Presymptomatic Treatment Research Articles

A critical evaluation of copper metabolism in Indian Wilson's disease children with special reference to their phenotypes and relatives.

Wilson's disease is an autosomal recessive disorder of copper accumulation in various organs, with most common clinical manifestations such as hepatic, neurological, and renal dysfunctions. Serum copper and ceruloplasmin in Wilson's disease were significantly lower as compared to normals, controls, and relatives of Wilson's disease patients, whereas marked hypercupriuria (145+/-7 microg/24 h) was observed in Wilson's children only. A good correlation (r=0.92) was found between non-ceruloplasmin-bound copper and 24-h urinary copper excretion in Wilson's disease patients. Further, copper studies among the different phenotypes of Wilson's disease revealed substantially low serum ceruloplasmin and a marked hypercupriuria in Wilson's disease children associated with renal tubular acidosis as compared to the patients with either hepatological or neurological manifestations. Serum ceruloplasmin levels in 14 patients of Wilson's disease were between 14 and 20 mg/dL. These patients of Wilson's disease were confirmed by measuring liver biopsy copper, which was about nine times higher than normal hepatic copper content. During the family screening by copper studies, four asymptomatic siblings were diagnosed for Wilson's disease. These subjects were then started on D-penicillamine therapy because presymptomatic treatment prevents progression of the disease complications.

From medical history and biochemical tests to presymptomatic treatment in a large MEN 2A family.

An extensive study was published in 1959 in the Netherlands on a large family, which initially attracted attention because of a family history of attacks of shaking. Clinical investigation revealed phaeochromocytomas in four family members. In 1975, the family was identified to be a MEN 2A family, and since then, the members were examined annually using measurement of catecholamine metabolites in 24-h excreted urine and C-cell stimulation tests. In 1993, the RET proto-oncogene on chromosome 10q11 was found to be associated with MEN 2A and a specific mutation in this gene was identified in the family. In this family, 32 MEN 2A patients were detected. Since screening started in 1975, no patient died of phaeochromocytoma; however, two patients died of metastasized medullary thyroid carcinoma (MTC) (mean age 46 years). Twelve patients were operated on for phaeochromocytoma, and 13 for MTC. The results of DNA-analysis revealed the failures of the biochemical tests to identify affected family members. Six disease gene carriers with normal C-cell stimulation test results appeared to have small multifocal MTCs. Two carriers with normal excretion levels of catecholamines had a small phaeochromocytoma. DNA-analysis enables the unambiguous diagnosis of MEN 2A gene carrier-ship, allowing presymptomatic surgery for MTC.

DNA analysis for detection of medium-chain acyl-CoA dehydrogenase deficiency in a Manitoba newborn population

Introduction: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the most frequent disorder of fatty acid β-oxidation, can cause episodic hypoglycemia, Reye-like encephalopathy and sudden death. A single mutation in the MCAD gene, K329E, has been associated with most cases of this disease. Consequently, unlike most other genetic disorders which are associated with multiplicities of mutations, it is possible to consider newborn screening for MCAD deficiency using a molecular genetic approach. Moreover, recent reports have stressed the need for instituting newborn screening for this disease to prevent the complications through presymptomatic detection and treatment. As a preliminary to this consideration, we prospectively surveyed 2000 consecutive newborn infants anonymously to determine the frequency of the K329E mutation in the Manitoba population. Methods: A 3 mm diameter disc punched from each of 2000 consecutive filter paper samples submitted for routine neonatal screening was treated with methanol for protein fixation and then directly subjected to PCR for amplication of a 199 base-pair segment surrounding nucleotide 985 in the MCAD gene. Samples found to have a K329E allele were tested by fast atom bombardment tandem mass spectrometry (FAB-MS) for the acylcarnitine profile consistent with MCAD deficiency. Results: Among the 2000 consecutive samples tested, 13 infants were found to be heterozygous for the K329E mutation. All had a normal acylcarnitine profile, indicating that a second unidentified mutation in these infants was unlikely. No homozygous infants were found. Discussion: The homozygote frequency predicted from this heterozygote frequency is 1:95 000 (CI 95%, 1:40 000–1:450 000). These results indicate that the K329E mutation is not sufficiently frequent in the Manitoba population to warrant DNA-based neonatal screening for MCAD deficiency.

Pre-symptomatic diagnosis and pre-emptive treatment of cytomegalovirus (CMV) infection after liver transplantation (LT)

Pre-symptomatic diagnosis and pre-emptive treatment of cytomegalovirus (CMV) infection after liver transplantation (LT)

Newborn screening for biotinidase deficiency: pilot study and follow-up of identified cases

Biotinidase deficiency is an inborn error of biotin recycling that can result in an organic aciduria and developmental delay, seizures, alopecia, hypotonia and hearing loss. Early presymptomatic biotin treatment may prevent these complications and, on that basis, newborn screening for the disorder has been developed. In Massachusetts we conducted a one-year pilot study of newborn screening for biotinidase deficiency. Among 99,398 screened neonates, we identified three with profound biotinidase deficiency (1:33,000) and seven with partial deficiency (1:14,000). None of the infants had biochemical or clinical complications when evaluated. The three with profound deficiency were begun on biotin therapy and have thrived. Those with partial deficiency have received no therapy and have had normal growth and development. Transient biotinidase deficiency was overrepresented among low birth weight infants, as expected. Just as this pilot study ended, an infant in a neighboring state was diagnosed with biotinidase deficiency after coming to attention because of seizures, developmental delay and hearing loss. His newborn blood specimen retrieved from storage gave no activity on biotinidase screening. Newborn screening for biotinidase deficiency is effective in identifying cases and probably is of value in preventing irreversible complications from this disorder in at least some of the identified infants.

Linear growth in children with acute lymphoblastic leukemia treated without cranial irradiation

Improved treatment regimens for acute lymphoblastic leukemia have resulted in long-term remission in nearly two thirds of affected children. However, many children have delayed effects of therapy, including neuropsychologic impairment and growth disturbances. Linear growth patterns of patients with ALL who received cranial irradiation as a component of presymptomatic treatment of the central nervous system have been studied by numerous investigators. 1-4 However, longitudinal growth measurements have not been characterized in patients who received only intrathecal chemotherapy to prevent C N S leukemia. Beginning in 1981, children with newly diagnosed non-T-cell, non-B-cell ALL treated at our center have not received CI. We retrospectively evaluated the growth patterns of these patients.

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors. Some patients may also develop carcinoid tumors, adrenocortical tumors, facial angiofibromas, collagenomas, and lipomas. MEN1 is an autosomal-dominant disorder, due to mutations in the tumor suppressor gene MEN1, which encodes a 610 amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. Patients with MEN1 have a decreased life-expectancy and the outcomes of current treatments, which are generally similar to that for the respective tumors occurring in non-MEN1 patients, are not as successful because of multiple tumors, which may be larger, more aggressive, and resistant to treatment, and the concurrence of metastases. The prognosis for MEN1 patients might be improved by pre-symptomatic tumor detection and undertaking treatment specific for MEN1-tumors. Thus, it is recommended that MEN1 patients and their families should be cared for by multi-disciplinary teams comprising relevant specialists with experience in the diagnosis and treatment of patients with endocrine tumors.

927 LONG TERM RESULTS AFTER CNS RELAPSE IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

The status of children with ALL treated on studies CCG-101/143 who developed CNS disease was investigated. Presymptomatic CNS therapy consisted of craniospinal radiation (XRT), cranial XRT plus IT MTX x6, or only IT MTX x6. Of the 791 pts who achieved remission, 63 (7.9%) developed CNS disease as the first evidence of relapse with no subsequent CNS episodes. The median time to isolated CNS relapse was 385 days, of these 63 pts 41 relapsed subsequently in the bone marrow (BM) and 38 died. Survivors had their initial relapse late (median: 457 days). Of the 63 pts with 1 isolated CNS relapse, 38 received presymptomatic CNS treatment with IT MTX alone; however, their disease-free (DF) survival was no different from the other 2 groups (p=0.1). Twenty-six pts (3.3%) developed 2 isolated CNS episodes and 20 of these pts subsequently relapsed in the BM. Only 3 pts survived, none of whom had any other relapses besides the 2 CNS relapses. Twenty-four pts (3%) had multiple CNS relapses (3 to 9 separate episodes); 20 died. The 4 survivors in this group have had no BM relapses, but have shown a pattern of chronic CNS disease. The DF survival at 84 mo for pts with 1 or more isolated CNS relapses was 16% and 8.4%, respectively. Time to the initial CNS relapse was found to be the most important factor for predicting outcome (p<0.0001). The data show that a CNS relapse is an indicator of poor prognosis. These pts require new therapeutic strategies to improve prevention and salvage.