Individualization of long-term enzyme replacement therapy for Gaucher disease.

Gaucher disease, the most common lysosomal storage disorder, is a heterogeneous condition affecting multiple organ systems. Patients with nonneuronopathic (type 1) Gaucher disease may suffer from hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase (imiglucerase, Cerezyme, Genzyme Corporation, Cambridge, MA) reverses or ameliorates many of the manifestations of type 1 Gaucher disease.

Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients.

For patients with type 1 Gaucher disease, challenges to patient care posed by clinical heterogeneity, variable progression rates, and potential permanent disability that can result from untreated or suboptimally treated hematologic, skeletal, and visceral organ involvement dictate a need for comprehensive, serial monitoring. An updated consensus on minimum recommendations for effective monitoring of all adult patients with type 1 Gaucher disease has been developed by the International Collaborative Gaucher Group (ICGG) Registry coordinators. These recommendations provide a schedule for comprehensive and reproducible evaluation and monitoring of all clinically relevant aspects of this disease.

Pyruvate carboxylase deficiency--insights from liver transplantation.

Pyruvate carboxylase deficiency, complex form, presents in early infancy with lethal metabolic acidosis, resulting from ketoacidosis and lactic acidemia. Renal tubular acidosis, hyperammonemia, and citrullinemia complete the picture. In an infant with this disease, large amounts of glucose ameliorated the ketoacidosis, but worsened the lactic acidosis.

Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry.

Purpose: Gaucher disease is the first lysosomal storage disorder to be treated with macrophage-targeted enzyme replacement therapy. Previous studies in relatively small numbers of patients demonstrated short-term efficacy of this treatment. This study describes the effects of 2 to 5 years of treatment on specific manifestations of type 1 Gaucher disease.

The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease.

Background: The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy.

Methods: Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review.

Management of phenylketonuria for optimal outcome: a review of guidelines for phenylketonuria management and a report of surveys of parents, patients, and clinic directors.

Objective: The development of guidelines for phenylketonuria (PKU) management in the United Kingdom has resulted in much discussion in the community of parents and PKU clinics and parents have asked why the United States does not have such guidelines. The objective of this report is to discuss PKU management in the United States, the British guidelines on PKU management, and the feasibility, suitability, and mechanism of developing PKU management guidelines in the United States.

Methods: Members of the American Academy of Pediatrics (AAP) Committee on Genetics (COG) reviewed the literature and conducted surveys of parents of children with PKU, young adults with PKU, and directors of PKU clinics in the United States.

Development of guidelines for treatment of children with phenylketonuria: report of a meeting at the National Institute of Child Health and Human Development held August 15, 1995, National Institutes of Health, Bethesda, Maryland.

Objective: To convene a small group of experts in diagnosis and management of PKU to discuss the following issues: the Subject Review of PKU management being performed by the American Academy of Pediatrics (AAP) Committee on Genetics (COG), the published British guidelines on PKU management, and the feasibility, suitability, and mechanism of developing PKU management guidelines for the United States.

Methods: A 1-day meeting was held at the National Institutes of Health under the auspices of National Institute of Child Health and Human Development, convening experts in PKU diagnosis and management and members of the AAP/COG.

Results: The group reviewed the published reports of outcomes of treatment of PKU and the British guidelines that were developed based on those data.

Gaucher disease: recommendations on diagnosis, evaluation, and monitoring.

Background: Timely diagnosis and continued monitoring of patients with type I Gaucher disease is critical because skeletal involvement can permanently disable patients and visceral organ involvement can lead to abdominal pain and secondary hematologic and biochemical complications.

Objective: To seek clinical consensus for minimum recommendations for effective diagnosis and monitoring of patients with type I Gaucher disease. PARTICIPANTS, EVIDENCE, AND CONSENSUS PROCESS: Contributing authors collaborated in quarterly meetings over a 2-year period to synthesize recommendations from peer-reviewed publications and their own medical experiences.

Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families.

Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. Children with inborn errors of PC metabolism have lactic acidosis, hypoglycemia, and mental retardation. The variable severity of the clinical phenotype is dependent on both genetic and environmental factors.

Acceleration of retarded growth in children with Gaucher disease after treatment with alglucerase.

Objectives: The incidence and severity of growth retardation in children with type 1 Gaucher disease and the response to enzyme replacement therapy with alglucerase were studied.

Study Design: A retrospective analysis of growth in 99 children and adolescents with type 1 Gaucher disease before treatment, and in 54 of those subjects during treatment, was done. Growth was compared with gender, age, and dosage of replacement enzyme.

Prenatal diagnosis of mitochondrial fatty acid oxidation defects.

Amniocytes isolated from two pregnancies at risk for fatty acid oxidation defects were incubated with stable isotopically labelled palmitate, in the presence of L-carnitine, to probe that pathway. The labelled acylcarnitines were then quantitated using tandem mass spectrometry. Amniocytes from a pregnancy at risk for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency produced a characteristic acylcarnitine profile with increased levels of octanoylcarnitine and decanoylcarnitine, indicative of MCAD deficiency.

Chiari I malformation: association with hypophosphatemic rickets and MR imaging appearance.

Purpose: To evaluate for an association between familial hypophosphatemic rickets (FHR) and Chiari I malformation (CM1).

Materials And Methods: Sixteen patients with FHR underwent magnetic resonance (MR) imaging of the cervicomedullary junction. Images were analyzed by three radiologists for cerebellar tonsillar ectopia, syringohydromyelia, calvarial bone thickening, a flat posterior fossa, and cervical spinal stenosis.

Sequence of the E1 alpha subunit of branched-chain alpha-ketoacid dehydrogenase in two patients with thiamine-responsive maple syrup urine disease.

Some patients with maple syrup urine disease respond to thiamine administration with a reduction in ketoaciduria and increase in activity of branched-chain alpha-ketoacid dehydrogenase. The biochemical mechanism underlying this effect is unknown but may result from decreased affinity of the mutant enzyme for thiamine or from stabilization of the abnormal enzyme by thiamine. The E1 alpha subunit of the complex participates in the thiamine-dependent decarboxylation of branched-chain alpha-ketoacids.

3-Hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured fibroblasts from patients with mevalonate kinase deficiency: differential response to lipid supplied by fetal bovine serum in tissue culture medium.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity was measured in extracts of cultured fibroblasts derived from patients with mevalonate kinase deficiency (MKD). For six patients studied, the mean activity of 63.3 +/- 41.

Peritoneal dialysis in the first 60 days of life.

This report describes a 7-year experience with acute peritoneal dialysis in 31 neonates and infants less than 60 days of age. There were 20 boys and 11 girls, ages 3 to 60 days. Tenckhoff catheters of modified length were placed in the newborn intensive care unit (ICU), pediatric ICU, or surgery suites, and hourly exchanges (20 cc/kg) were started immediately postoperatively.

Mevalonate kinase in lysates of cultured human fibroblasts and lymphoblasts: kinetic properties, assay conditions, carrier detection and measurement of residual activity in a patient with mevalonic aciduria.

An assay has been developed for the measurement of mevalonate kinase activity in extracts of cultured human fibroblasts and lymphoblasts. Individual elements of the assay were investigated in order to achieve optimum conditions. Apparent Michaelis constants (KMapp) for the substrates mevalonic acid and adenosine-5'-triphosphate were 22 +/- 10 mumol/l and 0.

Overgrowth, congenital hypotonia, nystagmus, strabismus, and mental retardation: variant of dominantly inherited Sotos sequence?

We report on 2 patients with macrocephaly, strabismus, esotropia, nystagmus, hypotonia, developmental delay, excessive size, unusual facial appearance, and improvement with age. Many of these abnormalities are present in Sotos sequence. The mothers of both patients share some characteristics with their children.

Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature.

The main features of Wiedemann-Beckwith syndrome (WBS) include macroglossia, abdominal wall defects, visceromegaly, gigantism, hypoglycemia, ear creases, nevus flammeus, and mid-face hypoplasia. Twenty-two cases of WBS were examined clinically and cytogenetically, and compared to 226 previously reported cases. Aspects of the clinical evaluations are discussed.

Mevalonic aciduria--an inborn error of cholesterol and nonsterol isoprene biosynthesis.

A two-year-old boy presented with severe failure to thrive, developmental delay, anemia, hepatosplenomegaly, central cataracts, and dysmorphic features. Quantitative analyses of urinary organic acids revealed massive excretion of mevalonic acid, a metabolic precursor of cholesterol and nonsterol isoprenes: 46,000 to 56,200 mmol per mole of creatinine, as compared with 0.2 to 0.

Lactation and phenylketonuria.

Many young women who were diagnosed as having phenylketonuria (PKU) during routine neonatal screening and effectively treated during childhood are now of childbearing age. Recent reports suggest that maternal dietary therapy instituted before conception may improve the likelihood of a successful pregnancy and normal offspring. However, it is not known whether the intake of phenylalanine (phe) should be restricted during lactation.