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At least 145 records · Page 8Linked to original sources
PubMed1979

Histochemical methods for dissociated muscle fibers.

Skeletal or cardiac muscle fibers can be separated by brief (3--5 second) dissociation of formalin-fixed pieces with a Willems Polytron (Brinkmann Instrument Co.). Such separated fibers are useful for demonstration of abnormal accumulations of lipids, carbohydrates, proteins and minerals in metabolic diseases. Staining techniques for demonstration of various stored materials include: 1) toluidine blue at pH 2.8 for acid mucopolysaccharide in skeletal muscle fibers in Pompe's glycogenesis 2, 2) one-step trichrome stain for nemaline myopathy and for abnormal mitochondria in X-linked infantile cardiomyopathy, 3) periodic acid-methenamine silver stain for glycolipid-containing lysosomes in I-cell disease (mucolipidosis 2), 4) Sudan black B stain for lipid in skeletal muscle fibers in Reye's syndrome, infantile lactic acidosis, Leigh's infantile subacute necrotizing encephalopathy and Jansky-Bielschowsky late infantile ceroid lipofuscinosis, 5) iron stain for iron in cardiac and skeletal muscle fibers in thalassemia with advanced hemosiderosis, and 6) autofluorescence for "ceroid" in skeletal muscle fibers in Jansky-Bielschowsky disease.

Carbohydrates↗
PubMed2026

Xp21 contiguous gene deletion syndrome presenting as congenital adrenal hypoplasia: molecular diagnosis and clinical re-evaluation of a pedigree.

OBJECTIVE: To investigate the molecular etiology in a male child clinically suspected of congenital adrenal hyperplasia (CAH) with negative conventional genetic testing, and to elucidate the genetic characteristics of his pedigree. METHODS: Clinical data from the proband and his family members were collected. Molecular diagnostics proceeded sequentially: initial targeted CAH testing (CYP21A2 and POR sequencing/MLPA, plus targeted NR0B1 CNV analysis) was followed by whole-exome sequencing coupled with genome-wide CNV analysis. RESULTS: The proband presented with neonatal cyanosis and hyperpigmentation. Laboratory tests showed markedly elevated ACTH (354.68 pmol/L) and low aldosterone (57.24 pg/mL). Molecular genetic testing identified a hemizygous deletion of approximately 4.44 Mb at Xp21.3-p21.1 (chrX:g.27080000_31520000), encompassing the NR0B1, GK, IL1RAPL1, and DMD genes. CNV-seq confirmed that the mother carried a heterozygous deletion of 4.38 Mb in the same region, while the father and four maternal aunts showed normal genotypes. CONCLUSION: This study ultimately diagnosed the proband with Xp21 contiguous gene deletion syndrome. The adrenal insufficiency resulted from X-linked congenital adrenal hypoplasia (AHC) due to NR0B1 haploinsufficiency, rather than CAH. These findings highlight the considerable clinical overlap between AHC and CAH, indicating that CNV analysis of the Xp21 region should be included in the diagnostic workup for male infants with suspected CAH but negative routine genetic testing. This provides a basis for the precise diagnosis and genetic counseling of such patients.

Humans↗
PubMed2026

A novel hemizygous missense variant in the BEND2 gene is associated with nonobstructive azoospermia.

Nonobstructive azoospermia (NOA), the most severe form of male infertility, frequently arises from genetic defects that disrupt spermatogenesis. In this study, a novel hemizygous missense variant (NM_001184767.2 [c.G1069A; p.V357I]) is identified in the X-linked BEN domain-containing 2 ( BEND2 ) gene of a patient with NOA characterized by spermatocyte maturation arrest. Whole-exome sequencing and Sanger validation confirmed that this rare variant is absent in fertile controls and that no pathogenic variants were detected in established NOA genes. Computational analysis predicted potential structural alterations via AlphaFold modeling, leading to the hypothesis that the ability of BEND2 to recognize genomic targets may be compromised. The patient's phenotype phenocopies the meiotic arrest observed in Bend2 -knockout mice. Expression profiling confirmed predominant BEND2 transcription in human and mouse testes, peaking in early spermatocytes and coinciding with meiotic initiation, with reduced transcript levels detected in the proband's peripheral blood compared with those in an obstructive azoospermia control. This study reports a pathogenic BEND2 variant associated with NOA with spermatocyte arrest, highlighting its critical role in human meiosis and expanding the genetic etiology of male infertility.

Adult↗
PubMed2026

Human GPR174 deficiency drives polyclonal lymphoproliferative disease via defects in T cell function.

The X-linked G-protein coupled receptor GPR174 is highly expressed in T and B lymphocytes and has immunoregulatory roles in mice, but its function in humans is unknown. We describe a cohort of six individuals who have function-disrupting variants in GPR174 and a clinical phenotype of lymphadenopathy and autoimmunity. Histological analysis of two patient lymph nodes revealed necrotizing lymphadenitis and lymphoproliferation resembling Kikuchi-Fujimoto disease. In-depth analysis of three patients and related carriers revealed overaccumulation of CD8 terminally differentiated effector memory cells re-expressing CD45RA (TEMRA). Patient cells and GPR174-deficient CD8 T cells generated from controls showed less repression of proliferation by the GPR174 ligand lysophosphatidylserine (lysoPS) and an effector-biased gene expression program. GPR174-deficient CD4 T cells were resistant to lysoPS-mediated suppression of IL2 production. In mice, chronic viral infection led to over-accumulation of GPR174-deficient effector CD8 T cells. We describe an inborn error of immunity associated with dysregulated lymphocyte responses that we propose predisposes to exaggerated lymphoproliferation and autoimmunity following viral infection.

Journal Article↗
PubMed1978

Iduronate sulfatase analysis of hair roots for identification of Hunter syndrome heterozygotes.

Iduronate sulfatase, the enzyme deficient in Hunter syndrome, can be readily measured in individual hair roots. Samples from Hunter syndrome hemizygotes had activities at or near the limits of detection. Samples from two mothers of Hunter syndrome patients, one an obligate heterozygote, had lower average iduronate sulfatase activity than the normal mean, and a significant number of hair roots had activity in the pathognomic range. A third mother showed a normal distribution of enzyme activity, and no hair roots were in the range of those from an affected individual. These results are similar to studies on the distribution of other X-linked enzymes in individual hair root samples from heterozygotes. This suggests that hair root iduronate sulfatase assessment is useful in the detection of Hunter syndrome carrier status, but further refinement of the test system is necessary.

Female↗
PubMed1979

Abnormalities of ultrastructure and calcium distribution in the flight muscle of a flightless mutant of Drosophila melanogaster.

An X-linked mutant of Drosophila melanogaster was isolated which was completely unable to fly. The map position of the mutation is 43 +/- 0.1. Gynandromorph analysis indicated that the mutation is autonomously expressed in the flight muscle. Fate-map data show that the focus of the mutation lies close to the ventral midline of the blastoderm. Flightlessness appears to be the result of abnormalities of the thoracic musculature, including highly irregular arrangement of the fibrils, lack of the normal striation pattern and abnormal structure of the mitochondria. X-ray microanalysis (EDAX) demonstrates a pronounced difference in the distribution of calcium in mutant and wild-type flight muscle at the fine-structural level. We propose that an abnormal calcium distribution in the mutant may be associated with the ultrastructural abnormalities and ultimately responsible for the flightless phenotype.

Animals↗
PubMed1976

Screening for fetal chromosome aberrations in early pregnancy.

Seven years' experience in prenatal screening for fetal chromosome aberrations in the west of Scotland is reviewed. Fetal chromosome analysis was undertaken in 716 pregnancies, 49% of which were judged to be at substantial risk of a fetal chromosome aberration. A chromosome aberration was found in 26 pregnancies, 14 of which were sufficiently severe to justify termination: the latter included nine cases of trisomic Down's syndrome, two cases of translocation, two cases of XXY Klinefelter's syndrome and one case of the triple-X syndrome. Ten pregnancies with balanced fetal chromosomal translocations and two with extra, small metacentric chromosomes of no clinical significance continued normally in pregnancy. Prenatal diagnosis permitted many mothers at risk the opportunity of having a family which otherwise they would not have attempted, and saved a number of pregnancies which would have been terminated solely on the risk, rather than the diagnosis, of fetal abnormality. An unexpectedly high frequency (6-6%) of severe fetal chromosome aberrations was found in pregnancies of mothers aged 40 years and over. In the maternal age groups 35-39 years the frequency was 1-4%. It is concluded that specialized cytogenetic facilities are urgently required to allow older mothers the option of prenatal screening. This is also required for younger mothers who have previously had a child with Down's syndrome, and for families at risk of chromosomal translocation and X-linked disease. Prenatal screening is best provided on a regional basis by a department of medical genetics experienced in genetic counselling, human cytogenetics, and cell culture techniques, working in close collaboration with obstetrical colleagues and the ultrasound department.

Amniocentesis↗
PubMed1977

Sensitive, optimized assay for serum AMP deaminase.

A sensitive, optimized assay for serum AMP deaminase (EC 3.5.4.6) is presented, which is based on a colorimetric indophenol determination of ammonia liberated during the enzyme reaction. An average enzyme activity in serum of 2.7 U/liter (n = 36, range 0-6.2) for healthy adults was established. Both the enzyme and colorimetric reactions were optimized to give an assay sensitivity of 0.2 U/liter of serum, a 98-99% analytical recovery in the normal serum enzyme concentration range, and a CV of 7.9% in-run and 10.6% between-run. This optimization included studies on specific buffer, pH, ionic strength, and potential activators. The Km for the enzyme in serum was determinated to be 1.4 X 10(-3) mol/liter, which agrees well with the value reported for human skeletal muscle enzyme. Above-normal serum AMP deaminase activity may be present in various myopathies and could be useful in detecting carriers of the X-linked dystrophies.

AMP Deaminase↗
PubMedDate not supplied

[Contribution of biology to nosology of depressive states. Neurochemical, endocrine and genetic factors (author's transl)].

Genetic factors have been evidenced in the etiology of manic-depressive syndromes through twins, morbidity risk studies, linkage studies with genetic markers such as color blindness and the Xga blood group, as well as through adoption studies. Most genetic studies indicate that there is a genetic and biological heterogeneity in manic-depressive illness. Among these manic-depressive syndromes, one group is consistent with a dominant X-linked transmission of the disease. From the neurochemical point of view, most investigators emphasize the importance of cerebral neurotransmitter substances such as catecholamines and indolamines in the pathogenesis of bipolar depressive states. According with this hypothesis, depression is associated with a functional deficit in brain monoamines while mania may be due to an hyperproduction of monoamines. These neuropharmacological studies are of importance because they also have neuroendocrine implications. Some pituitary hormones are secreted under the control of brain monoamines, and they are also implicated in the pathogenesis of depressive states.

Bipolar Disorder↗
PubMed1975

B lymphocytes lacking surface IG in patients with immune deficiency: initiation of IG synthesis in culture in cells of a patient with thymoma.

A 64-year-old woman with a syndrome of thymoma, severe hypogammaglobulinemia, seemingly normal cell-mediated immunity and aplastic anemia, was found to have virtually no immunoglobulin- (Ig) bearing peripheral blood lymphocytes (PBL). However, 7.8 +/- 3.4% of the PBL were positive for another B-cell marker, the receptor for aggregated IgG, while the remaining cells bound sheep erythrocytes. Those cells which were aggregate-reactive appeared to be immature or incomplete B cells. Cultures of peripheral blood leukocytes from the patient in various serum-containing media were studied by 3 independent technics for the development of lymphocyte surface Ig and for Ig in the culture supernatants. In vitro the patient's cells were able to develop surface Ig in media supplemented with fetal calf serum (FCS) or normal serum; in media supplemented with autologous serum, the cells developed no surface Ig. During the cultures in FCS, human Ig determinants became detectable in the medium, and both medium and cell-surface Ig underwent a shift from mu determinants early in the culture period to gamma and alpha determinants later. The development of Ig on the cells was not inhibited by the presence of autologous serum if FCS was included in the medium. These data support the concept that a factor, missing from this patient's serum, is required at an early stage in the maturation of the B cell. A patient with X-linked agammaglobulinemia had a population of circulating lymphocytes with surface characteristics similar to the B cells of the thymoma case. In contrast, no Ig synthesis by this patient's cultured cells could be demonstrated, indicating a different level of block in the 2 cases despite their similarity at the level of the cell surface.

Agammaglobulinemia↗
PubMed1975

On the diagnosis of Fabry's disease.

Fabry's disease is a recessive X-linked inborn error of metabolism due to deficiency of the lysosomal enzyme alpha-galactosidase. The large variety of symptoms may make the diagnosis difficult. A severely afflicted female patient is presented. For several years she had been treated under the diagnosis polyarteritis nodosa until the characteristic cutaneous lesions of Fabry's disease were recognized. Enzymatic studies and electronmicroscopic examinations confirmed the diagnosis. A symptomatic effect of corticosteroid treatment was proven. The grave prognosis, the recent attempts at enzyme substitution therapy and the possibility of preventing new cases by prenatal diagnosis should stimulate the efforts of the clinician to diagnose the disease.

Adult↗
PubMed1976

Peripheral blood T and B cell characteristics in a patient with severe combined immune deficiency (SCID) maintained in a gnotobiotic environment.

Peripheral blood lymphocytes obtained at 24-30 months after birth from a male with X-linked severe combined immune deficiency maintained in a gnotobiotic environment were characterized by T and B cell surface markers. A high proportion (55-80 percent) of circulating lymphocytes bore surface IgM as detected by direct immunofluorescence. A receptor for the activated C3 complement component was detected on 27-47 percent of his lymphocytes. Only 4-12 percent of the peripheral blood lymphocytes formed spontaneous rosettes with sheep erythrocytes (E-R). In general, no blastogenesis was detected in lymphocyte cultures stimulated with pokeweed mitogen or phytohemagglutinin although transient slightly positive responses to both mitogens were occasionally observed. Incubation of lymphocytes with bovine thymosin Fraction V did not increase the percentage of E-R nor induce lymphocyte blastogenesis in the presence of phytohemagglutinin.

B-Lymphocytes↗
PubMed1975

[First experiences with amniocentesis from genetic indications].

Genetically indicated amniocentesis was performed in 93 patients in the first half of pregnancy and in 36 in the second half. To the common and recognized indications several obstetric indications were added. Six (4.7%) fetal abnormalities were diagnosed by karyotyping and determination of alpha1-fetoprotein (AFP), i.e. a child with trisomy 21 and a boy with XXY Klinefelter syndrome, both in mothers aged over 40, a partial trisomy 3 in a pregnancy with a balanced anomaly, 2 boys with X-linked hereditary disease and an anencephalic. In 4 cases (3.1) abortion was performed at the parents' request. Three pregnancies ended in spontaneous abortion. In 54 cases in which amniocentesis was performed in the first half of pregnancy the babies have now been born. One was found to have a congenital heart defect and the remainder were healthy. In the cases which had undergone genetic screening during the second half of pregnancy 3 neonates displayed anomalies not detectable by karyotyping or AFP determination, one of which was hydrocephalus. The abortion rate was 0.8%.

Anencephaly↗
PubMed1976

Prenatal diagnosis of genetic disease in Canada: report of a collaborative study.

A study of 1223 amniocenteses carried out during 1020 pregnancies in 990 women showed that 2nd-trimester amniocentesis at about 16 weeks' gestation is a safe, accurate and reliable procedure for the diagnosis of certain classes of genetic disease when it is monitored by ultrasound, performed by a trained obstetrician and carried out in a major health sciences centre. The percentage of fetal losses (4.7%) and neonatal deaths (0.5%) during the study was not greater than in control samples for women 35 years of age and older. The best results were obtained when needles of gauge 20 or 21 were used. The use of needles of gauge 19 or larger and more than two insertions during a single amniocentesis were associated with a significantly greater frequency of fetal loss than a second or even a third amniocentesis during the same pregnancy. For 39 fetuses (3.8%) a diagnosis of a genetic abnormality was made and 23 male fetuses were found to be potentially hemizygous for an X-linked gene. There were 51 therapeutic abortions as a result of the diagnosis. Sixty-six tests (5.4%) gave an inconclusive result and seven (0.6%) gave an erroneous diagnosis; five of the latter (two false-positives and three false-negatives) resulted from the alpha1-fetoprotein test for neural-tube defects and in two cases the sex was incorrectly determined. The frequency of all chromosome abnormalities was 1:20 when the mother's age was 40 years or more and 1:60 when the mother's age was between 35 and 39 years. When a mother had previously had a child with a chromosome abnormality the risk of recurrence of such an abnormality was 1:100 when the age of the mother was 35 years or more.

Abortion, Therapeutic↗
PubMed1978

Antenatal diagnosis in practice.

Over a period of 5 years, 434 women at risk of having abnormal babies have had antenatal daignostic tests carried out during the first half of their pregnancy by the laboratories of the Department of Human Genetics, University of Cape Town. From these investigations, it was predicted that 13 fetuses had chromosomal abnormalities, 6 had severe central nervous system defects and 4 had autosomal recessive metabolic disorders. In addition, 4 cases with X-linked recessive traits were monitored and 3 male fetuses were recognized. Affected pregnancies were terminated except for 1 with a fetal sex-linked disorder where the parents revoked their original decision. The diagnosis was confirmed by fetal autopsies in all cases except 4 (2 spontaneous abortions and 2 out-of-town terminations). There was only 1 case where culture failed and the pregnancy went to term with the birth of a baby with Down syndrome. Antenatal diagnosis is now an important part of normal clinical practice. The fact that the fetal abnormalities were recognized in 6% of pregnancies is justification for the use of this procedure.

Amniocentesis↗
PubMed1979

[Prenatal diagnosis. Review, personal and prospective studies].

1. In a review of methods developed for the identification of fetal malformations, the technique, risks and results of amniocentesis are presented. 2. Large series already published have demonstrated the relative simplicity and feasibility of the procedure as well as current indications for its utilization. These include the detection of chromosomal anomalies, the determination of sex (in certain sex-linked disorders), documentation of enzymatic and metabolic deficiencies, and the demonstration of open lesions of the neural tube by appropriate techniques. 3. Experience with over 500 cases personally tested by the authors entirely confirms the major indications for and benefits of this modern method for the detection and prevention of severe congenital anomalies during early pregnancy. 4. The identification of chromosomal alterations is currently the major objective of the method. Increased risks are associated with pregnancies involving a maternal age of 35 years or older (which account for 1-3% of aneuploidies), the birth of a previous infant with free trisomy 21 (1% recurrence risk) or secondary to a parental chromosome translocation (as much as 10% risk of aneuploidy). Fetal karyotyping for determination of sex, in cases where the mother is a carrier of an X-linked recessive gene (on average, 50% of male offspring will be affected), is an inadequate method of diagnosis to be utilized only until alternative techniques render possible specific diagnosis of the anomalies under consideration (hemophilias A and B, muscular dystrophy, etc). 5. Several of these techniques are now nearing development through the advent of fetoscopy and advanced ultrasound methodology, and have already been applied to the detection of certain sex-linked disorders and also for diagnosis of hemoglobinopathies (thalassemias, sickel cell anemia) and other conditions requiring the obtaining of fetal blood for diagnosis. Technology allowing direct examination of fetal parts by means of optical instruments is particularly useful in cases where a severe fetal morphologic malformation cannot currently be identified by indirect visualization (ultrasound) or by analysis of cytogenetic or molecular markers. 6. Pathological accumulations of alpha-fetoprotein which are associated with diverse feto-placental abnormalities (particularly open malformations of the neural tube) can be detected in the amniotic fluid and/or maternal blood. In extension of this approach, it is foreseeable that conditions existing prenatally will be diagnosed in a growing number of cases from the study of fetal cells and molecules which can be isolated from the venous blood of pregnant women. This will become feasible as a result of some well-developed techniques which allow separation of fetal from maternal cells and metabolites, and also to some extremely fine analytic techniques, notably examination of the DNA itself by means of restriction enzymes.

Adult↗
PubMed1978

Isolation and characterization of flightless mutants in Drosophila melanogaster.

Since animal behaviour is executed through neuronal circuits including sensory receptors and muscle, genes vital for their development and differentiation must be found among mutants having behavioural anomaly. After mutagenesis with ethyl methanesulphonate (EMS), we screened for X-linked flightless mutants of Drosophila melanogaster by using column-type flight tester. Approximately 10(4) individuals were screened and 21 mutant genes were isolated. Chromosomal mapping and complementation experiments revealed that they belong to 15 cistrons randomly located on X chromosome, three cistrons having more than two alleles. Two of the isolated mutants (fltO2 and fltH, which are recessive both behaviourally and morphologically) were analysed with the mosaic fate mapping technique, and both were found to have their primary foci in mesodermal region of blastoderm, suggesting that the genes exert their primary effect in indirect flight muscle. Electronmicroscopic studies on the muscles from four alleles of the fltO2 cistron revealed an abnormality in myofibrillar arrangement. A possible deficit within Z-band components is discussed in relation to wings-up B mutants. The indirect flight muscle of flltH was also examined, and it was found that sarcomere length and diameter of myofibrils were abnormal. It was postulated that a possible factor which controls size of myofibrils is defective in this mutant. These examples indicate the advantage of combining ultrastructural examination with genetic mosaic mapping technique.

Animals↗
PubMed2026

EGFLAM Pathogenic Variants and Congenital Stationary Night Blindness.

IMPORTANCE: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous inherited retinal disorder (IRD), and in many complete CSNB (cCSNB) cases, the underlying genetic cause remains unknown. Uncovering the genetic defects of IRDs helps to refine diagnostic methods and supports the development of specific therapeutic approaches. OBJECTIVE: To describe the phenotype and the underlying gene defect in patients with cCSNB from 2 unrelated families. DESIGN, SETTING AND PARTICIPANTS: This retrospective case series was conducted from January 2023 to July 2025. Data for 3 patients from cohorts of genetically unsolved IRD cases in France (n = 140 for CSNB) and the Netherlands (n = 2730 for IRD) were analyzed clinically and genetically. EXPOSURES: Complete ocular examination, including multimodal retinal imaging and full-field electroretinography (ffERG) incorporating the International Society for Clinical Electrophysiology of Vision standards and multimodal retinal imaging, were performed. Gene defects were identified by genome sequencing (GS) and exome sequencing (ES). MAIN OUTCOMES AND MEASURES: The main outcome was a gene defect, EGFLAM, underlying cCSNB. Measures included phenotyping, GS, ES, Sanger sequencing, and cosegregation analysis. RESULTS: The series included 3 patients from 2 unrelated families of Moroccan ancestry showing high myopia, reduced visual acuity, and night blindness. Retinal imaging depicted myopic changes. ffERG revealed electronegative Schubert-Bornschein configuration in keeping with cCSNB with ON-bipolar cell dysfunction. Patients were lacking pathogenic variants in known genes implicated in IRDs, including CSNB. Two different homozygous pathogenic variants, c.1563_1566del, p.(Val522Glufs*18) and c.1795C>T, p.(Arg599*) in EGFLAM were identified by ES and GS. The corresponding protein is localized in the outer plexiform layer and important for ON-bipolar cell signaling in the retina. CONCLUSION AND RELEVANCE: This case series reports on a gene defect in EGFLAM implicated in human cCSNB. Clinicians should be aware about this association and consider including EGFLAM in diagnostic gene panels for IRDs. This discovery may lead to faster and more accurate diagnosis of cCSNB and genetic counseling, as well as a pathway for developing therapies.

Adolescent↗