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Biomedical subjects

A N Prasad

Publications and source records attributed to A N Prasad.

17 recordsLinked to original sources
PubMed2004

Preliminary attempts to establish a rat model of striatal injury in glutaric acidaemia type I.

Glutaric acidaemia type I (GA I) is caused by the deficiency of glutaryl-CoA dehydrogenase, resulting in accumulation of glutaric acid (GA) and 3- hydroxyglutaric acid (3-OH-GA) in blood and cerebrospinal fluid (CSF). Neuropathological changes with onset in childhood consist of severe neuronal loss in the caudate and putamen. An animal model is necessary to test possible intervention strategies, and prior reports suggested that GA or 3-OH-GA could be used to create specific neuron loss in adult rats. Adult, 3-week-old and 2-week-old rats received intrastriatal injections of GA and 3-OH-GA at a range of doses. High concentrations caused necrotic lesions in striatum. Low concentrations caused white-matter axonal damage and small areas of neuron loss. Injection of lipopolysaccharide prior to administration of 3-OH-GA was not associated with enhanced neuronal loss. Our findings contradict prior claims and we conclude that the simple model of a single GA or 3-OH-GA injection into rat brain does not replicate the neuropathological findings in humans.

Amino Acid Metabolism, Inborn Errors↗
PubMed2002

Outcome of the first 3-years of a DNA-based neonatal screening program for glutaric acidemia type 1 in Manitoba and northwestern Ontario, Canada.

Glutaric acidemia type 1 (GA1) is overrepresented in the aboriginal population of Island Lake, Manitoba, and northwestern Ontario who speak the Ojibway-Cree (Oji-Cree) dialect. The carrier frequency in these communities has been predicted to be as high as 1 in 10 individuals. Prior to beginning newborn screening for GA1 in May 1998, 18 of 20 affected patients diagnosed at this center have been from these high-risk communities. Most have followed an acute encephalopathic course with permanent neurologic sequelae and high mortality. They excrete small amounts of glutaric acid and 3-hydroxyglutaric acid and have significant residual enzyme activity. A single homozygous mutation in glutaryl-CoA-dehydrogenase (GCDH IVS-1 + 5g right arrow t) has been identified in this population. DNA-based newborn screening targeted to our high-risk communities was begun in order to provide presymptomatic detection and treatment of affected patients. Of the first 1176 newborns screened, 4 affected infants were identified and treated with a low-protein diet, carnitine, and riboflavin. All 4 infants have required numerous hospitalizations for treatment of intercurrent illnesses. Eventually, 3 infants presented with acute dystonic encephalopathy and seizures along with permanent neurological sequelae. One of these infants died unexpectedly at home at 18 months of age. The fourth, now 9 months old, has had a gastrostomy tube placed to facilitate fluid replacement in addition to a standard treatment protocol and is doing well. The reasons for our initial disappointing outcomes in the first 3 of 4 affected babies are likely multiple. Based on our early experience and that of other centers screening newborns for GA1, current therapeutic strategies may be insufficient in preventing the occurrence of neurologic sequelae in some children. An incomplete understanding of the neurotoxic mechanisms underlying this devastating disorder hampers effective management.

Canada↗
PubMed2001

Hepatic carnitine palmitoyl transferase 1 (CPT1 A) deficiency in North American Hutterites (Canadian and American): evidence for a founder effect and results of a pilot study on a DNA-based newborn screening program.

We describe six patients with hepatic carnitine palmitoyl transferase (CPT1 A) deficiency who are members of a large extended Hutterite kindred living in widely scattered communities in the United States and Canadian Prairies. Two patients have significant neurological impairment due to severe recurrent hypoglycemic crises. The remaining four patients with earlier detection and treatment have near normal outcomes. The Canadian and American Hutterite families share two common ancestors who married in 1812, about 60 years before the Hutterites arrived in North America and prior to their subdivision into the three groups (Schmiedeleut, Dariusleut, and the Lehrerleut). These patients share a common haplotype on chromosome 11q13 and are all homozygous for a common CPT1 A G710E mutation, suggesting a founder effect. The clustering of such a rare disorder of fatty acid oxidation prompted us to initiate a pilot DNA-based neonatal screening program to determine the carrier frequency of this mutation in Hutterite newborns with the participation and support of the community. To date our carrier frequency is 1/16, close to the predicted frequency based on diagnosed patients and number of births. We believe our newborn screening program for CPT1 A deficiency in the Hutterite community will serve as a prototype model for delivery of targeted genetic services to other similar unique genetic isolates.

Adolescent↗
PubMed2001

The role of vigabatrin in childhood seizure disorders: results from a clinical audit.

PURPOSE: The emergence of visual field defects attributed to vigabatrin (VGB) treatment and intramyelinic edema in animal experiments has raised concerns about its future role in the treatment of childhood seizures. METHODS: We evaluated our experience with this antiepileptic agent with retrospective analysis of database and chart audit. RESULTS: Of 73 patients, 43 girls and 33 boys were treated with VGB over a 7-year period. The mean age of patients at the introduction of VGB was 87 months (range, 5-257 months). In 12 of 73 cases, VGB was used as monotherapy; in 61 of 73 cases, it was used as an add-on drug. Seizure types included secondarily generalized seizures (21), mixed seizures (21), partial seizures (18), and generalized seizures (13). Seizure etiology was idiopathic/cryptogenic in 22 patients, symptomatic in 50, and undetermined in a single patient. The mean duration of therapy was 16 months (median, 10 months; range, 1-144 months). VGB was effective in 30 (seven seizure free, 23 with >90% reduction in seizures), partially effective in four (50-90% reduction in seizures), and ineffective in 38 (<50% reduction in seizures). Nearly 50% of patients with infantile spasms responded to VGB. All patients underwent ophthalmic evaluation; two (16%) of 12 patients who could undergo static threshold perimetry were demonstrated to have the characteristic visual field constriction. CONCLUSIONS: VGB is effective in producing a significant reduction in seizure frequency in nearly half the patients with childhood seizures, including refractory epilepsy. Despite emerging concerns regarding visual side effects, this drug retains an important role in the medical management of childhood epilepsy.

Adolescent↗
PubMed2001

De novo interstitial long arm deletion of chromosome 3 with facial dysmorphism, Dandy-Walker variant malformation and hydrocephalus.

We report an 8-year-old girl with coarse facial features, macrocrania and developmental delay. Cranial anomalies in the form of hydrocephalus and Dandy-Walker (DW) variant malformation were detected on neuro-imaging. Karyotyping revealed a de novo interstitial deletion of bands 3q25.1 to 3q25.33. Deletion of the 3q24-q26 region appears to be associated with a somewhat similar constellation of findings of craniofacial dysmorphism (broad and depressed nasal bridge and low set posteriorly rotated ears), mental retardation, congenital heart defects, and central nervous system malformations.

Child↗
PubMed2000

Genetic evaluation of pervasive developmental disorders: the terminal 22q13 deletion syndrome may represent a recognizable phenotype.

The evaluation of mental retardation is always a challenge to clinicians. The recognition of specific physical or behavioral characteristics can vastly improve diagnostic yield. Several genetic disorders have been identified to have certain behavioral characteristics, such as Williams syndrome, Smith-Magenis syndrome, and the velocardiofacial syndrome (VCFS). The deletion affecting the chromosome 22q in the most distal band (22q13) appears to define yet another neurobehavioral phenotype. In addition to our report, there are about 17 other cases published of this particular deletion syndrome. We describe three children who share features of developmental delay and pervasive behaviors in addition to normal to advanced growth patterns. Results of cytogenetic analysis suggest that the 3 patients share a deletion affecting the terminal 22q13 region. Two were found to have a cryptic deletion, in the third it was detected by conventional cytogenetics. The cryptic deletions were demonstrated using fluorescent in situ hybridization (FISH), where the control probe for the DiGeorge/VCFS region was deleted. While there remain gaps in our understanding of this particular deletion syndrome, we propose that patients with normal or advanced growth, significantly delayed speech, deviant development and pervasive behaviors, with minor facial dysmorphism, be screened for this deletion.

Autistic Disorder↗
PubMed1999

Clinical correlations of occipital epileptiform discharges in children.

OBJECTIVES: To determine the frequency of different causes of occipital epileptiform discharges (OEDs) in children and to analyze the EEG features that help predict epilepsy type and prognosis. METHODS: We identified children with OEDs in the absence of other focal discharges using an EEG database at our center; the presence of generalized spike-wave discharges (GSW) or slowing was not an exclusion criterion. Diagnosis, neurologic status, seizure semiology, and seizure remission status were recorded. RESULTS: Of 90 patients with OEDs, 50 (56%) had symptomatic seizures (18 with cerebral palsy, 11 with cerebral dysgenesis, 8 with genetic abnormalities); 31 (34%) had idiopathic seizures, including 6 with benign childhood epilepsy with occipital paroxysms (BCEOP), 8 (9%) had no seizures; and 1 (1%) had febrile seizures. Only two reported ictal visual symptoms. Eighty-seven percent with background slowing had symptomatic seizures, and 87% with normal backgrounds had idiopathic seizures (p < 0.001). Of 72 children with seizures and adequate follow-up, 28 of 45 (62%) with a normal background experienced seizure remission compared with 10 of 27 (37%) with background slowing (p = 0.04). Twenty of 81 patients with epilepsy had GSW. Twelve (60%) of the 20 GSW-positive patients had idiopathic epilepsy compared with 19 of 61 (31%) without GSW (p = 0.02). CONCLUSIONS: Most epilepsy in referred children with OEDs is symptomatic; syndromes such as BCEOP are rare. Visual ictal symptoms are rare. The presence of GSW or a normal background rhythm correlates with idiopathic seizures and a better prognosis.

Adolescent↗
PubMed1999

Recent advances in the genetics of epilepsy: insights from human and animal studies.

Progress in understanding the genetics of epilepsy is proceeding at a dizzying pace. Due in large part to rapid progress in molecular genetics, gene defects underlying many of the inherited epilepsies have been mapped, and several more are likely to be added each year. In this review, we summarize the available information on the genetic basis of human epilepsies and epilepsy syndromes, and correlate these advances with rapidly expanding information about the mechanisms of epilepsy gained from both spontaneous and transgenic animal models. We also provide practical suggestions for clinicians confronted with families in which multiple members are afflicted with epilepsy.

Animals↗
PubMed1998

Seizure exacerbation and developmental regression with carbamazepine.

BACKGROUND: Unexpected exacerbation of seizures may occur following initiation of treatment with carbamazepine (CBZ). We reviewed the occurrence of such reactions in our patient population at a tertiary care children's hospital. METHODS: A retrospective analysis of our clinic database identified 129/691 (18.6%) patients with epilepsy treated with CBZ, as monotherapy. 38/129 children were later switched to another drug. In 11/38 (28.5%) clinical and/or EEG deterioration was observed. Two patients identified at another institution with similar exacerbation were also included in our analysis. We report on the findings in these 13 cases. RESULTS: Two groups were identified: Group I--6 patients with normal neurological exam, normal EEG background, and a diagnosis of idiopathic generalized epilepsy. Group II--7 patients with an abnormal neurological exam and/or abnormal EEG background. Following introduction of CBZ therapy, worsening of preexisting seizures, appearance of new seizure types, behavioral regression, and accompanying EEG deterioration were reported in both groups. Dramatic improvement in seizure control occurred, following withdrawal of CBZ and substitution of another anticonvulsant. CONCLUSION: Physicians treating epilepsy must be aware that CBZ can exacerbate seizures, and cause developmental regression in children. Careful patient selection, when choosing CBZ as treatment, and prompt recognition of clinical deterioration and intervention, may help avoid or reverse these paradoxical reactions.

Adolescent↗
PubMed1997

Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review.

Argininemia, a rare autosomal recessive urea cycle disorder, is caused by a deficiency of arginase, with resulting elevated plasma arginine and ammonia levels. Reports to date have focused little on the neurology of this disorder or the efficacy of treatments. A MEDLINE search revealed 25 previously reported cases, to which we have added two brothers who presented with late onset progressive spastic diplegia. Though their degree of enzyme deficiency was comparable, the severity of their phenotypic abnormalities differed substantially. With dietary therapy, both showed improved cognitive and motor function. Late metabolic crises occurred in both, resulting in death of the less severely affected brother. Based on analysis of our clinical database, we report on the full spectrum of neurologic abnormalities seen in argininemia with particular focus on the accompanying progressive spastic diplegia and its response to treatment; progressive decline in head growth; distinctive neuroradiologic findings; and life-threatening later complications. Current and potential future therapies and long-term outcome are summarized.

Adolescent↗
PubMed1996

Alternative epilepsy therapies: the ketogenic diet, immunoglobulins, and steroids.

Despite the continued development and release of new antiepileptic drugs (AEDs), many children have seizures that do not respond to conventional therapy or have related side effects that preclude continued use. While some of these children are surgical candidates, the majority do not qualify for surgical resection. In these children alternative therapies are often considered by desperate physicians and parents. Three of the less conventional therapies which are currently used for intractable epilepsy are: the ketogenic diet, immunoglobulins, and steroids. None of these therapies has been adequately studied and it remains unclear which patients may benefit or be harmed by these therapies. Despite the lack of scientific vigor in evaluating these therapies, the television and print media has proclaimed these therapies as miraculous, yet grossly under-utilized by an ignorant medical community. The ketogenic diet has been demonstrated to reduce seizure frequency in some patients, but has an unclear mechanism of action, while immunoglobulins have both unknown efficacy and an unknown mechanism of action. While steroids are accepted as an effective therapy for infantile spasms, their role in the treatment of the Landau-Kleffner syndrome is far less clear. Although the ketogenic diet, immunoglobulins, and steroids may have a role in the treatment of severe childhood epilepsy, all three therapies need to be critically evaluated in regard to efficacy, mechanism of action, and safety.

Adolescent↗
PubMed1991

Iron deficiency; non-hematological manifestations.

Iron deficiency has far reaching consequences on systemic functions apart from the well known feature of anemia. Because iron deficiency anemia is easy to recognize and treat, the non-hematological manifestations of this trace element deficiency have been overlooked. There is a large body of evidence accumulated from animal and human studies to indicate that iron deficiency states are associated with alterations in cellular function, growth, motor development, behaviour and cognitive function. There are consequences for the host's level of immunocompetence against infection, for physical work and metabolic stress, for altered fetal outcome and premature labour in pregnant women. The gastrointestinal functions and other organ systems are also affected as a result of iron deficiency. The purpose of this review is to emphasize the importance of the non-hematological manifestations of iron deficiency and to highlight areas of interest, both to basic scientists and health care professionals.

Animals↗