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Biomedical subjects

H G Brunner

Publications and source records attributed to H G Brunner.

At least 109 records · Page 6Linked to original sources
PubMed1996

Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.

Monoamine oxidase (MAO) exists as two isoenzymes and plays a central role in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subjects with genetically determined selective lack of MAO-A or a lack of both MAO-A and MAO-B with those of two subjects with a previously described X chromosome microdeletion in whom we now demonstrate selective MAO-B deficiency. Mapping of the distal deletion breakpoint demonstrates its location in intron 5 of the MAO-B gene, with the deletion extending proximally into the Norrie disease gene. In contrast to the borderline mental retardation and abnormal behavioral phenotype in subjects with selective MAO-A deficiency and the severe mental retardation in patients with combined MAO-A/MAO-B deficiency and Norrie disease, the MAO-B-deficient subjects exhibit neither abnormal behavior nor mental retardation. Distinct neurochemical profiles characterize the three groups of MAO-deficient patients. In MAO-A-deficient subjects, there is a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites. These neurochemical changes are only slightly exaggerated in patients with combined lack of MAO-A and MAO-B. In contrast, the only biochemical abnormalities detected in subjects with the MAO-B gene deletion are a complete absence of platelet MAO-B activity and an increased urinary excretion of phenylethylamine. The differences in neurochemical profiles indicate that, under normal conditions, MAO-A is considerably more important than MAO-B in the metabolism of biogenic amines, a factor likely to contribute to the different clinical phenotypes.

Adult↗
PubMed1996

MAOA deficiency and abnormal behaviour: perspectives on an association.

We have recently described an association between abnormal behaviour and monoamine oxidase A (MAOA) deficiency in several males from a single large Dutch kindred. Affected males differed from unaffected males by borderline mental retardation and increased impulsive behaviour (aggressive behaviour, abnormal sexual behaviour and arson). Nevertheless, a specific psychiatric diagnosis was not made in four affected males who had psychiatric examination. Since MAOA deficiency raises 5-hydroxytryptamine (5-HT) levels, it provides an interesting exception to the low 5-HT paradigm of impulsive aggression. Even if the possible relationship between MAOA deficiency and abnormal behaviour is confirmed in other kindreds, the data do not support the hypothesis that MAOA constitutes an "aggression gene'. In fact, because genes are essentially simple and behaviour is by definition complex, a direct causal relationship between a single gene and a specific behaviour is highly unlikely. In the case of MAOA deficiency, some of the complexities are illustrated by the variability in the behavioural phenotype, as well as by the highly complex effects of MAOA deficiency on neurotransmitter function. Thus, the concept of a gene that directly encodes behaviour is unrealistic.

Aggression↗
PubMed1996

Hearing loss in the Saethre-Chotzen syndrome.

A three-generation family with Saethre-Chotzen syndrome and an isolated case are presented. The proband presented with conductive hearing loss. His mother and grandmother showed minor features of the syndrome including conductive hearing loss. Symptoms of the craniosynostosis syndromes can include stapes ankylosis, a fixed ossicular chain in a too small epitympanum, and small or even absent mastoids. The proband was treated with a bone-anchored hearing aid (BAHA) instead of reconstructive middle ear surgery. Current literature on the results of ear surgery is reviewed. In general, reconstructive middle ear surgery should be considered if congenital anomalies of the middle ear are the only presenting symptom. In cases with additional anomalies such as atresia of the ear canal or damage due to chronic ear infections, the outcome of reconstructive surgery to correct the anomalous ossicular chain is unsatisfactory. In such cases of the BAHA is probably the best solution.

Acrocephalosyndactylia↗
PubMed1996

Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4.

Small mutations in the POU domain gene POU3F4 were recently shown to cause X-linked deafness type 3 (DFN3) in nine unrelated males. The POU3F4 gene was found to be located outside four of five deletions associated with DFN3. Two of these deletions were situated more than 400 kb proximal to POU3F4. Employing PCR analysis of sequence tagged sites from this region we initially identified novel deletions in two DFN3 patients. To investigate this chromosomal segment in more detail, we extended a previously established 850 kb cosmid contig in the centromeric direction to a total size of 1500 kb. Cosmids from this contig were hybridized to DNA of 11 unrelated males with DFN3. In two patients, we identified deletions encompassing the POU3F4 gene and variably sized segments of Xq21.1. In six of the nine remaining patients which lacked mutations in the POU3F4 gene, smaller deletions were identified which, with one exception, overlap in a 8 kb segment 900 kb proximal to the POU3F4 gene. In one patient, we identified several small deletions in the vicinity of the 8 kb DNA segment. Together, deletions account for 56% (13/23) of all known DFN3 mutations, most (10/13) of which do not encompass the POU3F4 gene. The combined molecular data suggest that the deletion hot spot region in Xq21.1 contains another DFN3 gene or, alternatively, a sequence element involved in transcriptional regulation of POU3F4.

Base Sequence↗
PubMed1996

An inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46,XX female.

Hypergonadotropic hypogonadism is characterized by decreased gonadal function due to the inability of the gonads to respond to pituitary gonadotropins. Hypergonadotropic hypogonadism in females has many causes, among which are ovarian dysgenesis and abnormalities of the ovarian receptors for the pituitary gonadotropins. We evaluated a woman who presented with amenorrhea due to hypergonadotropic hypogonadism, but who had structurally normal ovaries. She is a sister of two previously identified 46,XY male pseudohermaphrodites with Leydig cell hypoplasia. Injection of hCG did not cause any change in plasma levels of estradiol or progesterone, suggesting complete ovarian resistance to LH. Analysis of the DNA sequence of the LH receptor gene revealed that the patient is homozygous for the same single base change as her two brothers. This mutation causes substitution of an alanine residue by a proline at position 593. In vitro analysis of the mutant LH receptor in cultured human embryonic kidney 293 cells documented that the receptor is unable to stimulate adenylyl cyclase in response to hCG. Plasma levels of estradiol and progesterone were low, whereas LH and FSH levels were increased. On histological analysis of the ovary, follicles were seen at all developmental stages. Nonetheless, primary amenorrhea had been present for 5 yr, and repeated measurements of plasma estradiol and progesterone indicate that ovulation does not occur. These results document the existence of inherited LH resistance as a cause of primary amenorrhea in women. The combined clinical and molecular observations are consistent with previous experimental data suggesting that in humans, LH is necessary for ovulation but follicular maturation can occur in the presence of FSH alone.

Adult↗
PubMed1996

Luteinizing hormone receptor mutations and sex differentiation.

Mutations in the luteinizing hormone (LH) receptor gene have been found in patients with abnormalities in their sexual differentiation. In this paper we review results obtained in the studies of these LH receptor mutations. Activating and inactivating mutations are discussed with respect to the mechanism of action of LH/human chorionic gonadotrophin but also in light of their impact of the present knowledge of the physiology of sex differentiation and gonadal function.

Disorders of Sex Development↗
PubMed1996

Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13.

Osteoporosis-pseudoglioma syndrome (OPS) is an autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or juvenile-onset blindness. The pathogenic mechanism is not known. Clinical, biochemical, and microscopic analyses suggest that OPS may be a disorder of matrix homeostasis rather than a disorder of matrix structure. Consequently, identification of the OPS gene and its protein product could provide insights regarding common osteoporotic conditions, such as postmenopausal and senile osteoporosis. As a first step toward determining the cause of OPS, we utilized a combination of traditional linkage analysis and homozygosity mapping to assign the OPS locus to chromosome region 11q12-13. Mapping was accomplished by analyzing 16 DNA samples (seven affected individuals) from three different consanguineous kindreds. Studies in 10 additional families narrowed the candidate region, supported locus homogeneity, and did not detect founder effects. The OPS locus maps to a 13-cM interval between D11S1298 and D11S971 and most likely lies in a 3-cM region between GSTP1 and D11S1296. At present, no strong candidate genes colocalize with OPS.

Alleles↗
PubMed1995

Autosomal recessive Melnick-Needles syndrome or ter Haar syndrome? Report of a patient and reappraisal of an earlier report.

We report on a patient with congenital glaucoma, brachycephaly with flat occiput, large anterior fontanel, hypertelorism, anteverted nostrils, thoracolumbar kyphosis, prominent coccyx with skin fold, short hands and feet, flexion deformity of fingers, and clubfeet. He had a double-outlet right ventricle with ventricular septal defect, and severe tricuspid insufficiency. Mild skeletal changes included short tubular bones, absence of distal phalanges of toes, caliber variation of ribs, and scalloping of the anterior surface of vertebrae. The patient died at age 21 months. He belongs to the same extended family as 3 similarly affected patients, previously described by ter Haar et al. [1982: Am J Med Genet 13:469-477] as representing an autosomal recessive form of Melnick-Needles syndrome. We believe this diagnosis is no longer tenable. After having reviewed the relevant literature, we conclude that most probably we are dealing with a new autosomal recessive syndrome. We propose to name this entity ter Haar syndrome.

Diagnosis, Differential↗
PubMed1995

Further delineation of the branchio-oculo-facial syndrome.

We review 43 patients (15 new, 28 literature) with the branchio-oculo-facial (BOF) syndrome, which has a distinctive phenotype ranging from mild to severe forms, consisting of eye, ear, oral, and craniofacial anomalies. Virtually ubiquitous and possibly pathognomonic are the cervical/infra-auricular skin defects. Much less common are supra-auricular defects occurring as isolated anomalies or with cervical defects. Regardless of location, these lesions may have aplastic, "hemangiomatous," or otherwise abnormal overlying skin, and draining sinus fistulae. Renal malformations are frequent, but congenital heart and central nervous system defects are rare. Psychomotor performance is usually normal, but development delays, hypotonia, and visual, hearing, and speech problems are common. Autosomal dominant inheritance seems likely. Overlap between the BOF and branchio-otorenal syndromes has been observed, but elucidation of its molecular basis is not yet available. This article also discusses 5 patients with atypical manifestations considered to be possibly affected or probably unaffected, who are sufficiently unusual to be excluded from the final data analysis.

Abnormalities, Multiple↗
PubMed1995

Plasma metadrenalines: do they provide useful information about sympatho-adrenal function and catecholamine metabolism?

1. The clinical utility of plasma metadrenalines for examination of sympatho-adrenal function and catecholamine metabolism was assessed from plasma measurements of these metabolites in a number of clinical conditions (hypertension, cardiac failure, bilateral adrenalectomy and X-chromosomal deletions of the gene for monoamine oxidase), and before and during activation of sympathetic outflow or infusions of noradrenaline and adrenaline. 2. Plasma concentrations of normetadrenaline were less than 25% of those of noradrenaline, concentrations of metadrenaline and adrenaline were similar and those of sulphate-conjugated metadrenalines were 20- to 30-fold higher than free metadrenalines. Hypertensive patients had elevated plasma concentrations of adrenaline, noradrenaline and conjugated but not free metadrenalines. Cardiac failure patients had 2- to 4-fold increases in plasma noradrenaline and free and conjugated normetadrenaline. Adrenalectomy resulted in undetectable plasma concentrations of adrenaline, 91-97% decreases in free and conjugated metadrenaline and a 40% decrease in normetadrenaline relative to noradrenaline. Patients with X-chromosomal deletions of the gene for monoamine oxidase had 6- and 16-fold increases in plasma free and conjugated normetadrenaline and 2- and 4-fold increases in free and conjugated metadrenaline. 3. Infusion of catecholamines increased plasma concentrations of free metadrenalines by less than 6% of increases in precursor amines, indicating that most plasma normetadrenaline (84%) and metadrenaline (90%) is derived from metabolism of catecholamines before their entry into the circulation. Considerable O-methylation of catecholamines within the adrenals explains why sympatho-adrenal activation resulted in smaller proportional increases in plasma metadrenalines than catecholamines. 4. Plasma metadrenalines provide supplementary information about sympatho-adrenal activity to that provided by catecholamines, but are more useful for examination of the extraneuronal inactivation of catecholamines, particularly detection of neurochemical phenotypes in genetic disorders of catecholamine metabolism. Significant formation of metadrenalines within chromaffin tissue explains why measurements of plasma metadrenalines provide an extraordinarily sensitive method for diagnosis of phaeochromocytoma.

Adrenal Glands↗
PubMed1995

Nevo syndrome.

We describe a male patient born to consanguineous parents with a syndrome of tall stature at birth, hypotonia, wrist drop and long spindle shaped fingers. The clinical features are identical to those previously described in three cases from a single family by Nevo et al. (1974: J Med Genet 11: 158-165). Autosomal recessive inheritance is supported by consanguinity in our case. Follow-up at age 3 years demonstrated significant improvement of hypotonia and motor function, and normal cognitive ability.

Body Height↗
PubMed1995

A missense mutation in the second transmembrane segment of the luteinizing hormone receptor causes familial male-limited precocious puberty.

Patients with familial male-limited precocious puberty present with early onset of puberty. Several missense mutations in the LH receptor gene that cause amino acid substitutions in the sixth transmembrane segment of the receptor protein have been shown to be a cause of the disorder. We have identified a novel LH receptor gene mutation in a patient with familial male-limited precocious puberty that results in a threonine for methionine substitution at position 398 in the second transmembrane segment of the receptor protein. In vitro expression in human embryonic kidney 293 cells of this LH receptor mutant and two previously described LH receptor mutants showed that cAMP production in the absence of hormone was elevated up to 25-fold compared to the basal level of the wild-type receptor. The ED50 values of hormone-induced cAMP production were within the same range for wild-type and mutant receptors, but maximal hormone-induced cAMP production was relatively low for mutant receptors. We also produced receptors containing amino acid substitutions in both the second and sixth transmembrane segments. For these double mutants, basal receptor activities were similar to the basal activities observed in single mutants, whereas hormone-induced receptor activation was almost completely abolished.

Base Sequence↗
PubMed1995

Zimmermann-Laband syndrome in a patient with severe mental retardation.

Zimmermann-Laband syndrome in a patient with severe mental retardation: The Zimmermann-Laband syndrome (ZLS) is a rare autosomal dominant disorder characterized by gingival hyperplasia or fibromatosis, various skeletal anomalies including dysplasia of the distal phalanges of thumbs and halluces, vertebral defects, and hepatosplenomegaly. Thus far, 23 cases, including 11 patients from 2 families, have been reported. Most cases of ZLS have a normal intelligence although some cases are mildly retarded. Differential diagnosis includes other causes of gingival hyperplasia. We report on a patient with ZLS and severe mental retardation and review the literature. We conclude that severe mental retardation is a feature of the syndrome.

Abnormalities, Multiple↗
PubMed1994

Deafness, sensory neuropathy, and ovarian dysgenesis: a new syndrome or a broader spectrum of Perrault syndrome?

We report on 3 sibs (2 males and one female) with sensorineural deafness. The presence of ovarian dysgenesis in the girl suggested a diagnosis of Perrault syndrome. In addition our patients have a sensory polyneuropathy and amelogenesis imperfecta. Two of the patients have mild mental retardation, fine choreatic movements, and dyspraxia. It is discussed whether these findings are part of a separate clinical entity or should be included within the spectrum of the Perrault syndrome.

Abnormalities, Multiple↗