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1.
Knee ; 34: 1-8, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34871972

ABSTRACT

BACKGROUND: The new software, mediCAD® 3D Knee Sport (mediCAD Hectec GmbH, Altdorf/Landshut, Germany), promises to combine automated digital 3D bone model generation, 3D analysis of lower limb geometry including analysis of the patellofemoral joint, and osteotomy planning. The aim of this study was to evaluate its reliability and accuracy. METHODS: In this retrospective multi-observer study, three post-mortem CTs were analysed by three observers at three points in time. Reliability was evaluated by calculating the intraclass correlation coefficient (ICC) of interobserver agreement. Accuracy was evaluated using the mean deviation D from the mean and the standard deviation SD from D. RESULTS: Ten of 18 alignment parameters showed excellent, two good and three moderate interobserver agreement. Poor agreement was found for the mechanical medial proximal tibial angle, the trochlear sulcus angle and trochlea depth. Mean interobserver ICC of all parameters ranged from 0.32 to 0.99. Fifteen of 18 parameters showed a low mean deviation D from the mean of < 2 mm / 2°. Three parameters related to the patellofemoral joint showed medium or high D (patella tilt, trochlear sulcus angle, patellar ridge angle). These parameters also showed the highest values for the SD of D. The trochlear sulcus angle was found to be the only parameter with high mean deviation (D ≥ 5 mm/5°) with D being 5.67 ± 3.23°. CONCLUSIONS: The current version of the software achieves good interobserver reliability and accuracy with the exception of a few measurement parameters.


Subject(s)
Patella , Patellofemoral Joint , Humans , Lower Extremity , Patellofemoral Joint/diagnostic imaging , Reproducibility of Results , Retrospective Studies , Software
2.
Knee ; 29: 271-279, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33677151

ABSTRACT

BACKGROUND: Three-dimensional (3D) imaging and analysis offer new possibilities in preoperative diagnostics and surgical planning. Simultaneous 3D analysis of the joint angles and the patellofemoral anatomy allow for a realistic assessment of bony pathologies in patients with patellofemoral complaints. This study aims to develop a standardized and validated assessment of the 3D patellofemoral morphology and to establish reference ranges. METHODS: Thirteen patellofemoral anatomic landmarks were defined on 3D bone models of the lower limbs based on computer tomography data and evaluated regarding inter- and intra-observer variability. Further, 60 3D models of the lower limbs of young subjects without any previous knee operation/injury were assessed and rescaled reference values for relevant patellofemoral indices were obtained. RESULTS: The mean inter- and intra-observer deviation of all landmarks was below 2.3 mm. The interobserver intraclass correlation coefficient (ICC) was between 0.8 and 1.0 and the intra-observer ICC between 0.68 and 0.99 for all patellofemoral parameters. The calculated reference ranges are: Insall-Salvati index 1.0-1.4; patella tilt 6-18°; patella shift -4 to 3 mm; patella facet angle 118-131°; sulcus angle 141-156°; trochlear depth 3-6 mm; tibial-tuberosity to trochlear groove distance(TT-TG) 2D 14-21 mm; TT-TG 3D 11-18 mm; lateral trochlear inclination 13-23°; trochlear facet angle 43-65°. CONCLUSION: The demonstrated 3D analysis of the patellofemoral anatomy can be performed with high inter- and intra-observer correlation. Applying the obtained reference ranges and using existing 3D assessment tools for lower limb alignment, a preoperative 3D analysis and planning for complex knee procedures now is possible.


Subject(s)
Imaging, Three-Dimensional , Patellofemoral Joint/anatomy & histology , Patellofemoral Joint/diagnostic imaging , Adolescent , Adult , Anatomic Landmarks , Computer Simulation , Humans , Middle Aged , Reference Values , Reproducibility of Results , Tomography, X-Ray Computed , Young Adult
3.
Knee ; 27(2): 428-435, 2020 Mar.
Article in English | MEDLINE | ID: mdl-31806504

ABSTRACT

BACKGROUND: Three-dimensional (3D) preoperative planning and assisted surgery is increasingly popular in deformity surgery and arthroplasty. Reference ranges for 3D lower limb alignment are needed as a prerequisite for standardized analysis of alignment and preoperative planning in 3D, but are not yet established. METHODS: On 60 3D bone models of the lower limbs based on computed tomography data, fifteen parameters per leg were assessed by standardized validated 3D analysis. Distribution parameters and differences between sexes were evaluated. Reference values were generated by adding/subtracting one standard deviation from the mean. RESULTS: Women had a significantly lower mean mechanical lateral distal femoral angle compared with men (86.4 ±â€¯2.1° vs. 87.8 ±â€¯2.0°; P < .05) and significantly lower mean joint line convergence angle (-2.5 ±â€¯1.4° vs. -1.3 ±â€¯1.2; P < .01), but higher mean hip knee ankle angle (178.9 ±â€¯1.9° vs. 177.8 ±â€¯2.3°; P < .05) and mean femoral torsion (18.2 ±â€¯9.5° vs. 13.2 ±â€¯6.4°; P < .05), resulting in a tendency towards valgus alignment and vice versa for men. Differences in mean medial proximal tibial angle were not significant. The mean mechanical axis deviation from the tibial knee joint center was 6.9 ±â€¯7.3 mm medial and 1.4 ±â€¯16.1 mm ventral without significant differences between sexes. CONCLUSIONS: We describe total and sex-related reference ranges for all alignment relevant axes and joint angles of the lower limb. There are sex-related differences in certain alignment parameters, which should be considered in analysis and surgical planning.


Subject(s)
Bones of Lower Extremity/anatomy & histology , Bones of Lower Extremity/diagnostic imaging , Imaging, Three-Dimensional , Adolescent , Adult , Anatomic Landmarks , Computer Simulation , Female , Humans , Male , Middle Aged , Reference Values , Sex Characteristics , Tomography, X-Ray Computed , Young Adult
4.
Knee ; 26(1): 185-193, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30473372

ABSTRACT

INTRODUCTION: Three-dimensional (3D) surgical planning and patient-specific implants are becoming increasingly popular in orthopedics and trauma surgery. In contrast to the established and standardized alignment assessment on two-dimensional (2D) long standing radiographs (LSRs) there is neither a standardized nor a validated protocol for the analysis of 3D bone models of the lower limb. This study aimed to create a prerequisite for pre-operative planning. METHODS: According to 2D analysis and after meticulous research, 24 landmarks were defined on 3D bone models obtained from computed axial tomography (CT) scans for a 3D alignment assessment. Three observers with different experience levels performed the test three different times on three specimens. Intraobserver and interobserver variability of the landmarks and the intraclass correlation coefficient (ICC) of the resulting axes and joint angles were evaluated. RESULTS: Overall, the intraobserver and interobserver variability was low, with a mean deviation <5 mm for all landmarks. The ICC of all joint angles and axis deviations was >0.8, except for tibial torsion (ICC = 0.69). All knee joint angles showed excellent ICC (>0.95). CONCLUSIONS: Using the defined landmarks, a standardized 3D alignment assessment with low intraobserver and interobserver variability and high ICC values for the knee joint angles can be performed regardless of examiner's experience. The described method serves as a reliable standardized protocol for a 3D malalignment test of the lower limb. Three-dimensional pre-operative analysis might enhance understanding of deformities and lead to a new focus in surgical planning.


Subject(s)
Arthroplasty, Replacement, Knee/methods , Imaging, Three-Dimensional/methods , Knee Joint/surgery , Lower Extremity/diagnostic imaging , Tomography, X-Ray Computed/methods , Adult , Aged , Female , Humans , Knee Joint/diagnostic imaging , Male , Middle Aged , Preoperative Period , ROC Curve , Reproducibility of Results , Young Adult
5.
J Inherit Metab Dis ; 35(1): 51-63, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22033733

ABSTRACT

Deficiency of propionyl CoA carboxylase (PCC), a dodecamer of alpha and beta subunits, causes inherited propionic acidemia. We have studied, at the molecular level, PCC in 54 patients from 48 families comprised of 96 independent alleles. These patients of various ethnic backgrounds came from research centers and hospitals in Germany, Austria and Switzerland. The thorough clinical characterization of these patients was described in the accompanying paper (Grünert et al. 2012). In all 54 patients, many of whom originated from consanguineous families, the entire PCCB gene was examined by genomic DNA sequencing and in 39 individuals the PCCA gene was also studied. In three patients we found mutations in both PCC genes. In addition, in many patients RT-PCR analysis of lymphoblast RNA, lymphoblast enzyme assays, and expression of new mutations in E.coli were carried out. Eight new and eight previously detected mutations were identified in the PCCA gene while 15 new and 13 previously detected mutations were found in the PCCB gene. One missense mutation, p.V288I in the PCCB gene, when expressed in E.coli, yielded 134% of control activity and was consequently classified as a polymorphism in the coding region. Numerous new intronic polymorphisms in both PCC genes were identified. This study adds a considerable amount of new molecular data to the studies of this disease.


Subject(s)
DNA Mutational Analysis , Propionic Acidemia/diagnosis , Propionic Acidemia/genetics , Adolescent , Alleles , Child , Child, Preschool , Escherichia coli/genetics , Female , Humans , Infant , Introns , Lymphocytes/cytology , Male , Mutagenesis , Mutation , Polymorphism, Genetic , Recombinant Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods
6.
J Inherit Metab Dis ; 35(1): 41-9, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22134541

ABSTRACT

BACKGROUND: Whereas propionic acidemia (PA) is a target disease of newborn screening (NBS) in many countries, it is not in others. Data on the benefit of NBS for PA are sparse. STUDY DESIGN: Twenty PA patients diagnosed through NBS were compared to 35 patients diagnosed by selective metabolic screening (SMS) prompted by clinical findings, family history, or routine laboratory test results. Clinical and biochemical data of patients from 16 metabolic centers in Germany, Austria, and Switzerland were evaluated retrospectively. Additionally, assessment of the intelligent quotient (IQ) was performed. In a second step, the number of PA patients who have died within the past 20 years was estimated based on information provided by the participating metabolic centers. RESULTS: Patients diagnosed through NBS had neither a milder clinical course regarding the number of metabolic crises nor a better neurological outcome. Among NBS patients, 63% were already symptomatic at the time of diagnosis, and <10% of all patients remained asymptomatic. Among all PA patients, 76% were found to be at least mildly mentally retarded, with an IQ <69. IQ was negatively correlated with the number of metabolic decompensations, but not simply with the patients' age. Physical development was also impaired in the majority of patients. Mortality rates tended to be lower in NBS patients compared with patients diagnosed by SMS. CONCLUSION: Early diagnosis of PA through NBS seems to be associated with a lower mortality rate. However, no significant benefit could be shown for surviving patients with regard to their clinical course, including the number of metabolic crises, physical and neurocognitive development, and long-term complications.


Subject(s)
Neonatal Screening/methods , Propionic Acidemia/diagnosis , Adolescent , Austria , Child , Child, Preschool , Female , Germany , Humans , Infant , Infant, Newborn , Intelligence Tests , Male , Outpatients , Retrospective Studies , Surveys and Questionnaires , Switzerland
8.
Nucleosides Nucleotides Nucleic Acids ; 29(4-6): 509-14, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20544545

ABSTRACT

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine degradation pathway. In a patient presenting with convulsions, psychomotor retardation and Reye like syndrome, strongly elevated levels of uracil and thymine were detected in urine. No DPD activity could be detected in peripheral blood mononuclear cells. Analysis of the gene encoding DPD (DPYD) showed that the patient was homozygous for a novel c.505_513del (p.169_171del) mutation in exon 6 of DPYD.


Subject(s)
Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydrouracil Dehydrogenase (NADP)/genetics , DNA Mutational Analysis , Exons/genetics , Female , Humans , Infant , Sequence Deletion/genetics
9.
J Lipid Res ; 51(6): 1591-8, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20093478

ABSTRACT

The aim of the study was to develop a method for fast and reliable diagnosis of peroxisomal diseases and to facilitate differential diagnosis of cholestatic hepatopathy. For the quantification of bile acids and their conjugates as well as C(27) precursors di- and trihydroxycholestanoic acid (DHCA, THCA), in small pediatric blood samples we combined HPLC separation on a reverse-phase C18 column with ESI-MS/MS analysis in the negative ion mode. Analysis was done with good precision (CV 3,7%-11.1%) and sufficient sensitivity (LOQ: 11-91 nmol/L) without derivatization. Complete analysis of 17 free and conjugated bile acids from dried blood spots and 10 microL serum samples, respectively, was performed within 12 min. Measurement of conjugated primary bile acids plus DHCA and THCA as well as ursodeoxycholic acid was done in 4.5 min. In blood spots of healthy newborns, conjugated primary bile acids were found in the range of 0.01 to 2.01 micromol/L. Concentrations of C(27) precursors were below the detection limit in normal controls. DHCA and THCA were specifically elevated in cases of peroxysomal defects and one Zellweger patient.


Subject(s)
Bile Acids and Salts/blood , Bile Acids and Salts/chemistry , Blood Chemical Analysis/methods , Blood Specimen Collection , Carbon/chemistry , Serum/chemistry , Biliary Atresia/blood , Chromatography, Liquid , Galactosemias/blood , Humans , Infant , Infant, Newborn , Linear Models , Peroxisomal Disorders/blood , Tandem Mass Spectrometry , Time Factors , Ursodeoxycholic Acid/therapeutic use
10.
Klin Padiatr ; 222(1): 35-7, 2010.
Article in English | MEDLINE | ID: mdl-20084589

ABSTRACT

We report on a 4.5-year-old patient diagnosed with Glutaric aciduria type I (GAI), an autosomal recessive inborn error of lysine, hydroxylysine and tryptophan metabolism. Enzymatic assay in cultivated skin fibroblasts revealed complete absence of glutaryl-CoA dehydrogenase activity. All 11 Exons of the GCDH-Gen were sequenced and homozygosity for a yet undescribed mutation was identified. The patient was treated following the recently published guidelines for GA-I. Following this treatment regimen, the child developed normally without any manifest clinical crises. Our patient provides evidence that early commencement and strict adherence to treatment improves clinical outcome even in patients with complete absence of enzyme activity.


Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Glutarates/urine , Glutaryl-CoA Dehydrogenase/deficiency , Guideline Adherence , Neonatal Screening , Amino Acid Metabolism, Inborn Errors/diet therapy , Amino Acid Metabolism, Inborn Errors/genetics , Brain/pathology , Carnitine/administration & dosage , Cephalometry , Child, Preschool , Chromosome Aberrations , DNA Mutational Analysis , Diagnosis, Differential , Diet, Protein-Restricted , Exons/genetics , Genes, Recessive , Humans , Infant , Infant, Newborn , Lysine/administration & dosage , Magnetic Resonance Imaging , Male , Prognosis , Tryptophan/administration & dosage
11.
J Inherit Metab Dis ; 32 Suppl 1: S21-5, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19169842

ABSTRACT

D-2-hydroxyglutaric aciduria (D-2-HGA; OMIM 600721) is a rare autosomal recessive neurometabolic disorder with a wide clinical spectrum. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy with hypotonia, delayed cerebral visual development, cardiomyopathy and facial dysmorphic features. The mild phenotype has a more variable clinical expression with hypotonia and developmental delay. We present peripheral neuropathy as an additional clinical and electrophysiological feature in a 16-year-old boy with a homozygous missense mutation in exon 3 of the D-2-hydroxyglutarate dehydrogenase gene (D2HGDH) at position c.458T>C. This mutation results in replacement of a methionine residue, which was highly conserved during evolution, by threonine (p.Met153Thr).


Subject(s)
Alcohol Oxidoreductases/genetics , Brain Diseases, Metabolic, Inborn/complications , Peripheral Nervous System Diseases/etiology , Adolescent , Brain/pathology , Brain Diseases, Metabolic, Inborn/enzymology , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/pathology , Electrophysiological Phenomena , Genes, Recessive , Homozygote , Humans , Magnetic Resonance Imaging , Male , Mutation, Missense , Neural Conduction/genetics , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/physiopathology , Phenotype
12.
Neuropediatrics ; 39(2): 119-22, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18671189

ABSTRACT

L-2-Hydroxyglutaric aciduria (L-2-HGA, MIM 236792) is a rare autosomal recessive neurodegenerative disorder characterized by psychomotor delay, cerebellar and extrapyramidal signs and subcortical leukoencephalopathy with basal ganglia and dentate nuclei involvement. Mutations in the gene L2HGDH ( C14ORF160/DURANIN/) have been identified as causative for L-2-HGA. A feature disproportionally associated with L-2-HGA is the development of malignant brain tumors. In our cohort of 40 patients with L-2-HGA, two developed medulloblastoma and glioblastoma multiforme during the course of the disease. Two missense mutations in two patients were identified in the L2HGDH gene in exon 3 (c.292C-->T) and in exon 7 (c.887T-->A). Both mutations were present in the homozygous state. Serial MR imaging findings as well as MR spectroscopy imaging is reported in a patient who developed glioblastoma multiforme.


Subject(s)
Alcohol Oxidoreductases/genetics , Amino Acid Metabolism, Inborn Errors/genetics , Brain Neoplasms/diagnosis , Mutation, Missense , Alcohol Oxidoreductases/metabolism , Amino Acid Metabolism, Inborn Errors/complications , Amino Acid Metabolism, Inborn Errors/metabolism , Brain Neoplasms/etiology , Child , Child, Preschool , DNA Mutational Analysis , Glutarates/metabolism , Humans , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male
13.
J Inherit Metab Dis ; 31(3): 395-8, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18392751

ABSTRACT

The characteristic elevation of plasma glycine concentrations observed in propionic acidaemia (PA) and other 'ketotic hyperglycinaemias' has been attributed to secondary inhibition of the hepatic glycine cleavage system (GCS) by accumulating CoA derivatives of branched-chain amino acid metabolites. In nonketotic hyperglycinaemia (NKH), cerebrospinal fluid (CSF) and plasma glycine levels and their ratio are increased due to primary deficiency of central nervous system (CNS) as well as hepatic GCS. Whether the GCS in the CNS is also inhibited in PA is unclear, as there are scant data available on CSF glycine levels in this disorder. We studied the relation of CSF and plasma glycine levels in 6 paired samples from 4 PA patients, including one PA patient with bacterial meningitis who underwent ventriculoperitoneal shunting and multiple CSF analyses (n = 26). In contrast to the CSF glycine levels which were generally elevated in all four PA patients, the CSF/plasma glycine concentration ratios in paired samples were normal (0.016-0.029), with the exception of a single sample (0.132) with extremely high CSF protein concentration (2010 mg/L) during the course of meningitis indicating a disturbed blood-brain barrier. This finding of normal CSF/plasma glycine ratio in PA suggests that the observed elevations of CSF glycine levels are a reflection of the concurrent hyperglycinaemia resulting from secondary inhibition of hepatic GCS, but that brain GCS is not affected, in contrast to the situation in NKH. The neurological sequelae in PA are therefore unlikely to be related to disturbed glycine metabolism.


Subject(s)
Amino Acid Metabolism, Inborn Errors/metabolism , Glycine/blood , Glycine/cerebrospinal fluid , Propionates/blood , Brain/metabolism , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male
14.
J Inherit Metab Dis ; 31 Suppl 2: S275-9, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18415700

ABSTRACT

L-2-hydroxyglutaric aciduria (L-2-HGA) is a metabolic disease with an autosomal recessive mode of inheritance. It was first reported in 1980. Patients with this disease have mutations in both alleles of the L2HDGH gene. The clinical presentation of individuals with L-2-HGA is somewhat variable, but affected individuals typically suffer from progressive neurodegeneration. Analysis of urinary organic acids reveals an increased signal of 2-hydroxyglutaric acid, mainly as the L-enantiomer. L-2-HGA is known to occur in individuals of various ethnic backgrounds, but up to now mutation analysis has been mainly focused on patients of Turkish and Portuguese origin. This led us to confirm the diagnosis on the DNA level and undertake the corresponding mutation analysis in individuals of diverse ethnicity previously diagnosed with L-2-HGA on the basis of urinary metabolites and clinical/neuroimaging data. In 24 individuals from 17 families with diverse ethnic and geographic origins, 13 different mutations were found, 10 of which have not been reported previously. At least eight of the patients were compound heterozygotes. The identification of two mutations (c.751C > T and c.905C > T in exon 7) in patients with different origins supports the view that they occurred independently in different families. In contrast, the mutation c.788C > T was detected in all six Venezuelan patients originating from the same Caribbean island of Margarita, but not in other patients, thus rendering a founder effect likely. None of the mutations was found in the control population, indicating that they are most probably causative. Mutation analysis may improve the quality of diagnosis and prenatal diagnosis of L-2-HGA.


Subject(s)
Alcohol Oxidoreductases/genetics , Brain Diseases, Metabolic, Inborn/enzymology , Brain Diseases, Metabolic, Inborn/genetics , Mutation , Adult , Biomarkers/urine , Brain Diseases, Metabolic, Inborn/diagnosis , Brain Diseases, Metabolic, Inborn/ethnology , DNA Mutational Analysis , Disease Progression , Europe/ethnology , Female , Genetic Predisposition to Disease , Glutarates/urine , Humans , Infant , Male , Pakistan/ethnology , Phenotype , Predictive Value of Tests , Saudi Arabia/ethnology , Severity of Illness Index , Venezuela/ethnology
16.
Gut ; 56(8): 1105-10, 2007 Aug.
Article in English | MEDLINE | ID: mdl-16956918

ABSTRACT

BACKGROUND AND AIMS: To investigate the relationship between lipid profiles and diabetes with past and chronic hepatitis C virus (HCV) infection among village residents of Egypt. PATIENTS AND METHODS: Fasting lipids and glucose profiles were compared among adults never infected with HCV (negative HCV antibodies), infected in the past (positive HCV antibodies and negative HCV RNA) and chronically infected (positive HCV antibodies and HCV RNA). RESULTS: Of the 765 participants, 456 (59.6%) were female, and median age was 40 (range 25-88) years. Chronic HCV infection was present in 113 (14.8%) and past infection in 67 (8.8%). After adjustment for age and sex, participants with chronic HCV infection had lower plasma low density lipoproteins (LDL) cholesterol and triglyceride levels compared with those never infected (age and sex adjusted differences (95% CI) were -19.0 (-26.3 to -11.7) mg/dl and -26.2 (-39.0 to -13.3) mg/dl, respectively). In contrast, participants with cleared HCV infection had higher triglyceride levels compared with those never infected (age and sex adjusted difference (95% CI) was +16.0 (0.03 to 31.9) mg/dl). In multivariate analysis, participants with chronic HCV infection were more likely to have diabetes (OR 3.05, 95% CI 1.19 to 7.81) compared with those never infected, independent of LDL cholesterol levels. CONCLUSION: In conclusion, this community based study has shown that in a single population, chronic HCV infection is associated with glucose intolerance and, despite that, a favourable lipid pattern. An intriguing finding was the high triglyceride levels observed among participants with past infection, suggesting that elevated triglycerides at the time of acute infection may facilitate viral clearance.


Subject(s)
Blood Glucose/analysis , Hepatitis C/epidemiology , Lipids/analysis , Adult , Age Distribution , Aged , Aged, 80 and over , Atherosclerosis/epidemiology , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Diabetes Mellitus/blood , Diabetes Mellitus/epidemiology , Egypt/epidemiology , Female , Hepatitis C/blood , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/epidemiology , Humans , Male , Middle Aged , Prevalence , Risk Factors , Rural Health , Sex Distribution , Triglycerides/blood
17.
Neuropediatrics ; 36(4): 252-5, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16138249

ABSTRACT

Canavan disease is characterised as a rare, neurodegenerative disease that usually causes death in early childhood. It is an autosomal recessive disorder due to an aspartoacylase (ASPA) deficiency. The causative gene has been mapped to chromosome 17 pter-p13. Here we describe three affected children from two Greek families with an unusually mild course of Canavan disease. All children presented with muscular hypotonia and macrocephaly. Diagnosis was based on elevated N-acetylaspartate in urine, reduced aspartoacylase activity in fibroblasts, and marked white matter changes on cerebral imaging. All three affected individuals exhibited continuous psychomotor development without any regression. Genetic analyses revealed compound heterozygous mutations (Y288 C; F295 S) in two individuals. The Y288 C variant was previously described in a child with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia, partial cortical blindness and retinitis pigmentosa, and slightly elevated N-acetylaspartate in the urine. Demonstration of the same variant in two unusually mildly affected Canavan disease patients and absence of this variant in 154 control chromosomes suggest a possible pathogenic role in mild Canavan disease. In the third individual, two homozygous sequence variants were identified, which comprise the known G274R mutation and a novel K213E variant.


Subject(s)
Amidohydrolases/genetics , Canavan Disease/genetics , Mutation , Phenotype , Adolescent , Amidohydrolases/deficiency , Canavan Disease/pathology , Canavan Disease/physiopathology , Child , Child, Preschool , DNA Mutational Analysis/methods , Female , Genotype , Humans , Magnetic Resonance Imaging/methods , Male
18.
Clin Pediatr (Phila) ; 43(9): 837-43, 2004.
Article in English | MEDLINE | ID: mdl-15583780

ABSTRACT

Propionic acidemia (PA) is one of the most frequent organic acidurias, but information on the outcome of individuals with PA is rather limited. We present data of 49 patients with PA, which were gathered from 18 metabolic centers throughout Central Europe on the occasion of an international workshop. All patients were identified by selective metabolic screening, and 86% of them were classified as having early-onset PA owing to their presentation with clinical symptoms within the first 90 days of life. Mortality rate was one third, and details of symptoms and treatment of the surviving patients are discussed. The great variation of phenotypic expression of the disease and different therapeutic strategies (especially in regard to the degree of protein restriction) used at the various institutions involved in this study imply the need for a registry of PA patients and for a multicenter prospective treatment study.


Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/therapy , Propionates/blood , Child , Child, Preschool , Eating , Humans , Infant , Time Factors
19.
J Inherit Metab Dis ; 27(6): 741-5, 2004.
Article in English | MEDLINE | ID: mdl-15505379

ABSTRACT

Isobutyryl-CoA dehydrogenase (IBD) is an enzyme involved in the catabolism of the branched-chain amino acid valine. We report a third and a fourth child with IBD deficiency who were both detected during newborn screening with tandem mass spectrometry and so far do not receive any treatment. The diagnosis was confirmed by biochemical and molecular studies. One of the children is homozygous for the mutation M128I in the ACAD8 gene, which is predicted to affect the substrate binding cavity. The other child is compound heterozygous for a frameshift mutation F33fsins and a missense mutation V203I. It is as yet uncertain whether IBD deficiency may cause significant morbidity in affected children and whether treatment is necessary. In view of the limited experience worldwide, careful monitoring of the children is recommended.


Subject(s)
Acyl-CoA Dehydrogenases/genetics , Carnitine/analogs & derivatives , Mutation/genetics , Oxidoreductases Acting on CH-CH Group Donors/deficiency , Carnitine/blood , Carnitine/urine , Female , Frameshift Mutation/genetics , Humans , Infant, Newborn , Male , Mass Spectrometry , Mutation, Missense/genetics , Neonatal Screening
20.
Arch Dermatol Res ; 296(4): 188-91, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15232704

ABSTRACT

The term "trichothiodystrophy" (TTD) covers several autosomal recessive diseases whose diagnostic hallmark is short, brittle hair low in sulfur and cystine because of impaired synthesis of high-sulfur matrix protein. Clinical symptoms associated with TTD represent a variable range of abnormalities in organs derived from ectoderm and neuroectoderm. Important laboratory tests of the hair for the diagnosis of TTD comprise polarizing microscopy ("tiger-tail" pattern), electron microscopy, and amino acids analysis of hydrolyzed hair with a special focus on cystine. However, only very few institutions determine the amino acid composition of human hair and nail clippings, which requires special sample preparation including hydrolysis. If no special precautions are taken, quantification of cysteine and cystine becomes inaccurate because of decomposition of these residues during hydrolysis. We therefore performed the sample work-up with azide-dependent oxidation which we have for the first time adapted for analysis of hair and nail clippings. With our control and parent data resembling published data on hair and nail samples, we obtained a decreased proportion of cysteine (half cystine, determined as cysteic acid) in materials obtained from a boy with TTD. Clearly, the method for the quantification of cysteine following sodium azide-dependent oxidation is a suitable and rather convenient approach to the quantification of cyst(e)ine and other amino acids in hair and nail proteins, and is a valuable contribution to the diagnosis of TTD.


Subject(s)
Cysteic Acid/metabolism , Cysteine/metabolism , Genes, Recessive , Hair Diseases/diagnosis , Hair Diseases/metabolism , Hair/metabolism , Nails/metabolism , Sodium Azide , Hair/pathology , Hair Diseases/genetics , Hair Diseases/pathology , Humans , Infant , Male , Oxidation-Reduction/drug effects , Sodium Azide/pharmacology
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