Fetal tissue amino acid concentrations in argininosuccinic aciduria and in "maternal homocystinuria".

Free amino acid concentrations have been measured in the tissues of a fetus at risk for argininosuccinic aciduria and of an obligate heterozygous fetus in a mother homozygous for homocystinuria. Argininosuccinic acid was detected in all tissues studied of the homozygous affected fetus from the heterozygous mother. Abnormal concentrations of methionine and cystathionine were observed in the tissues of the fetus who was an obligate heterozygote for homocystinuria. These abnormal free amino acid concentrations occur early in fetal development and may be related to later brain dysfunction.     

Residual Right-to-Left Shunt Following Repair of Atrial Septal Defect

Information about 5 patients with residual right-to-left shunts following repair of an atrial septal defect is presented. In each patient the defect was located low in the atrial septum adjacent to the inferior vena cava. During operation, either the eustachian valve of the inferior vena cava had been mistaken for the lower margin of the defect or the lower portion of the defect was not closed; blood flow was then diverted from the inferior vena cava into the left atrium. To prevent this occurrence, the inferior margin of the atrial septal defect should be closed first.     

The binding and processing of monoclonal human IgG1 by cells of a human macrophage-like cell line (U937)

The goal of these experiments was to assess the relationship between the binding and processing of IgG by Fc-receptor-bearing cells. Cells of the U937 human macrophage-like cell line were incubated with 125I- labeled monomers, dimers, oligomers (composed of 2-4 IgG1 subunits), and HP (heavy polymers composed of 5 or more subunits per polymer) of monoclonal human IgG1 in vitro. Binding was assessed by spinning cells through a layer of phthalate oils. Internalization of IgG1 was assessed by quantitating residual binding to cells after surface-bound IgG was removed by a brief treatment with a solution containing 0.25 M acetic acid and 0.5 M sodium chloride. Catabolism was assessed by measuring the release of radioactive fragments of IgG1, which were not precipitated by 10% trichloroacetic acid. Unstimulated U937 bound about 10,000 molecules per cell of IgG1 monomer, with an equilibrium binding constant (Ka) of 5 X 10(8) M-1. After stimulation with a conditioned medium in vitro, binding per cell was increased 3-7--fold, and the Ka was decreased 2-4--fold. Both unstimulated and stimulated cells internalized and catabolized labeled IgG1 HP, but stimulated cells internalized and digested much more IgG1 HP per cell than unstimulated cells. Both monomers and dimers of IgG1 were internalized and degraded very slowly by stimulated cells, even though both preparations readily bound to cells. In contrast, oligomers and (to an even greater extent) IgG1 HP were internalized and degraded much more rapidly. Internalization of IgG1 HP was markedly inhibited by incubation at 4 degrees C, but not by incubation with a variety of metabolic inhibitors. Catabolism was inhibited by chloroquine and monensin (inhibitors of lysosomal acidification) and by cytochalasin (an inhibitor of microfilament polymerization). Binding to the surface of cells was not markedly inhibited by any agent tested. The capacity of cells to bind labeled IgG1 was markedly reduced by prior incubation in the presence of unlabeled IgG1. This reduction was in part due to the steric blockade of receptors caused by the avid, but reversible, binding of IgG1. In addition, IgG1 oligomers or HP (but not IgG1 monomers or dimers) also caused an irreversible reduction in the number of Fc receptors by a process analogous to receptor down-regulation, as observed in other receptor--ligand systems.     

Possibility of selection against mtDNA mutations in tumors

Several studies of tumors have revealed substantial numbers of clonally expanded somatic mutations in mitochondrial DNA (mtDNA), not observed in adjacent intact tissues. These findings were interpreted as indicating the involvement of mtDNA mutations in tumorigenesis. Such comparisons, however, ignore an important confounding factor: the monoclonal origin of tumors as opposed to the highly polyclonal nature of normal tissues. Analysis of recently published data on the incidence of somatic mutations in nontumor monoclonal cells suggests that, contrary to the prevailing view, the process of tumorigenesis may be accompanied by active selection against detrimental mtDNA mutations.     

Two brothers with mild congenital erythropoietic porphyria due to a novel genotype

BACKGROUND: Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disease caused by the deficient activity of the heme biosynthetic enzyme, uroporphyrinogen III synthase (URO-synthase), and the accumulation of the nonphysiologic and phototoxic porphyrin I isomers. Clinical manifestations range from severe mutilation to mild erosions and blisters on sun-exposed areas. Evaluation of the URO-synthase mutation and residual enzyme activity has been correlated with the phenotypic expression of the disease. OBSERVATIONS: We describe 16- and 4-year-old brothers with CEP with a mild phenotype due to a novel genotype, one allele having a promoter mutation (-76G-->A) and the other having an exonic missense mutation (G225S). The father and a 4-year-old fraternal twin brother were carriers of the -76G-->A mutation, whereas the mother and a 15-year-old brother were carriers of the G225S mutation. Previous in vitro expression studies demonstrated that the G225S mutation severely decreased URO-synthase activity to 1.2% of normal, whereas the promoter mutation decreased the activity to approximately 50% of wild type, accounting for the mild clinical phenotype. CONCLUSION: The mild disease phenotype in these patients is a further example of the clinical heterogeneity seen in CEP and is additional proof that in vitro enzyme expression studies provide dependable genotype-phenotype correlations.     

Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes

OBJECTIVE: To describe the renal ultrasonography (US) and magnetic resonance imaging (MRI) findings in affected males and female carriers with the classic and cardiac variant phenotypes of Fabry disease (alpha-galactosidase A [alpha-Gal A] deficiency). METHODS: The renal US and MRI features of 76 classically affected males (aged 7-53 years), 40 female carriers from classically affected families (aged 18-66 years), and 6 males with the cardiac variant phenotype (aged 17-59 years) were reviewed by 3 blinded board-certified radiologists. The images were evaluated for the presence of cortical cysts, parapelvic cysts, renal atrophy, decreased cortical thickness, increased echogenicity (US only), and decreased corticomedullary differentiation (MRI only). The consensus findings were analyzed with respect to the patients' sex, age, Fabry genotype and phenotype, and renal function. RESULTS: MRI was more sensitive than US in detecting radiographic abnormalities. In the 76 classically affected males, the most common US abnormalities were cysts (36.9%; cortical cysts = 22.4%, parapelvic cysts = 14.5%), increased echogenicity (17.1%), and decreased cortical thickness (11.9%), whereas the most common MRI abnormalities were cysts (47.3%; cortical cysts = 28.9%, parapelvic cysts = 18.4%), loss of corticomedullary differentiation (43.4%), and decreased cortical thickness (7.9%). Among the 40 female carriers, common US abnormalities included cysts (20%; cortical cysts = 10%, parapelvic cysts = 10%) and increased echogenicity (7.5%), whereas MRI findings included decreased corticomedullary differentiation (40%) and cysts (37.5%; cortical cysts = 20%; parapelvic cysts = 17.5%). Renal US and MRI were normal in 5 classically affected males aged 12 years or younger and 2 female carriers aged 20 years or younger. Among the 6 male cardiac variants, abnormal US findings included cysts (66.3%; cortical cysts = 50%, parapelvic cysts = 16.3%) and increased echogenicity (33.3%), whereas MRI detected decreased corticomedullary differentiation in all (100%) and cysts in 83% (cortical cysts = 66.7%; parapelvic cysts = 16.3%). Serum creatinine levels were elevated (>1.2 mg/dL) in 40.8% and 15% of the classically affected males and female carriers with US and/or MRI abnormalities compared with 14.8% and 0%, respectively, who had elevated serum creatinine levels but no detectable radiographic abnormalities. There was no association of alpha-Gal A genotype with type or frequency of abnormalities in classically affected patients. CONCLUSIONS: Among classically affected males and female carriers, renal US and/or MRI abnormalities were detected in 64.5% and 60%, respectively. The occurrence and number of abnormalities increased with age in affected males and female carriers. Cysts, particularly parapelvic cysts, were more common and appeared earlier than in the general population. No renal abnormalities were detected in classically affected males or female carriers <12 years or <20 years of age, respectively. Five of the 6 males with the later-onset milder cardiac variant phenotype had loss of corticomedullary differentiation on MRI. Renal imaging abnormalities were more frequent in older patients with elevated serum creatinine levels, regardless of alpha-Gal A genotype or Fabry phenotype.     

Ocular manifestations of Niemann-Pick disease type B

PURPOSE: To investigate the ocular manifestations in Niemann-Pick disease type B (NPD-B). DESIGN: Observational case series. PARTICIPANTS: Forty-five patients (23 male and 22 female) with NPD-B from 37 unrelated families. METHODS: Serial clinical evaluations were carried out over a 2- to 14-year period, including a complete physical examination, neurologic assessment, and ophthalmologic examination. Genotyping of the specific mutations in the acid sphingomyelinase (ASM) gene was performed when possible for genotype-phenotype correlations. MAIN OUTCOME MEASURES: Fundus photographs to evaluate the retina, ASM genotype, and neurologic examination findings. RESULTS: Ophthalmoscopic examination revealed retinal stigmata in 15 of 45 patients, 3 with macular halos and 12 with cherry red maculae. Neurologic examinations did not reveal any evidence of neurodegeneration, and there was no consistent relationship between retinal findings and genotype. CONCLUSIONS: The presence of macular halos and/or cherry red maculae is not an absolute predictor of neurodegeneration, but should prompt a thorough evaluation to determine the underlying etiology and the precise diagnosis.     

Growth restriction in children with type B Niemann-Pick disease

OBJECTIVES: To compare growth of children with type B Niemann-Pick disease (NPD) with disease variables including genotype, organomegaly, bone age, and serum insulin-like growth factor-1 (IGF-1). STUDY DESIGN: A cross-sectional analysis of growth was performed in 23 children and adolescents with enzymatically and genotypically confirmed NPD. Liver and spleen volumes were measured by quantitative computed tomography and skeletal age by a wrist radiograph. RESULTS: The mean Z scores for height and weight were -1.24 (29th percentile) and -0.75 (34th percentile). The mean liver and spleen volumes were 2.06 and 13.46 times normal for weight, respectively. Skeletal age was delayed by an average of 2.5 years, and serum IGF-1 level was at or below the 2nd percentile in 8 of 12 patients. Short stature and low weight were significantly correlated with large organ volumes, delayed bone age, and low IGF-1 levels. In contrast to patients with other mutations, individuals homozygous for the DeltaR608 mutation had normal height and weight, markedly less hepatosplenomegaly and bone age delay, and normal IGF-1 levels. CONCLUSIONS: Abnormal linear growth and delayed skeletal maturation are common in children and adolescents with type B NPD; however, homozygosity for DeltaR608 is associated with normal growth.