia Lentis/genetics , Genetic Testing/methods , High-Throughput Nucleotide Sequencing/methods , Sequence Analysis, DNA/methods , ADAMTS Proteins/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Ectopia Lentis/diagnosis , False Positive Reactions , Female , Genetic Testing/standards , High-Throughput Nucleotide Sequencing/standards , Humans , Infant , Male , Middle Aged , Sensitivity and Specificity , Sequence Analysis, DNA/standardsABSTRACT
OBJECTIVE: Evaluation of causal abnormalities identified on CT and MR imaging in children with unilateral sensorineural hearing loss (USNHL), and the association with age and severity of hearing loss. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral otology/audiology center. PATIENTS AND DIAGNOSTIC INTERVENTIONS: 102 children diagnosed with USNHL between 2006 and 2016 were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss. MAIN OUTCOME MEASURES: Radiologic abnormalities of the inner ear and brain associated with USNHL. RESULTS: Using CT and/or MR imaging, causal abnormalities were identified in 49%, which is higher than previously reported (25-40%). The most frequently affected site was the labyrinth (29%), followed by the cochlear nerve (9%) and brain (7%). No significant difference in the number or type of abnormalities was found for the degree of hearing loss or age categories. CONCLUSIONS: Imaging is essential in the etiologic analysis of USNHL because of the high prevalence of causative abnormalities that can be identified with radiology, irrespective of the patients' age or degree of hearing loss. CT and MR imaging are complementary imaging options. The ideal imaging algorithm is controversial. Based on our findings, we conclude that there is limited additional diagnostic value of simultaneous dual modality imaging over sequential diagnostics. We therefore perform a stepwise radiological workup in order to maximize the diagnostic yield while minimizing impact and costs. If the primary imaging modality does not identify a cause for USNHL, performing the alternative imaging modality should be considered. LEVEL OF EVIDENCE: Retrospective cohort study 2b.
Subject(s)
Brain/pathology , Ear, Inner/pathology , Hearing Loss, Sensorineural/etiology , Magnetic Resonance Imaging/methods , Tomography, X-Ray Computed/methods , Adolescent , Audiometry , Brain/diagnostic imaging , Child , Child, Preschool , Cohort Studies , Ear, Inner/diagnostic imaging , Female , Hearing Loss, Sensorineural/diagnostic imaging , Humans , Infant , Male , Netherlands , Prevalence , Retrospective Studies , Tertiary Care CentersABSTRACT
Mesenchymal stem cells (MSC) are precursor cells of mesodermal tissue and, because of their trophic phenotype, they are known to play beneficial roles in wound healing. In addition, various tissue engineering strategies are based on MSC/biomaterial constructs. As the isolation and expansion of MSCs is a long-term process, a major goal is to develop an endogenous stem cell recruitment system that circumvents all ex vivo steps generally used for tissue engineering. Therefore collagen and silk fibroin were loaded with hepatocyte growth factor (HGF), a chemoattractant for MSCs. Collagen was mixed with HGF during polymerization, while silk fibroin and HGF were produced as fusion proteins by transgenic silkworms. To demonstrate release of active HGF, enzyme-linked immunosorbent assay, in vitro migration assays and animal studies were performed to demonstrate MSC migration in vivo, followed by detailed examinations of the immunological effects of the biomaterials. Hepatocyte growth factor was released burst-like, both from silk fibroin and collagen during the first 8 h and gradually for up to 168 h in vitro. Directed migration in vitro was demonstrated when MSCs were exposed to HGF. In vivo, HGF-loaded collagen and silk fibroin were tolerated as subcutaneous implants. In addition, it was proved that endogenous MSCs were recruited from the local environment. These results show for the first time recruitment of endogenous MSCs to HGF-loaded collagen (fast degradable) and silk fibroin scaffolds (long-term degradable) in vitro and in vivo. This knowledge could be applied to make off-the-shelf, readily available constructs for use in patients with chronic wound or burns. Copyright © 2016 John Wiley & Sons, Ltd.
Subject(s)
Biocompatible Materials , Cell Movement/drug effects , Hepatocyte Growth Factor , Mesenchymal Stem Cells/metabolism , Wounds and Injuries/therapy , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacokinetics , Biocompatible Materials/pharmacology , Drug Implants/chemistry , Drug Implants/pharmacokinetics , Drug Implants/pharmacology , Female , Fibroins/chemistry , Fibroins/pharmacokinetics , Fibroins/pharmacology , Hepatocyte Growth Factor/chemistry , Hepatocyte Growth Factor/pharmacokinetics , Hepatocyte Growth Factor/pharmacology , Humans , Male , Mesenchymal Stem Cells/pathology , Wounds and Injuries/metabolism , Wounds and Injuries/pathologyABSTRACT
The BCAP31 gene is located between SLC6A8, associated with X-linked creatine transporter deficiency, and ABCD1, associated with X-linked adrenoleukodystrophy. Recently, loss-of-function mutations in BCAP31 were reported in association with severe developmental delay, deafness and dystonia. We characterized the break points in eight patients with deletions of SLC6A8, BCAP31 and/or ABCD1 and studied the genotype-phenotype correlations. The phenotype in patients with contiguous gene deletions involving BCAP31 overlaps with the phenotype of isolated BCAP31 deficiency. Only deletions involving both BCAP31 and ABCD1 were associated with hepatic cholestasis and death before 1 year, which might be explained by a synergistic effect. Remarkably, a patient with an isolated deletion at the 3'-end of SLC6A8 had a similar severe phenotype as seen in BCAP31 deficiency but without deafness. This might be caused by the disturbance of a regulatory element between SLC6A8 and BCAP31.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Cholestasis, Intrahepatic/genetics , Intellectual Disability/genetics , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/genetics , ATP Binding Cassette Transporter, Subfamily D, Member 1 , Adrenoleukodystrophy/genetics , Adrenoleukodystrophy/mortality , Adrenoleukodystrophy/pathology , Adult , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/mortality , Brain Diseases, Metabolic, Inborn/pathology , Child , Child, Preschool , Cholestasis, Intrahepatic/mortality , Cholestasis, Intrahepatic/pathology , Creatine/deficiency , Creatine/genetics , Gene Deletion , Genetic Association Studies , Humans , Infant , Infant, Newborn , Intellectual Disability/mortality , Intellectual Disability/pathology , Male , Mental Retardation, X-Linked/genetics , Mental Retardation, X-Linked/mortality , Mental Retardation, X-Linked/pathology , Phenotype , Plasma Membrane Neurotransmitter Transport Proteins/deficiencyABSTRACT
BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.
Subject(s)
Brain Diseases, Metabolic, Inborn/genetics , Creatine/deficiency , Creatine/metabolism , Mental Retardation, X-Linked/genetics , Nerve Tissue Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/deficiency , Adult , Child , Creatine/genetics , Genes, X-Linked , Genetic Testing , Genotype , Humans , Male , Phenotype , Plasma Membrane Neurotransmitter Transport Proteins/genetics , Retrospective StudiesABSTRACT
Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males.
Subject(s)
Abnormalities, Multiple/diagnosis , Chromosome Duplication , Chromosomes, Human, X/genetics , Intellectual Disability/genetics , Methyl-CpG-Binding Protein 2/genetics , Phenotype , Abnormalities, Multiple/genetics , Child , Chromosome Banding , Female , Genetic Association Studies , Humans , Pedigree , X Chromosome InactivationABSTRACT
OBJECTIVE: Better recruitment strategies are needed to improve the identification of people at ultra-high risk of developing psychosis. This study explores the effectiveness of two recruitment strategies: a screening method in a consecutive help-seeking population entering secondary mental health services for non-psychotic problems vs. a population referred to the diagnostic center of an early-psychosis clinic. METHOD: From February 2008 to February 2010, all general practitioner and self-referrals (aged 18-35 years) to the secondary mental healthcare service in The Hague and Zoetermeer were screened with the Prodromal Questionnaire; patients who scored above the cutoff of 18 and had a decline in social functioning were assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS). All referrals (aged 14-35 years) to the diagnostic center in Amsterdam were also assessed with the CAARMS. RESULTS: The screening detected a three-fold higher prevalence of at-risk mental states: these subjects were older and more often female. manova showed significantly higher scores for the screened population on depression, social anxiety, distress with positive symptoms, and a higher rate of transition to psychosis within 12 months. CONCLUSION: The screening method detects more patients with at-risk mental states than the referral method. The latter method is biased to young male patients in an earlier prodromal stage and a lower transition rate.
Subject(s)
Psychotic Disorders/diagnosis , Adolescent , Adult , Chi-Square Distribution , Female , Humans , Male , Multivariate Analysis , Patient Acceptance of Health Care/psychology , Psychiatric Status Rating Scales , Risk Factors , Young AdultABSTRACT
The creatine transporter defect is an X-linked cause of mental retardation. We investigated the clinical features and pattern of X-inactivation in a Dutch cohort of eight female heterozygotes. We show that symptoms of the creatine transporter defect (mental retardation, learning difficulties, and constipation) can be present in female heterozygotes. We further show that the diagnosis in females is not straightforward: (i) The creatine/creatinine ratio in urine was elevated only in three of eight females. (ii) Although as a group the females had a significantly decreased cerebral creatine concentration, individual females had creatine concentrations overlapping with normal controls. (iii) Skewed X-inactivation was found in the cultured fibroblasts, in favour of either the mutated or the wild-type allele, leading to either deficient or normal results in the creatine uptake studies in fibroblasts. Thus, screening by these tests is unreliable for the diagnosis. In addition, we found no consistent skewing of the X-inactivation in peripheral tissues indicating that there is no selection against the creatine transporter defect. We conclude that testing for creatine transporter defect should be considered in females with (mild) mental retardation. Screening by DNA analysis of the SLC6A8 gene is recommended.
Subject(s)
Heterozygote , Mental Retardation, X-Linked/genetics , Nerve Tissue Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/genetics , X Chromosome Inactivation/genetics , Adult , Aged , Cells, Cultured , Creatine/metabolism , Female , Humans , Male , Mental Retardation, X-Linked/diagnosis , Middle Aged , Mutation , Netherlands , Neuropsychological TestsSubject(s)
Brain/pathology , Insomnia, Fatal Familial/genetics , Insomnia, Fatal Familial/pathology , Insomnia, Fatal Familial/physiopathology , Prions/genetics , Black People , Blotting, Western , Egypt , Female , Humans , Immunohistochemistry , Male , Middle Aged , Netherlands , Pedigree , Point Mutation , Prion ProteinsABSTRACT
Mucopolysaccharidosis IIIC (MPS IIIC, Sanfilippo C syndrome) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT). We performed a clinical study on 29 Dutch MPS IIIC patients and determined causative mutations in the recently identified HGSNAT gene. Psychomotor development was reported to be normal in all patients during the first year of life. First clinical signs were usually noted between 1 and 6 years (mean 3.5 years), and consisted of delayed psychomotor development and behavioral problems. Other symptoms included sleeping and hearing problems, recurrent infections, diarrhoea and epilepsy. Two sisters had attenuated disease and did not have symptoms until the third decade. Mean age of death was 34 years (range 25-48). Molecular analysis revealed mutations in both alleles for all patients except one. Altogether 14 different mutations were found: two splice site mutations, one frame shift mutation due to an insertion, three nonsense mutations and eight missense mutations. Two mutations, p.R344C and p.S518F, were frequent among probands of Dutch origin representing 22.0% and 29.3%, respectively, of the mutant alleles. This study demonstrates that MPS IIIC has a milder course than previously reported and that both severity and clinical course are highly variable even between sibs, complicating prediction of the clinical phenotype for individual patients. A clear phenotype-genotype correlation could not be established, except that the mutations p.G262R and p.S539C were only found in two sisters with late-onset disease and presumably convey a mild phenotype.
Subject(s)
Acetyltransferases/deficiency , Acetyltransferases/genetics , Mucopolysaccharidosis III/enzymology , Mucopolysaccharidosis III/genetics , Mutation , Acetyltransferases/chemistry , Adolescent , Adult , Age of Onset , Child , Child, Preschool , DNA/genetics , DNA Mutational Analysis , Female , Genotype , Humans , Infant , Male , Middle Aged , Models, Molecular , Mucopolysaccharidosis III/classification , Mucopolysaccharidosis III/physiopathology , Mutation, Missense , Netherlands , PhenotypeABSTRACT
There is a growing awareness that inborn errors of metabolism can be a cause of non-immune hydrops fetalis. The association between congenital disorders of glycosylation (CDG) and hydrops fetalis has been based on one case report concerning two sibs with hydrops fetalis and CDG-Ik. Since then two patients with hydrops-like features and CDG-Ia have been reported. Two more unrelated patients with CDG-Ia who presented with hydrops fetalis are reported here, providing definite evidence that non-immune hydrops fetalis can be caused by CDG-Ia. The presence of congenital thrombocytopenia and high ferritin levels in both patients was remarkable. These might be common features in this severe form of CDG. Both patients had one severe mutation in the phosphomannomutase 2 gene, probably fully inactivating the enzyme, and one milder mutation with residual activity, as had the patients reported in literature. The presence of one severe mutation might be required for the development of hydrops fetalis. CDG-Ia should be considered in the differential diagnosis of hydrops fetalis and analysis of PMM activity in chorionic villi or amniocytes should also be considered.
Subject(s)
Abnormalities, Multiple/genetics , Glycosylation , Hydrops Fetalis/genetics , Phosphotransferases (Phosphomutases)/genetics , Protein Processing, Post-Translational/genetics , Codon, Nonsense , Fatal Outcome , Female , Ferritins/blood , Frameshift Mutation , Glycoproteins/metabolism , Heart Defects, Congenital/genetics , Humans , Hydrops Fetalis/diagnostic imaging , Hypoalbuminemia/congenital , Hypoalbuminemia/genetics , Infant, Newborn , Isoelectric Focusing , Male , Mutagenesis, Insertional , Mutation, Missense , Pericardial Effusion/congenital , Phosphotransferases (Phosphomutases)/deficiency , Thrombocytopenia/congenital , Thrombocytopenia/genetics , Transferrin/analysis , Ultrasonography, PrenatalABSTRACT
Bifurcation of the femur and tibial agenesis are rare anomalies and have been described in both the Gollop-Wolfgang Complex and the tibial agenesis-ectrodactyly syndrome. We report on two patients with bifurcation of the femur and tibial agenesis. Hand ectrodactyly was seen in one of these patients. Both patients had unusual additional anomalies. The first patient had in addition proximal focal femoral deficiency, the other patient had a tracheo-esophageal fistula and pyloric stenosis. Clinical and genetic aspects are discussed.
Subject(s)
Abnormalities, Multiple/pathology , Femur/abnormalities , Limb Deformities, Congenital/pathology , Tibia/abnormalities , Abnormalities, Multiple/genetics , Foot Deformities, Congenital/pathology , Hand Deformities, Congenital/pathology , Humans , Infant , Infant, Newborn , Karyotyping , Male , Pyloric Stenosis/pathology , Tracheoesophageal Fistula/pathologyABSTRACT
The kynurenine (KYN) pathway of tryptophan metabolism produces several neuroactive metabolites, including 3-hydroxykynurenine (3HK). The pathway is subject to regulation by a number of effectors including pregnancy and availability of vitamin B-6. Vitamin B-6 depleted humans and animals excrete abnormally high concentrations of KYN metabolites in urine. In pregnancy, vitamin B-6 deficiency is commonly seen, and tryptophan metabolism is often found to be altered. We measured concentrations of 3HK in brains of DBA/2Ibg and A/Ibg mice as functions of pregnancy and dietary level of vitamin B-6. Pregnant DBA mice are more susceptible to flurothyl-induced seizures than controls, pregnant A mice are not. Significant elevations of 3HK were found in brains of pregnant mice, and the increases were greater in the pregnancy-associated seizure prone DBA, than in the A mice. In the A mice, brain 3HK concentrations were negatively correlated with dietary vitamin B-6 levels, as expected; however, in the DBA mice these correlations were positive, indicating an unusual response to vitamin B-6 restriction. The accumulation of a cytotoxic, excitatory metabolite, 3HK, in brain may contribute to the increased seizure susceptibility of susceptible pregnant mice, perhaps though its effects as an endogenous modulator of excitatory amino acid receptor systems.
ABSTRACT
Sanfilippo B syndrome (mucopolysaccharidosis IIIB, MPS IIIB) is caused by a deficiency of alpha-N-acetylglucosaminidase, a lysosomal enzyme involved in the degradation of heparan sulphate. Accumulation of the substrate in lysosomes leads to degeneration of the central nervous system with progressive dementia often combined with hyperactivity and aggressive behaviour. Age of onset and rate of progression vary considerably, whilst diagnosis is often delayed due to the absence of the pronounced skeletal changes observed in other mucopolysaccharidoses. Cloning of the gene and cDNA encoding alpha-N-acetylglucosaminidase enabled a study of the molecular basis of this syndrome. We were able to identify 31 mutations, 25 of them novel, and two polymorphisms in the 40 patients mostly of Australasian and Dutch origin included in this study. The observed allellic heterogeneity reflects the wide spectrum of clinical phenotypes reported for MPS IIIB patients. The majority of changes are missense mutations; also four nonsense and nine frameshift mutations caused by insertions or deletions were identified. Only five mutations were found in more than one patient and the observed frequencies are well below those observed for the common mutations in MPS IIIA. R643C and R297X each account for around 20% of MPS IIIB alleles in the Dutch patient group, whilst R297X, P521L, R565W and R626X each have a frequency of about 6% in Australasian patients. R643C seems to be a Dutch MPS IIIB allele and clearly confers the attenuated phenotype. One region of the gene shows a higher concentration of mutations, probably reflecting the instability of this area which contains a direct repeat. Several arginine residues seem to be 'hot-spots' for mutations, being affected by two or three individual base pair exchanges.
Subject(s)
Alleles , Genetic Heterogeneity , Mucopolysaccharidosis III/genetics , Acetylglucosaminidase/genetics , Base Sequence , DNA Primers , Genotype , Humans , Mutation , PhenotypeABSTRACT
We have identified a common mutation (R245H) in the sulphamidase gene of Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA, MPS IIIA) patients from The Netherlands. Allele-specific oligonucleotide hybridization was used to determine the incidence of this mutation in 45 unrelated MPS IIIA patients from different regions of The Netherlands. R245H was present in 51 alleles, representing 56.7% of the total allelic population. Of 39 patients, for whom we have uniform clinical details, 13 MPS IIIA patients who were homozygous for this common mutation had a more uniform but severe clinical phenotype than the remaining 21 or 5 patients, containing respectively one or no R245H alleles. The R245H allele had a higher prevalence in western rather than eastern regions of The Netherlands.
Subject(s)
Hydrolases/genetics , Mucopolysaccharidosis III/genetics , Mutation , Adolescent , Adult , Alleles , Amino Acid Substitution , Arginine/genetics , Child , Child, Preschool , Female , Gene Frequency , Histidine/genetics , Humans , Male , Mucopolysaccharidosis III/enzymology , NetherlandsABSTRACT
UNLABELLED: Osteoporosis is an important feature of osteogenesis imperfecta (OI). So far, no effective medical treatment is available. We treated three boys with severe OI type III and vertebral deformities for 5-7 years with continuous oral administration of the bisphosphonate, olpadronate. Treatment resulted in a decreased number of bone fractures, an increased calcification of the long bones and an amelioration of vertebral shape. No side-effects were encountered. CONCLUSION: These preliminary but long-term observations suggest that the bisphosphonate olpadronate may be a useful treatment for patients with OI and vertebral fractures. Bisphosphonates may be promising drugs for children with OI.