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Biomedical subjects

D Schnabel

Publications and source records attributed to D Schnabel.

At least 19 recordsLinked to original sources
PubMed2005

[Rickets. Diagnosis and therapy].

Rickets is caused by deficient mineralization at the level of growth plate and is usually due to a decreased serum calcium/phosphate product. Although the diagnosis of rickets can usually be suspected on the basis of a clinical examination (bone deformities in legs, impaired growth), radiological examination and detailed biochemical work-up are necessary to elucidate the etiology of the underlying disease. It is important to differentiate between calcipenic/vitamin deficient and phosphopenic rickets. The former is due to vitamin D deficiency, and the ultimate cause of this usually lies in altered vitamin D supply; however, impaired synthesis of or resistance to the actions of vitamin D can also be a cause. Phosphopenic rickets is usually related to impaired phosphate reabsorption in the proximal renal tubule. Both calcipenic and phosphopenic rickets can be acquired or hereditary in origin.

Diagnosis, Differential↗
PubMed2004

The use of L-T4 as liquid solution improves the practicability and individualized dosage in newborns and infants with congenital hypothyroidism.

UNLABELLED: Dosage recommendations for the initial therapy of congenital hypothyroidism (CH) in newborns vary between 8 microg/kg/d and 10-15 microg/kg/d. AIM: To evaluate the practicability of LT4 in liquid form and to define the initial dosage for optimal treatment. METHODS: Liquid LT4 solution was administered to 28 consecutive newborns with primary CH. We measured TSH, T3, T4, free T3 and free T4 before therapy and during follow-up up to 2 years. After 2 years a standardized developmental test (Griffith) was performed. RESULTS: The median dosage at start of therapy was 12.3 microg LT4/kg/d and decreased to about 5 microg LT4/kg/d after 9 months. The median time of normalization of TSH (< or =6 mU/l) was 2 weeks. In 21 patients, who received a median starting dosage of 12.7 microg LT4/kg (range 9.8-17.1 microg/kg), TSH levels normalized within a median of 1 week. Seven patients receiving only 10.1 microg LT4/kg normalized their TSH only after a median of 2 months. CONCLUSIONS: Newborns with CH should normalize their TSH within 1-2 weeks. The initial dose necessary to normalize TSH is not lower when a liquid solution is used. The higher dose used in tablets is not due to inefficient absorption, but rather reflects the increased demand for thyroid hormone in the first weeks of life.

Congenital Hypothyroidism↗
PubMed2001

Short stature homeobox-containing gene deletion screening by fluorescence in situ hybridisation in patients with short stature.

UNLABELLED: The short stature homeobox-containing gene (SHOX) on the short arm of the X and Y chromosomes is an important determining factor of stature phenotype. Absence of the SHOX gene is a main cause for short stature in patients with Turner syndrome. Mutations of the SHOX gene can also be responsible for Léri-Weill syndrome (dyschondrosteosis). The aim of this study was to determine the frequency of SHOX deletions in short stature children and to delineate indications for SHOX deletion screening. Out of 50 probands, 35 had idiopathic short stature, 12 cases showed additional anomalies of the forearms (in particular Madelung deformity) and three patients were affected by a congenital heart defect. Chromosomal investigations with fluoresence in situ hybridisation did not reveal a SHOX deletion in any patient with idiopathic short stature. In five of the 12 patients (41.7%) with anomalies of the forearms, a SHOX deletion on one sex chromosome could be detected. No deletion was observed in the three cases with additional heart defects. CONCLUSION: The frequency of short stature homeobox-containing gene deletions in patients with idiopathic short stature appears to be very low and does not require a fluorescence in situ hybridisation analysis. Short stature in association with anomalies of the forearms such as Madelung deformity makes a deletion more probable and therefore screening for such deletions is recommended in these cases.

Adolescent↗
PubMed2001

Decreased expression of IGF-II and its binding protein, IGF-binding protein-2, in genital skin fibroblasts of patients with complete androgen insensitivity syndrome compared with normally virilized males.

The action of androgen by way of the AR is required for the development of male gonads and external genitalia. The interplay between androgens and the somatotropic axis, in particular the IGFs in sexual development, is currently under thorough investigation. The IGF system is thought to mediate the androgen action in androgen-responsive cells. To investigate the interaction of androgens with the IGF system, we compared the expression of IGFs and IGF-binding proteins in cultured genital skin fibroblasts from nine patients with the syndrome of complete androgen insensitivity with that in genital skin fibroblasts from 10 normally virilized males. Mutations in the AR gene and/or abnormalities of the AR protein in the immunoblot were detected in all complete androgen insensitivity genital skin fibroblast strains. They caused a complete failure of DHT binding. RIA and RT-PCR demonstrated that the genital skin fibroblast strains expressed IGF-II, IGF-binding protein-2, and IGF-binding protein-3, but no IGF-I. Most strikingly, complete androgen insensitivity genital skin fibroblast strains produced significantly lower IGF-II (P < 0.001; 42.2 +/- 9.7 vs. 106.9 +/- 11.8 ng/mg protein) and IGF-II mRNA (P < 0.01, by RT-PCR) than control genital skin fibroblast strains. The production of IGF-binding protein-2 was also decreased (P < 0.03) in complete androgen insensitivity genital skin fibroblasts, whereas that of IGF-binding protein-3 did not differ. Furthermore, high levels of IGF-binding protein-5 mRNA were detected in all genital skin fibroblast strains, whereby the 28-kDa band in the ligand blot, probably representing IGF-binding protein-5, was more abundant in complete androgen insensitivity genital skin fibroblasts. Exposure of the genital skin fibroblasts to T (5 x 10(-8) M) had only weak effects on the expression of IGFs and IGF-binding proteins. In conclusion, although the mechanism underlying these differences requires further study, it is conceivable that in addition to the endocrine actions of IGF-I, IGF-II and IGF-binding protein-2, as local growth factors, are involved in the mediation of androgen action and growth of genital tissues.

Androgen-Insensitivity Syndrome↗
PubMed2000

Free and protein bound leptin are distinct and independently controlled factors in energy regulation.

AIMS/HYPOTHESIS: Leptin exerts important regulating effects on energy homeostasis and could have a central role in our understanding of obesity, diabetes mellitus and the metabolic syndrome. Leptin circulates in a free and protein bound form. The aim of the present study was to test whether both fractions of the leptin system can be selectively regulated and thus serve independent physiological roles. METHODS: Using specific radioimmunoassays we measured both leptin components in relation to BMI in healthy subjects before and after weight reduction and in hyperthyroid patients during correction of thyrotoxicosis. In the latter group body composition and resting energy expenditure was monitored. In addition, we measured serum and cerebrospinal fluid concentrations of free and bound leptin in patients with neurological disorders. RESULTS: Under all conditions free leptin concentrations reflected body fat mass. Bound leptin concentrations decreased during weight reduction but also after treatment of hyperthyroidism despite an increase in fat mass. Direct measurement of resting energy expenditure and bound leptin in hyperthyroid patients and under thyrostatic treatment showed a significant positive correlation of both variables. In contrast to free leptin whose transport into the cerebrospinal fluid appears to be saturated at low physiological concentrations of serum free leptin, bound leptin concentrations in the cerebrospinal fluid increased in parallel to serum concentrations over the whole physiologically relevant range. CONCLUSION/INTERPRETATION: Our data indicate a distinct role of free and bound leptin in the feedback regulating energy intake and expenditure and could have important implications for our understanding of the physiology and pathophysiology of leptin-dependent signalling.

Adolescent↗
PubMed2000

Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency.

Combined pituitary hormone deficiency (CPHD) has been linked with rare abnormalities in genes encoding transcription factors necessary for pituitary development. We have isolated LHX3, a gene involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins, consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consanguineous families displaying a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged anterior pituitary. These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain. These data are consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and extrapituitary structures.

Abnormalities, Multiple↗
PubMed2000

Molecular pathogenesis of neonatal hypothyroidism.

In patients with congenital hypothyroidism (CH), the autosomal recessive inheritance of mutations of thyroid peroxidase, thyroglobulin and the NIS and pendrin genes encoding for sodium iodide transporters has been identified. CH due to thyroid dysgenesis was considered to be a sporadic disease, but recently, inheritable defects of thyroid development have been described. The autosomal recessive inheritance of mutations of the thyroid-stimulating hormone receptor gene was recognized in patients with CH and thyroid hypoplasia, while autosomal dominant mutations of the Pax-8 gene were described in patients with thyroid dysgenesis. In addition, analysis of mutations of the beta-thyrotropin gene has resulted in a new understanding of the pathogenesis of central CH. Molecular genetic studies in patients with CH detected by newborn screening will provide the information necessary for genetic counselling and may help to explain the less favourable outcome present in 5-10% of the patients.

Carrier Proteins↗
PubMed2000

How a patient homozygous for a 30-kb deletion of the C4-CYP 21 genomic region can have a nonclassic form of 21-hydroxylase deficiency.

A case of nonclassic (NC) 21-hydroxylase deficiency, with a moderately elevated 17-hydroxyprogesterone level (145 nmol/L in filter paper blood spot), was detected in newborn screening. The newborn's phenotype was female, with no sign of virilization. Confirmatory diagnosis revealed elevated serum levels of 17-hydroxyprogesterone and of 21-desoxycortisol, whereas cortisol, PRA, and electrolytes were normal. Hydrocortisone substitution was considered at the age of 6 months, when virilization became obvious. For clinical reasons, this case had to be classified as late-onset congenital adrenal hyperplasia (CAH) with unusually early manifestation. However, the diagnosis of classic 21-hydroxylase deficiency was obtained by Southern blotting studies, showing that she was homozygous for the 30-kb deletion, including the 3' end of CYP21P pseudogene, the C4B gene, and the 5' end of the functional CYP21 gene. Further studies, using PCR and sequencing, were conducted to explain the discrepancy between this genotype, usually associated with a classic salt-wasting form, and the girl's phenotype. Typically, patients homozygous for the 30-kb deletion encoding classic CAH possess a unique CYP21P/21 hybrid gene with the junction site located after the third exon, yielding a nonfunctional pseudogene. The girl in question, however, was heterozygous for the 8-bp deletion, suggesting that the chimeric pseudogene on one allele had a junction site before the third exon. She was compound heterozygous for a 30-kb deletion encoding classic CAH on the paternal allele, and a 30-kb deletion encoding NC CAH on the maternal allele. This novel maternal CYP21P/21 hybrid gene is characterized by a junction site before intron 2 and differs from the normal CYP21 gene only by the P30L mutation in exon 1 and the promoter region of the CYP21P pseudogene. Because the P30L mutation has been described to result in an enzyme with 30-60% activity of the normal P450c21 enzyme, and the CYP21P promoter reduced the transcription to 20% of normal, this puzzling phenotype of a NC CAH with early onset may be fully explained by the genotype of the patient and considered as an intermediate form between the simple virilizing and NC form.

17-alpha-Hydroxyprogesterone↗
PubMed1999

Complete androgen insensitivity caused by a new frameshift deletion of two base pairs in exon 1 of the human androgen receptor gene.

We describe a novel mutation in exon 1 of the androgen receptor gene in a patient with complete androgen insensitivity (CAIS). Endocrine findings were typical for androgen insensitivity (testosterone serum levels in the upper limit of normal males and increased LH serum concentrations). Biochemical investigations in cultured genital skin fibroblasts of the patient showed a normal 5alpha-reductase activity but a complete absence of androgen binding. Western blot analysis revealed no detectable protein product. Sequence analysis of the entire coding region of the androgen receptor gene resulted in the identification of a 2-bp deletion in codon 472, causing frameshift and introduction of a premature stop codon 27 codons downstream of the mutation.

Adult↗
PubMed1997

Functional activity of CD44 isoforms in haemopoiesis of the rat.

Expression of CD44 is involved in the maturation as well as the homing of haemopoietic progenitor cells. Whether these processes are mediated by CD44 standard (CD44s) or variant (CD44v) isoforms is unknown. To assign functional activities of CD44 in haemopoiesis of the rat to distinct isoforms, ligand binding of haemopoietic progenitor cells was inhibited by monoclonal antibodies recognizing an epitope on CD44s (Ox50) or CD44 exon v6, (1.1ASML). The vast majority of rat bone marrow cells (BMC) as well as stromal cells and non-adherent cells in long-term bone marrown culture (LTBMC) expressed CD44s. Bone marrow cells and non-adherent cells in LTBMC, but not the stromal cells, also contained a population of large and granulated cells, which stained with anti-CD44v6. In vivo and in vitro reconstitution experiments revealed that homing of BMC as well as settlement on stromal elements was influenced exclusively by anti-CD44s, which also inhibited proliferation of progenitor cells. Anti-CD44v6 had no influence on homing and seeding, but interfered with stroma formation and progenitor maturation. Finally, restoration of functional activity of T-lineage cells was impaired in the presence of anti-CD44v6. The data indicate that CD44s and CD44v6 fulfilled distinct functions in haemopoiesis of the rat. Although CD44s facilitated homing and expansion of stem cells, progenitor cells, CD44v6 was involved in differentiation processes, particularly of lymphoid progenitor cells.

Animals↗
PubMed1996

Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase. Identification Of the first molecular lesion causing Farber disease.

Human acid ceramidase ((AC) N-acylsphingosine amidohydrolase, EC 3.5. 1.23) hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid. Ceramide is an essential component of all sphingolipids and an important cell-signaling molecule. Moreover, an inherited deficiency of AC activity leads to the lysosomal storage disorder known as Farber disease. Human AC was purified from urine, and 117 amino acid residues were determined by microsequencing. Degenerative oligonucleotide probes were then constructed and used to screen for human fibroblast and pituitary cDNA libraries. Several partial cDNA clones were obtained, and two of these were combined to construct a full-length cDNA containing a 17-base pair (bp) 5'-untranslated sequence, a 1185-bp open reading frame encoding 395 amino acids, a 1110-bp 3'-untranslated sequence, and an 18-bp poly(A) tail. Transient expression of the full-length cDNA in COS-1 cells led to a 10-fold increase in AC activity. In addition, biosynthetic studies carried out in the transfected cells demonstrated that 13-kDa (alpha) and 40-kDa (beta) AC subunits were derived from a common 55-kDa precursor encoded by the full-length cDNA. This protein pattern was identical to that seen in normal human skin fibroblasts. A homoallelic point mutation (T222K) was also identified in the AC gene of a patient suffering from Farber disease, further confirming the authenticity of the full-length cDNA.

Acid Ceramidase↗
PubMed1996

Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency.

Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5 alpha-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5 alpha-reductase 2 deficiency (SRD). Phenotypes, which were classified according to the severity of the masculinization defect, varied between completely female (SRD type 5), predominantly female (SRD type 4), ambiguous (SRD type 3), predominantly male with micropenis and hypospadias (SRD type 2), and completely male without overt signs of undermasculinization (SRD type 1). T/DHT-ratios were highly increased ( > 50) in the classical syndrome (SRD type 5), but variable in the less severe affected patients (SRD types 1-4) (14-35). Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5 alpha-reductase deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms of undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1996

Transient congenital hypothyroidism and hyperthyrotropinemia: normal thyroid function and physical development at the ages of 6-14 years.

Since the introduction of screening programs for congenital hypothyroidism, transient disturbances of thyroid function, especially transient congenital hypothyroidism and hyperthyrotropinemia, mostly due to iodine deficiency or contamination have been observed with variable frequencies. This study was carried out to reevaluate the thyroid function and physical development of 61 schoolchildren with transient congenital hypothyroidism or transient congenital hyperthyrotropinemia. Abnormalities were observed in 3 children. Thyroid function and growth were normal in all children, except 2 with moderately elevated TSH levels at the age of 7.7 and 10 yr in the presence of normal thyroid hormone levels. In 1 child, the TSH elevation was due to an ectopic hemithyroidea; in the other child, an unknown familial cause was suggested. In 1 girl (aged 12 yr), a euthyroid goiter caused by autoimmune thyroiditis was detected. We conclude from our investigation that frequent monitoring of thyroid function in children with transient congenital hypothyroidism or transient congenital hyperthyrotropinemia is not necessary during childhood if, postnatally, thyroid function recovered spontaneously. However, the growth and development of children with neonatal thyroid dysfunction should be followed, and if abnormalities occur, thyroid function tests are essential.

Adolescent↗
PubMed1995

Urinary excretion of galactosyl-hydroxylysine is a marker of growth in children.

Galactosyl-hydroxylysine (Gal-Hyl) is the predominant product of the posttranslational glycosylation of skeletal collagen. Urinary Gal-Hyl excretion is regarded as a marker of bone resorption in adults, but little information is available on the validity of this parameter in pediatric age groups. Using 24-h urine samples from 88 healthy children and adolescents ages 4-18 yr, reference ranges were established for this age group, and values were compared with measurements in children with overt GH deficiency (n = 14) or Ullrich-Turner syndrome (n = 21). When expressed relative to body weight (Gal-Hyl/wt), urinary Gal-Hyl excretion was 3.2 to 4.7 times higher in subjects 4-16 yr of age than in adults. Highest values were observed in very young children and during the pubertal growth spurt. In the total population, urinary Gal-Hyl/wt was closely related to growth velocity (r = 0.72) and significantly correlated with the urinary excretion of both hydroxyproline (r = 0.74) and deoxypyridinoline (r = 0.88; P < 0.001 each). Urinary Gal-Hyl/wt was significantly lower in children with GH deficiency or Ullrich-Turner syndrome than in healthy children (P < 0.001 each). The urinary excretion of Gal-Hyl was significantly correlated with growth velocity in GH-deficient children (r = 0.69; P = 0.004) but not in patients with Ullrich-Turner syndrome. In the latter, the increase in urinary Gal-Hyl excretion after 3 months of treatment with recombinant human GH correlated significantly with the increase in growth velocity after 12 months of treatment (r = 0.76; P = 0.002). We conclude that the urinary excretion of Gal-Hyl is a valid and potentially useful index of skeletal growth in children.

Adolescent↗
PubMed1993

Molecular genetics of GM2-gangliosidosis AB variant: a novel mutation and expression in BHK cells.

The GM2 activator is a hexosaminidase A-specific glycolipid-binding protein required for the lysosomal degradation of ganglioside GM2. Genetic deficiency of GM2 activator leads to a neurological disorder, an atypical form of Tay-Sachs disease (GM2 gangliosidosis variant AB). Here, we describe a G506 to C transversion (Arg169 to Pro) in the mRNA of an infantile patient suffering from GM2-gangliosidosis variant AB. Using the polymerase chain reaction amplification and direct-sequencing technique, we found the patient to be homozygous for the mutation, whereas the parents were, as expected, heterozygous. BHK cells transfected with a construct of mutant cDNA gave no GM2 activator protein detectable by the Western blotting technique, whereas those transfected by a wild-type cDNA construct showed a significant level of human GM2 activator protein. The substitution of proline for the normal Arg169 therefore appears to result in premature degradation of the mutant GM2 activator, either during the post-translational processing steps or after reaching the lysosome. The basis for the phenotype of GM2 gangliosidosis variant AB may therefore be either inactivation of the physiological activator function by the point mutation or instability of the mutant protein.

Animals↗