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. RESULTS: Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2. 3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. CONCLUSIONS: The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.

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. These physicians care for most patients with Gaucher disease in the United States and serve as the US Regional Coordinators for the International Collaborative Gaucher Group Registry, the world's largest database for this disorder. CONCLUSIONS: The definitive method of diagnosis is enzyme assay of beta-glucocerebrosidase activity. Schedules differ for monitoring complications of type I Gaucher disease, depending on symptoms and whether enzyme replacement therapy is used. Hematologic and biochemical involvement should be assessed by complete blood cell count, including platelets, acid phosphatase, and liver enzymes, at baseline and every 12 months in untreated patients and every 3 months and at enzyme replacement therapy changes in treated patients. Visceral involvement should be assessed at diagnosis using magnetic resonance imaging or computed tomographic scans. Skeletal involvement should be assessed at diagnosis using T1- and T2-weighted magnetic resonance imaging of the entire femora and plain radiography of the femora, spine, and symptomatic sites. Follow-up skeletal and visceral assessments are recommended every 12 to 24 months in untreated patients, and every 12 months and at enzyme replacement therapy changes in treated patients.

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. Two consanguineous families with moderate forms of PC deficiency were characterized at the biochemical and molecular levels. In both families, the probands were found to have low PC activity (range, 2-25% of control) in blood lymphocytes and skin fibroblasts associated with either diminished or normal protein levels. In the first case, sequencing of patient-specific PC cDNA demonstrated a T to C substitution at nucleotide 434, which causes a valine to alanine change at amino acid residue 145. Direct sequencing of the parents showed that they are heterozygous for this mutation. In the second family, a brother and sister had mental retardation and episodes of severe lactic/ketoacidosis in early childhood. In these cases, a C to T substitution at nucleotide 1351 results in a cysteine for arginine substitution at amino acid residue 451; the parents were also found to be heterozygous for this mutation. In both families, no other mutations were found, and both substitutions occurred in relatively conserved amino acid residues. These mutations, located in the biotin carboxylase domain, provide a unique opportunity to analyze how natural occurring mutations affect PC function.

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. RESULTS: Linear growth was normal in the first 1 to 2 years of life and then decelerated. Height was at or below the 5th percentile in 50% of all subjects immediately before treatment. The mean z score was -1.49 (95% confidence interval, -1.83 to -1.16), corresponding to the 6.8th percentile for height. Seventy-two percent were below the 50th percentile and 50% were at or below the 5th percentile for mid-parental height (p <0.001). One and one-half years after treatment was started, the estimated mean z score for all subjects was -1.01, which corresponds to the 16th percentile for height. Normal growth was achieved within 4 to 30 months in eight of nine subjects who were at or below the 5th percentile. It occurred only in those receiving higher doses (60 to 120 U/kg per 4-week period) of alglucerase. There was a significant association between z scores for height before treatment and liver enlargement (r= 0.57; p < 0.01). CONCLUSIONS: Half of the subjects who manifest type 1 Gaucher disease in childhood have growth retardation. Treatment with adequate amounts of modified enzyme replacement was effective in normalizing linear growth.

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. DNA analysis confirmed that the fetus was homozygous for the MCAD A985G mutation. Acylcarnitine and DNA analysis of the infant's blood obtained post-partum confirmed MCAD deficiency. Amniocytes from a pregnancy at risk for an unspecified fat oxidation defect produced increased levels of long-chain acylcarnitines consistent with a deficiency in very-long-chain acyl-CoA dehydrogenase (VLCAD). Measurements of the enzymatic activity confirmed VLCAD deficiency in amniocytes. Acylcarnitine profiles of the infant's blood obtained post-partum in addition to enzyme activities measured in fibroblasts confirmed VLCAD deficiency. The successful prenatal diagnosis of VLCAD and MCAD deficiencies using in vitro probes of fatty acid oxidation in fibroblasts suggests that this approach can potentially recognize many mitochondrial fatty acid oxidation defects even if no prior diagnosis is determined in the family at risk.

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. Final diagnoses were made by means of consensus. Tonsillar ectopia of 4 mm indicated CM1. Subjects underwent neurologic examination and completed a questionnaire. Medical records were retrospectively reviewed. A two-sided Fisher exact test was used to test for independence between CM1 and bone thickening or ventriculomegaly. RESULTS: Seven subjects (44%) had CM1. The more severe the bone thickening, the more likely that a CM1 was present. Four subjects (25%) had cervical spinal stenosis. CONCLUSION: Findings indicate that CM1 is associated with FHR and that the primary abnormality in patients with CM1 is a small posterior fossa caused by a bony malformation.

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. We sequenced the E1 alpha subunit by using reverse transcription of RNA followed by enzymatic amplification of cDNA in two patients with thiamine-responsive maple syrup urine disease. The deduced amino acid sequence of this subunit in the patients was identical to that in normal controls, suggesting that in the patients the thiamine-binding site is abnormal because of a mutation in the E1 beta subunit. Other possible explanations are (a) that a mutation in the E1 beta or E2 subunits either alters thiamine binding by E1 alpha because of allosteric interactions or causes the complex to be unstable and (b) that thiamine stabilizes the complex.

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 +/- 41.1 pmol/min-mg protein (+/- 1 SD, range 37.7-146.2) was significantly higher than the mean value in three control fibroblast lines of 11.1 +/- 3.5 (+/- 1 SD, range 8.0-14.9). These values were obtained using cells subcultured in medium supplemented with 10% fetal bovine serum (FBS) 21 h prior to assay. When cells were deprived of cholesterol by subculturing for 21 h in delipidated FBS, the mean value for patient cells was increased to 230.8 +/- 78.5 pmol/min-mg protein (range 130.9-333.8) as compared to 109.5 +/- 47.1 (range 78.0-163.6) for controls. The activity of HMG-CoA synthase in extracts of fibroblasts derived from the patients was not elevated. The mevalonic acid concentration in the surrounding culture medium was assessed by stable isotope dilution assay. For five patients, the mean concentration in medium containing FBS was 0.92 +/- 0.37 microM (+/- 1 SD, range 0.46-1.48) in contrast to 1.24 +/- 0.83 microM (range 0.46-2.54) for cells subcultured in delipidated FBS. The mean value for three control fibroblast lines was 0.22 +/- 0.12 microM (+/- 1 SD, range 0.11-0.35) for cells subcultured in FBS as compared to 0.01 +/- 0.01 microM (range 0.0-0.01 microM) for cells sucultured in delipidated FBS.(ABSTRACT TRUNCATED AT 250 WORDS)

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. Diagnoses included congenital metabolic disorders (11), acute tubular necrosis (6), postcardiopulmonary bypass with renal failure (5), renal cortical necrosis (5), obstructive uropathy (2), renal agenesis (1), and bilateral renal dysplasia (1). Complications included: peritonitis (4), bowel perforation (1), exit site infection (3), leaking dialysate (4), catheter obstruction (2), inguinal hernias (3), umbilical hernia (1), and retroperitoneal hemorrhage (1). There were 19 deaths (61.3%) from 1 to 90 days postinsertion in this high risk group. The (1), and post liver transplant (1). Effective dialysis (lowering of blood urea nitrogen (BUN) or ammonia, correction of acidosis, decrease in fluid overload) was possible in all cases. Five of the 12 survivors remain on chronic dialysis awaiting renal transplantation. Peritoneal dialysis is effective in the newborn period in the management of metabolic disturbances as well as renal failure. Morbidity and mortality (61.3%) is related to the near-morbid condition of the baby at the time of insertion and the severity of the complex underlying diagnosis often associated with multiorgan failure.

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 0.42-0.53 mmol/l, respectively, in lysates of control fibroblast lines. The same values in lysates of a control lymphoblast line were 17 mumol/l and 0.23 mmol/l, respectively. Mevalonate kinase activity in extracts of cultured fibroblasts derived from 6 control individuals was 3.24 +/- (SD) 0.91 nmol/min/mg protein. The activity in extracts of fibroblasts derived from a patient with mevalonic aciduria was 0.15 +/- 0.10 nmol/min/mg protein, approximately 5% of the control mean. The parents and brother of the patient displayed mevalonate kinase activities in fibroblast extracts approximating 38-42% of the control mean. Substantially higher mevalonate kinase activity was documented in extracts of cultured lymphoblasts. When assayed on various occasions, the mean activity of mevalonate kinase in extracts of lymphoblasts derived from the parents, brother and maternal grandmother of the patient ranged from 27 to 32% of the mean activity of 9.8 +/- (SD) 3.4 nmol/min/mg protein measured in a parallel control lymphoblast line, while the mean activity in a maternal and paternal uncle approximated 65-89% of the same control mean. The mean activity in extracts of lymphoblasts derived from the patient approximated 2% of the control mean. The data suggest that the parents, brother and maternal grandmother are carriers of the defective gene responsible for mevalonate kinase deficiency, consistent with an autosomal recessive mode of inheritance.

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. These patients may represent an autosomal dominant form of Sotos sequence.

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. All individuals examined were chromosomally normal with no evidence of 11p abnormality as has been reported recently. The relevance of a possible relationship between clinical findings, chromosome abnormalities, and genes present on 11p is discussed. Transmission of this condition is most consistent with autosomal dominant inheritance with incomplete penetrance.

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 0.3 mmol per mole in normal children. The mevalonic acid concentration in plasma was also greatly increased at 440 mumol per liter (normal, less than 0.05). The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, was severely deficient in the patient's fibroblasts, lymphocytes, and lymphoblasts. In the subsequent pregnancy of the patient's mother, gas chromatography-mass spectrometry demonstrated a marked elevation of mevalonic acid in the mother's urine and a 3000-fold elevation, as compared with control levels in the amniotic fluid, suggesting that the fetus was affected. The diagnosis was confirmed by demonstration of the deficiency of mevalonate kinase in amniocytes and ultimately in liver from the abortus. Intermediate activities of the enzyme in both parents indicated an autosomal recessive mode of inheritance. These observations identify an inherited disorder of cholesterol and nonsterol isoprene biosynthesis in humans.

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. While phe levels in breast milk from women with PKU are markedly elevated, to our knowledge serum phe levels have not been measured in nursing newborn infants of PKU mothers. The present case report describes the pregnancy and early lactation of a mother with PKU, including serial measurements of serum phe levels in her offspring while being breast-fed.

Carrier detection in Sanfilippo syndrome type B: report of six families.

Serum samples from 175 individuals in six Sanfilippo syndrome type B (SFB) families and 360 White controls were assayed for serum alpha-N-acetyl-D-glucosaminidase (NAG) activity. Only minimal overlap was observed between the controls' NAG activity distribution and that of the 12 obligate heterozygotes. The distribution of NAG activity was log transformed to reduce skewness, and segregation of family members with a prior risk of being a SFB carrier was well within expected limits. However, in one consanguineous family the NAG activity of both parents of one SFB obligate heterozygote was within the normal range for NAG activity. Plausible explanations for this finding are discussed. Additionally, the serum NAG activity of one control and her mother were found to lie within one standard deviation of the obligate heterozygote mean. These individuals are most probably carriers for SFB.