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Biomedical subjects

M Zatz

Publications and source records attributed to M Zatz.

At least 109 records · Page 6Linked to original sources
PubMed1995

Absence of correlation between utrophin localization and quantity and the clinical severity in Duchenne/Becker dystrophies.

While present in the surface membrane of embryonic muscle fibers, in adult normal muscle fibers, utrophin is restricted to the motor endplate and cells of blood vessel walls. However, the observation that utrophin is maintained in the extrajunctional plasma membrane in Duchenne (DMD) and in mdx muscle fibers has led to the suggestion that excess utrophin might compensate for dystrophin deficiency in the Xp21 muscular dystrophies. In order to detect an inverse correlation of utrophin presence and clinical severity, we have assessed utrophin distribution and quantity in DMD and Becker (BMD) patients of different ages and stages of clinical severity. All patients showed a positive discontinuous immunolabeling of utrophin on the sarcolemma, staining equally small and large muscle fibers, indicating that immature characteristics are maintained in such fibers. On Western blot, utrophin bands with concentrations 2- to 10-fold greater than in normal controls were detected in all DMD/BMD patients. However, no negative correlation was found between the amount of utrophin and the severity of clinical course, implying that the detectable utrophin levels in these patients did not compensate for dystrophin deficiency. In a DMD patient with growth hormone (GH) deficiency and a BMD-like clinical course, utrophin levels were comparable to the other typical DMD cases, which reinforces the hypothesis that the observed increase in utrophin is apparently not responsible for a milder clinical course in some patients with Xp21 muscular dystrophies.

Adolescent↗
PubMed1995

Why is the reproductive performance lower in Becker (BMD) as compared to limb girdle (LGMD) muscular dystrophy male patients?

We had previously reported that patients affected with BMD have a significantly reduced reproductive performance (f = 0.12) as compared to male LGMD patients of similar age and physical impairment (f = 0.98). In the present study parameters such as the socio-economic level, as well as psychosocial, intellectual, and psychiatric functionings could not explain the low fitness of BMD patients. The effect of genetic counseling, a greater difficulty in coping with the disease, and relating to women and/or a potential malfunction of reproductive physiology are discussed as possible causes.

Adult↗
PubMed1995

Properties of clock-controlled and constitutive N-acetyltransferases from chick pineal cells.

The pineal gland synthesizes its hormone melatonin (O-methyl-N-acetylserotonin) from serotonin. Acetyl-CoA: serotonin N-acetyltransferase (SNAT), the enzyme that catalyzes the committed step in this biosynthesis, is largely restricted to the pineal gland and is regulated by adrenergic and circadian mechanisms. Another enzyme, acetyl-CoA: arylamine N-acetyltransferase (ANAT), having an apparently similar activity, is also present in the pineal. This enzyme, however, is not rhythmically regulated. SNAT activity of cultured chick pineal cells was obtained without ANAT after ammonium sulfate precipitation. ANAT activity was retained without SNAT activity after pre-incubation at 37 degrees C. Thus, each enzyme could be examined independently. Overlap in substrate specificity between the two enzymes was minimal. Kinetic analysis of the separated enzyme activities revealed that while SNAT operates via a random or ordered bi bi mechanism, ANAT catalysis occurs through a ping pong bi bi mechanism with substrate inhibition by acetyl-CoA. By size-exclusion chromatography, ANAT was confirmed to be 30-35 kDa, and SNAT was estimated at 15-20 kDa. Taken together, these results indicate that the two enzymes differ in their structure, reactivity, stability, and mechanism of catalysis.

Acetyl Coenzyme A↗
PubMed1995

Is dystrophin always altered in Becker muscular dystrophy patients?

The differential diagnosis between autosomal recessive limb-girdle (LGMD) and X-linked Becker muscular dystrophy (BMD) is very important for genetic counseling. It has been hypothesized that all BMD patients would have dystrophin alterations and dystrophin analysis could identify the Xp21 MD. Qualitatively abnormal dystrophin is easily detectable, but it is generally associated with in-frame DNA deletions or duplications. In patients with no detectable DNA deletions, in which X-linked inheritance cannot be proved, dystrophin quantification is still the only available test for differential diagnosis. In order to assess the accuracy of dystrophin quantification test in delineating Becker patients, we analyzed dystrophin abundance in BMD patients with a positive history of X-linked inheritance and no DNA detectable mutation, as compared to patients from families with LGMD. We observed that patients from 2 among the 5 BMD families have nearly normal dystrophin, while alteration in dystrophin content was observed in patients from 2 among the 7 LGMD families studied (probably as a secondary effect of alteration in the whole dystrophin-glycoproteins complex). These results suggest that dystrophin quantification, as an isolated test is not helpful for differential diagnosis between BMD and LGMD.

Adolescent↗
PubMed1995

Molecular characterization of further dystrophin gene microsatellites.

Microsatellites of the dystrophin gene have been used extensively in the genetic analysis of Duchenne and Becker muscular dystrophy families. The microsatellites that have been reported to date are clustered within disparate regions of the dystrophin gene, specifically at the 5'-end and in the central rod-domain. YACs encompassing the gene were screened for further microsatellites to improve the density of available genetic markers. Four microsatellites were localized to defined regions of the dystrophin gene by the analysis of patient DNA samples, somatic cell hybrids and YACs. In addition, varying combinations of microsatellite loci were amplified in multiplex PCRs, which complement those loci that have been studied to date.

Base Sequence↗
PubMed1995

Calcium and photoentrainment in chick pineal cells revisited: effects of caffeine, thapsigargin, EGTA, and light on the melatonin rhythm.

Chick pineal cells in dispersed cell culture display a persistent, photosensitive, circadian rhythm of melatonin production and release. Light pulses have at least two distinguishable effects on these cells, i.e., acute suppression of melatonin output and phase shifts (entrainment) of the underlying circadian pacemaker. Previous results linked calcium influx through voltage-sensitive calcium channels in the plasma membrane to acute regulation of melatonin synthesis but denied a role for such influx in entrainment. Those experiments did not, however, address the role of intracellular calcium metabolism. Here we describe the effects of pulses of caffeine, thapsigargin, and EGTA on the melatonin rhythm, and their interactions with the effects of light pulses. Caffeine had two distinguishable effects on these cells, acute enhancement of melatonin output (attributable to phosphodiesterase inhibition) and phase shifts of the circadian pacemaker with a light-like pattern (attributable to effects on intracellular calcium). Phase shifts induced by light and caffeine were not additive. Thapsigargin (which specifically blocks the pump that replenishes intracellular calcium stores, thereby increasing cytoplasmic calcium and depleting intracellular stores) had no phase-shifting effects by itself but reduced the size of the phase advances induced by caffeine or light. Low calcium solution acutely suppressed melatonin output without inducing phase shifts or affecting those induced by caffeine or light. However, addition of EGTA (which specifically chelates calcium, thereby lowering cytoplasmic calcium and depleting intracellular stores) did reduce the size of phase advances induced by caffeine or light, in normal medium or in low calcium solution, without inducing a phase shift by itself at that phase. Taken together, these results point toward a role for intracellular calcium fluxes in entrainment of the circadian pacemaker.

Animals↗
PubMed1995

Deficiency of merosin (laminin M or alpha 2) in congenital muscular dystrophy associated with cerebral white matter alterations.

Recently, a deficiency of merosin has been reported in patients with classical congenital muscular dystrophy (CMD), while other patients, with indistinguishable clinico-pathological features, do not present this deficiency, suggesting genetic heterogeneity. The purpose of the present investigation was to assess merosin distribution and quantity in 21 clinically well characterized Brazilian CMD patients, in order to: a) estimate the proportion of merosin-deficient cases in this group of patients; b) characterize phenotypically merosin-negative, as compared to merosin-positive patients. Merosin deficiency was found in 11 patients and all the seven who had been submitted to neuroimaging studies showed evidence of periventricular dysmyelination. A normal pattern of 43 DAG was found in all patients, which suggest that this protein is not preferentially involved in a third form of merosin-positive CMD. Results from the present study are further suggestive, but do not prove, that the association of merosin deficiency with white matter alterations represents a genetic entity with common clinical, laboratory and neuroimaging findings.

Adolescent↗
PubMed1995

Analysis of the CTG repeat in skeletal muscle of young and adult myotonic dystrophy patients: when does the expansion occur?

The purpose of this investigation was to analyze the CTG expansion in muscle as compared to lymphocytes DNA in a sample of selected myotonic dystrophy (DM) patients of different ages and degrees of clinical severity, ranging from severe congenital to minimally affected. Results from the present study showed that the size of the CTG repeat was markedly larger in skeletal muscle than in lymphocytes in all DM patients. In contrast to lymphocytes, no significant correlation was found between the size of the CTG expansion in muscle and age at onset. In addition, large expansions were observed in muscle from all adult symptomatic patients independently of the presence of muscle weakness, which raises the question of the value of analyzing CTG expansions in muscle for predicting the severity of the phenotype. Differences between the size of the CTG expansions in muscle as compared to lymphocytes were smaller in affected children suggesting an apparent tendency to increase with aging and reaching a plateau in adulthood.

Adolescent↗
PubMed1995

A common missense mutation in the adhalin gene in three unrelated Brazilian families with a relatively mild form of autosomal recessive limb-girdle muscular dystrophy.

Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a heterogeneous group of diseases with a wide spectrum of clinical variability, classified phenotypically into two main groups, the most severe forms (Duchenne-like muscular dystrophy, DLMD, or severe childhood autosomal recessive muscular dystrophy, SCARMD) and the milder forms. Four genes causing AR LGMD have been mapped: the 15q (LGMD2a), the 2p (LGMD2b), the 13q locus (LGMD2c) and the adhalin gene on chromosome 17q (LGMD2d). In the present report we have performed linkage analysis with 17q markers in three mild AR LGMD and in four DLMD families with adhalin deficiency and unlinked to 2p, 15q or 13q genes. Linkage was observed only among the mild cases. Patients from these three 17q-linked families showed near or total deficiency of adhalin in muscle biopsies. An identical missense mutation was identified in all three 17q-linked unrelated families. These results indicate that AR LGMD with a mild phenotype is caused by mutations in the adhalin gene. In addition, they demonstrate that there is at least one other locus for DLMD associated with adhalin deficiency.

Base Sequence↗
PubMed1995

Myotonic dystrophy: genetic, clinical, and molecular analysis of patients from 41 Brazilian families.

Results of genealogical, DNA, and clinical findings in 41 families with 235 patients affected with myotonic dystrophy (DM) led to the following observations. (1) The relative proportion of affected patients among blacks is apparently lower than among whites or orientals. (2) A significant excess of males was observed. (3) The frequency of DM patients who did not reproduce was similar for males and females; however, female patients had on average 25% fewer children than male patients. (4) There was a significant intergenerational increase in the mean length of the CTG repeat which was also correlated with the severity of the phenotype. (5) No significant difference was observed in the mean size of the CTG repeat in offspring of male as compared to female transmitters. (6) With the exception of the congenital cases of maternal origin, the largest expansions were paternally inherited, but did not lead to congenital DM.

Adolescent↗
PubMed1995

High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families.

A gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has been localized at 4q35. Subsequently, it was found that probe p13E-11 detects a polymorphic EcoRI fragment, usually > 28 kb, in normal individuals, whereas in sporadic and familial FSHD cases, an EcoRI fragment, usually < 28 kb, was found. Although these findings have been amply confirmed, several aspects are as yet either controversial or unsolved. In the present investigation, 34 Brazilian FSHD families were studied at the clinical and the molecular level for the following purposes: to assess the frequency of new mutations and their effect on estimates of biological fitness, to characterize FSHD-associated EcoRI fragments detected with probe p13E-11 in familial--as compared with isolated--FSHD cases, and to assess whether anticipation occurs in multigenerational families. Results from our study suggest that new mutations are apparently frequent for FSHD and may account for at least one-third of the cases, that somatic mosaicism may not be rare, and that biological fitness appeared to be reduced in FSHD, ranging from 0.6 to 0.82 by different estimates, with no difference in sexes. Interestingly, the size of the new EcoRI fragment is apparently smaller in more severely affected isolated patients. Moreover, the age at onset of clinical signs, as well as the age at ascertainment, in patients from multigenerational families suggests that anticipation occurs for FSHD in the majority of the families.

Adolescent↗
PubMed1994

Synthesis of heat shock proteins in cultured chick pineal cells.

Chick pineal cells in static culture display a persistent, photosensitive, circadian rhythm of melatonin synthesis and release. Melatonin synthesis and its rhythm are also sensitive to temperature changes. By SDS-PAGE autoradiography, we found that several heat shock proteins (HSPs 25, 70, and 90) are synthesized under temperature conditions which also cause changes in melatonin production and rhythms. We did not see substantial phase-dependent differences in the induction of HSP synthesis, nor did we detect any clear effect of light on the synthesis of these proteins.

Animals↗
PubMed1994

Knobloch syndrome in a large Brazilian consanguineous family: confirmation of autosomal recessive inheritance.

Knobloch syndrome is a rare genetic disorder characterized by high myopia, vitreoretinal degeneration with retinal detachment and occipital cephalocele. The inheritance has been described as autosomal recessive (AR) but in addition to the original report with 5 affected patients [Knobloch and Layer, 1971] only one other family with 2 affected sibs has been described [Czeizel et al., 1992]. We have studied a large consanguineous kindred in which there are 12 patients with severe ocular alterations associated with a congenital occipital encephalocele, compatible with the diagnosis of Knobloch syndrome. CT scan and MRI performed in one of the patients, allowed a better understanding of the cranial and ocular alterations in this syndrome. The pattern of occurrence in this highly inbred family clearly confirms autosomal recessive inheritance of Knobloch syndrome.

Adolescent↗
PubMed1994

A Caucasian family with the 3271 mutation in mitochondrial DNA.

The second most common mutation associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) in Japan is the 3271 mutation. This mutation was found in a Brazilian family of Portuguese and Italian descent, indicating that this mutation also exists in a race other than Japanese. The propositus had mild clinical manifestations atypical of MELAS, suggesting that patients with the 3271 mutation exhibit heterogeneous phenotypic expression as seen in the 3243 mutation.

Acidosis, Lactic↗
PubMed1994

Assessment of the 50-kDa dystrophin-associated glycoprotein in Brazilian patients with severe childhood autosomal recessive muscular dystrophy.

Recently, we have demonstrated the specific deficiency of the 50-kDa dystrophin-associated glycoprotein (50DAG) in severe childhood autosomal recessive muscular dystrophy with Duchenne-like phenotype (SCARMD or AR-DLMD), a disease first reported in Tunisia and now presumed to be prevalent in North Africa and the Middle East. Here we demonstrate the deficiency of the 50DAG in one caucasoid and 5 negroid Brazilian patients with severe muscular dystrophy, which confirms that AR-DLMD with the 50DAG deficiency is not confined to the Arab populations. Without the analysis of both dystrophin and 50DAG, isolated male patients with this condition could be undiagnosed or misdiagnosed as having Duchenne or severe Becker muscular dystrophy. We also report, for the first time, the normal expression of the 50DAG and other dystrophin-associated proteins in one negroid and 2 caucasoid Brazilian patients with a phenotype indistinguishable from that of AR-DLMD with 50DAG deficiency. This is consistent with the genetic heterogeneity for the phenotype of AR-DLMD.

Adolescent↗
PubMed1994

Photoendocrine transduction in cultured chick pineal cells: IV. What do vitamin A depletion and retinaldehyde addition do to the effects of light on the melatonin rhythm?

Light has at least two distinguishable effects on the circadian rhythm of melatonin output displayed by dispersed chick pineal cells in static culture: acute suppression of melatonin output and entrainment (phase shifts) of the underlying pacemaker. Previous results indicated that these two effects of light are mediated by different mechanistic pathways. The pathways for the acute and phase-shifting effects of light either branch from the same, single photopigment or differ from the outset, starting from separate photopigments. If a single rhodopsin-like photopigment mediates both effects of light, then vitamin A depletion and retinoid addition should affect both responses in parallel, although not proportionately. We therefore compared the effects of vitamin A depletion and retinoid addition on the acute and phase-shifting effects of light under several experimental conditions. When chick pineal cells were depleted of vitamin A, acute responses to light were markedly reduced. Addition of 11-cis-retinaldehyde specifically restored (and enhanced) the acute response. When allowed to free run in constant red light, depleted cells displayed a rhythm of melatonin output with the same period as that of control cells. In contrast to the acute effects, phase shifts in response to 2- or 4-h light pulses did not differ between depleted and control cells. Addition of retinaldehyde to depleted cells did not, by itself, reduce melatonin output or induce phase shifts. Retinaldehyde did increase the acute response to 4-h light pulses but not the ensuing phase shifts. Responses increased with duration of the light pulse: Both the acute effect and the phase shifts induced by 4-h light pulses were considerably larger than those induced by 2-h (or 1-h) light pulses. Addition of retinaldehyde to depleted cells increased the acute effect of 2-h (or 1-h) light pulses to at least that seen with 4-h light pulses but did not increase the size of the ensuing phase shifts. These results strongly confirm previous dissociations of the mechanistic pathways mediating the acute and phase-shifting effects of light on chick pineal cells. They also support a role for rhodopsin-like photopigment in the acute, but not phase-shifting, response. They favor, but do not prove, the conclusion that separate photopigments mediate the acute and entraining effects of light.

Activity Cycles↗
PubMed1994

Half the dystrophin gene is apparently enough for a mild clinical course: confirmation of its potential use for gene therapy.

The largest in-frame deletion in the dystrophin gene previously reported in a BMD patient encompasses exons 17 to 48, which corresponds to 46% of the coding region. Here we report a larger deletion of exons 13 to 48 in a 37 year-old BMD patient with a mild phenotype. Such deletion, which corresponds to 50% of the coding region is the largest reported so far associated with a benign clinical course. Dystrophin assessment (through immunofluorescence and Western blot) using antibodies against different regions of the dystrophin was concordant with his deletion. The observation of this patient has important implication for gene therapy trials based on minigenes, since it confirms that deletions of up to 66% of the rod domain are compatible with a mild phenotype.

Adolescent↗