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S Naidu

Publications and source records attributed to S Naidu.

At least 19 recordsLinked to original sources
PubMed1999

Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2).

Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2) comprises a spectrum of diseases that range from severe to quite mild. The reasons for the variation in severity are not obvious, but suggested explanations include the extent of disruption of the transmembrane portion of the proteolipid protein caused by certain amino acid substitutions and interference with the trafficking of the PLP molecule in oligodendrocytes. Four codons in which substitution of more than one amino acid has occurred are available for examination of clinical and potential structural manifestations: Valine165 to either glutamate or glycine, leucine 045 to either proline or arginine, aspartate 202 to asparagine or histidine, and leucine 223 to isoleucine or proline. Three of these mutations, Val165Gly, Leu045Pro, and Leu223Ile have not been described previously in humans. The altered amino acids appear in the A-B loop, C helix, and C-D loop, respectively. We describe clinically patients with the mutations T494G (Val165Gly), T134C (Leu045Pro), and C667A (Leu223Ile). We discuss also the previously reported mutations Asp202Asn and Asp202His. We have calculated the changes in hydrophobicity of short sequences surrounding some of these amino acids and compared the probable results of the changes in transmembrane structure of the proteolipid protein for the various mutations with the clinical data available on the patients. While the Val165Glu mutation, which is expected to produce disruption of a transmembrane loop of the protein, produces more severe disease than does Val165Gly, no particular correlation with hydrophobicity is found for the other mutations. As these are not in transmembrane domains, other factors such as intracellular transport or interaction between protein chains during myelin formation are probably at work.

Codon↗
PubMed1999

Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls.

The assay of plasma very long chain fatty acids (VLCFAs), developed in our laboratory in 1981, has become the most widely used procedure for the diagnosis of X-linked adrenoleukodystrophy (X-ALD) and other peroxisomal disorders. We present here our 17 years' experience with this assay. Three VLCFA parameters, the level of hexacosanoic acid (C26:0), the ratio of C26:0 to tetracosanoic acid (C24:0), and of C26:0 to docosanoic acid (C22:0), were measured in 1,097 males (hemizygotes) with X-ALD, 1,282 women heterozygous for this disorder, including 379 obligate heterozygotes, 797 patients with other peroxisomal disorders, and 29,600 control subjects. All X-ALD hemizygotes who had not previously received Lorenzo's oil or a diet with a high erucic acid content had increased VLCFA levels, but the application of a discriminant function based on all three measurements is required to avoid the serious consequences of a false-negative result. VLCFA levels are increased at day of birth, thus providing the potential for neonatal mass screening, are identical in the childhood and adult forms, and do not change with age. Eighty-five percent of obligate heterozygotes had abnormally high VLCFA levels, but a normal result does not exclude carrier status. VLCFA levels were increased in all patients homozygous for Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, and in patients with deficiencies of peroxisomal acyl-coenzyme A oxidase, bifunctional enzyme, and 3-oxoacyl-coenzyme A thiolase. In these patients the degree of VLCFA excess correlated with clinical severity.

Adolescent↗
PubMed1999

Development of amino acid receptors in frontal cortex from girls with Rett syndrome.

To determine whether a disorder of excitatory neurotransmission plays a role in the pathophysiology of Rett syndrome (RS), N-methyl-D-aspartate (NMDA), adenosine monophosphate acid (AMPA), kainate, and metabotropic types of glutamate receptors were labeled autoradiographically in the superior frontal gyrus (SFG) from 9 RS patients and 10 female controls. The results showed a trend for the densities of NMDA, AMPA, gamma-aminobutyric acid, and metabotropic glutamate receptors to be higher in younger patients than in controls and for densities in older patients to fall below those of controls. The age-related changes in SFG NMDA receptor density may be correlated with the shift from psychomotor regression and seizures in younger stage II/III RS girls to the less epileptic plateau stage in older girls.

Adolescent↗
PubMed1999

Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome.

Rett syndrome (RS), a genetic disorder found almost exclusively in females, is associated with psychomotor regression and stereotyped hand movements. To determine whether a defect in basal ganglia amino acid neurotransmission plays a role in RS, NMDA-, AMPA-, kainate (KA)-, and metabotropic (mGluR)-type glutamate receptors (GluRs) and GABA receptors were labeled autoradiographically in the caudate, putamen, and globus pallidus of postmortem brain slices from 9 RS girls and 10 age-related controls. The cases were divided into younger (8 years or younger) and older age groups to study age-related changes in receptor binding density. We found significant reductions in AMPA and NMDA receptor density in the putamen and in KA receptor density in the caudate of older RS cases compared to controls. In contrast, mGluR density in the basal ganglia of RS patients was not altered significantly. The density of GluRs in control subjects generally showed more limited changes with age than in RS cases. In contrast to ionotropic GluRs, GABA receptor density was significantly increased in the caudate of young RS patients. The effects on GluR density in the putamen, which serves a primary motor function, were consistent with the motor deficits observed in RS, while those on amino acid transmitter receptors in the caudate may account for some cognitive features. Our studies demonstrate regional, receptor-subtype, and age-specific alterations in amino acid neurotransmitter receptors in the basal ganglia of RS girls. These changes may correlate with age-related clinical stages observed in RS.

Adolescent↗
PubMed1999

Vascular surgical society of great britain and ireland: influence of contralateral stenosis on long-term mortality rate following carotid surgery

BACKGROUND: Recent evidence suggests that high-grade contralateral stenosis has an adverse effect on perioperative morbidity in carotid endarterectomy (CEA). The relationship between contralateral high-grade stenosis and long-term survival after CEA was examined. METHODS: Three hundred and twenty-seven patients undergoing 333 CEA operations were entered prospectively into a database and long-term follow-up was instituted. Cardiac and stroke risk factors were identified before operation and correlated with long-term survival and cause of death. RESULTS: Mean age at operation was 68 (range 42-86) years. Median follow-up was 2 (range 1-8) years. There were 45 deaths (seven perioperative), 17 myocardial, 16 from stroke (four perioperative), five from neoplasia, three respiratory and four others. The cumulative 5-year survival rate was 75 per cent. Patients with high-grade contralateral stenosis (greater than 80 per cent) had a significantly reduced life expectancy after CEA (P < 0. 05). CONCLUSION: Severe contralateral carotid disease is not only an adverse perioperative risk factor but also has negative implications for survival of the patient in the longer term. Following CEA, patients in general have a lower life expectancy than a normal age-matched population.

Journal Article↗
PubMed1998

Mutation analysis of the M6b gene in patients with Rett syndrome.

Human Xp22.2 has been proposed as a candidate region for the Rett syndrome (RTT) gene. M6b, a member of the proteolipid protein gene family, was mapped to Xp22.2 within one of the RTT candidate regions. In this article we describe the structure of the M6b gene, refine the physical mapping of M6b between markers DXS69E and DXS414, and present the results of mutation analysis of the M6b gene in patients with RTT. The data from mutation analysis on 55 RTT patients make it very unlikely that M6b is involved in RTT.

Animals↗
PubMed1997

Glutaraldehyde-tanned bovine carotid artery graft for infrainguinal vascular reconstruction: 5-year follow-up.

OBJECTIVE: To assess the long-term patency of a modified biological conduit, the glutaraldehyde-tanned bovine carotid artery, in above-knee infrainguinal arterial reconstruction. PATIENTS AND METHODS: Prospective follow-up of a cohort of 58 above-knee femoropopliteal grafts in 55 patients. Graft patency was assessed at yearly intervals with doppler ankle pressure measurements. RESULTS: The median follow-up period has been 67 months. Nine grafts occluded within 30 days of surgery and a further 19 graft closures have been observed in the follow-up period. The overall cumulative primary graft patency at 1, 3 and 5 years was 70%, 61% and 56%, respectively. If the 30-day graft failures are excluded, the primary graft patency rises to 83%, 74% and 68% at 1, 3 and 5 years, respectively. Six limbs have been amputated, four above the knee and two below the knee. There were no graft aneurysms and no graft infections. CONCLUSION: Results indicate that the modified bovine carotid artery graft with an above-knee anastomosis does not seem to be inferior to PTFE, but is inferior to reversed vein. Modified biological conduits offer a reasonable alternative to synthetic grafts for infrainguinal arterial reconstruction and appear to maintain acceptable long-term mechanical stability.

Aged↗
PubMed1997

A male child with the rumpshaker mutation, X-linked spastic paraplegia/Pelizaeus-Merzbacher disease and lysinuria.

A 3.5-year-old boy had intact cognition, delayed walking, progressive spastic paraparesis and congenital nystagmus. The mother denied family history of any neurological disorders, so an extensive work-up was begun. Lysinuria, increased signal on cerebral T2-weighted MRI imaging and the rumpshaker mutation (Ile186Thr) in his proteolipid protein gene. PLP, were found. When faced with these facts, the mother admitted that she was related to the family reported by Johnston and McKusick in 1962 and Kobayashi in 1994, in whom this mutation has been reported. This is the first report of an abnormal MRI scan in this family.

Brain↗
PubMed1997

Mesenteric revascularisation for acute-on-chronic intestinal ischaemia.

Eleven patients (eight women) underwent urgent revascularisation for acute-on-chronic mesenteric ischaemia. Four patients had dual vessel and seven single vessel reconstructions. Two patients underwent simultaneous bowel resection and one patient has had three separate grafts to the superior mesenteric artery. There were two peri-operative deaths and three have died in the late follow-up period after 18, 24 and 36 months. The remainder have survived for between five and 63 months. Revascularisation for acute-on-chronic mesenteric ischaemia has been shown to be technically possible and of substantial benefit to patients who would otherwise be treated as terminal cases.

Acute Disease↗
PubMed1997

Assessment of adrenal function in women heterozygous for adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked recessive disorder that destroys the white matter of the brain and is associated with adrenal insufficiency. The prevalence of adrenal dysfunction in 71 women carriers of the X-linked ALD gene was studied. These subjects were identified initially on the basis of being obligate carriers of the X-linked trait by pedigree analysis and were confirmed by plasma very long chain fatty acid levels consistent with a heterozygote status. One subject had well documented overt adrenal insufficiency, diagnosed and treated since age 9 yr. Among the remaining women, the mean serum 0800 h and 1 h post-ACTH cortisol concentrations [16 +/- 7 (+/-SD) and 34 +/- 8 micrograms/dL, respectively] were normal. All subjects had normal ACTH-stimulated serum cortisol levels, i.e. more than 20 micrograms/dL. However, 4 subjects (6%) had subnormal ACTH-stimulated aldosterone concentrations (mean, 9 +/- 6 vs. 42 +/- 16 ng/dL for other subjects; P = 0.001, by Mann Whitney rank sum test). Three of these women (75%) were taking nonsteroidal antiinflammatory agents (NSAIDs), whereas only 4 of 67 (6%) subjects with normal aldosterone responsiveness were NSAIDs users (P < 0.01, by Fisher's exact test). Thus, NSAIDs use was associated with increased risk of hypoaldosteronism (odds ratio, 50.2; 95% confidence interval, 3.3-266; P < 0.002). Three of these four women had symptoms consistent with mineralocorticoid deficiency. Serum sodium and potassium concentrations were normal in all subjects. Basal and metyrapone-stimulated plasma ACTH concentrations were also normal in adequately tested subjects with and without mineralocorticoid insufficiency. Five of eight subjects (63%) who underwent testing with synthetic ovine CRH (oCRH) had abnormalities. Three did not meet the criteria for adequate cortisol stimulation (i.e. > 20 micrograms/dL) and had peak ACTH levels greater than 30 pg/mL. Two other subjects had exaggerated ACTH responses with normal cortisol levels. There were no significant differences in the mean or median levels of very long chain fatty acid, C26:0, C24/22 ratios, or C26/22 ratios among the entire subject group, the subgroup with blunted aldosterone responses to ACTH, and the subgroup with blunted responses to oCRH (P > 0.05, by ANOVA and Kruskall-Wallis test for C26, C24/22 ratio, and C26/22 ratio). We conclude that 1) adrenal cortical insufficiency rarely develops in ALD heterozygotes; 2) isolated mineralocorticoid insufficiency can occur in ALD heterozygotes, as has been previously reported to occur with autoimmune and acquired immunodeficiency syndrome-related adrenal dysfunction; 3) ALD heterozygosity may predispose these individuals to NSAID-related hypoaldosteronism; and 4) a subclinical decrease in glucocorticoid reserve, as measured by oCRH testing, may be present in a majority of these women. Aldosterone levels should be included in the ACTH stimulation testing when seeking evidence of adrenal insufficiency in affected women. NSAIDs should be considered a risk factor for the development of hypoaldosteronism in women heterozygous for ALD.

Adolescent↗
PubMed1997

Neuroanatomy in Rett syndrome: cerebral cortex and posterior fossa.

Rett syndrome (RS), a neurodevelopmental disorder of unknown etiology occurring almost exclusively in females, is characterized by autistic-like behavior, motor dysfunction, loss of language skills, dementia, and microcephaly. This study is a follow-up and extension of a previously reported neuroimaging study of patients with RS. We replicated previously reported findings with a larger patient population, and the volumetric MRI analysis was extended to include an analysis of neuroanatomy of the posterior fossa. Twenty girls with RS were compared with individually age- and gender-matched normal controls. Patients with RS showed global reduction in gray- and white-matter volumes. The prefrontal, posterior-frontal, and anterior-temporal regions showed the largest bilateral decrease in gray-matter volume, whereas white-matter volume was uniformly reduced throughout the brain. We found confirmation for the preferential reduction in caudate nucleus volume. However, we observed no preferential reduction in midbrain volume despite a preferential reduction in the midsagittal area of this region. We also present an individual case comparison between monozygotic twins discordant for RS.

Adolescent↗
PubMed1997

Rett syndrome: natural history and underlying disease mechanisms.

Rett syndrome (RS) is a neurological disorder that mainly, and possibly exclusively, affects girls. Diagnosis continues to be based upon a consistent constellation of clinical features observed in all of the patients worldwide. A biological marker has not been identified. In spite of this serious limitation, it is generally agreed that RS is a distinct entity and that it is genetically determined. Although it is associated with loss of function between infancy and the fifth year of life, its course becomes relatively static thereafter, setting it apart from most of the genetic neurodegenerative disorders of childhood. Neuropathological and neurochemical studies call attention to RS as a neurodevelopmental disorder of infancy resulting in failed brain growth. Clarification of its pathogenesis may provide new insight into normal brain development.

Adolescent↗
PubMed1997

Abnormalities in neuronal maturation in Rett syndrome neocortex: preliminary molecular correlates.

In correspondence with the severe cognitive impairment and autistic features of Rett syndrome (RS), multiple anomalies of the cerebral cortex that include generalized reductions in dendritic arborizations and in cholinergic markers have been found. Considering the potential role of neurotransmitters in cortical differentiation, we have studied the relationship between cholinergic deficit and dendritic protein expression in RS and in a relevant animal model. Dendritic development is characterized by the sequential expression of cytoskeletal proteins whose levels remain relatively stable in adult life. Using quantitative immunoblotting, we have determined that in RS there is a reduction in proteins linked to early dendritic development [microtubule-associated protein (MAP)-5, MAP-2]. By contrast, in Down syndrome there is relative generalized increase in dendritic proteins. Mice with basal forebrain lesions at birth, which transiently decrease cholinergic innervation to the cortex, showed in adulthood reductions in MAP-2 that resemble those seen in RS. We conclude that dendritic anomalies in RS represent disturbances in early cortical differentiation and that cholinergic deficit may play a critical role in their pathogenesis as suggested by the animal data.

Adolescent↗