Fumarase Deficiency: A Case With a New Pathogenic Mutation and a Review of the Literature.

Fumarase deficiency (FD) is a rare and severe autosomal disorder, caused by inactivity of the enzyme fumarase, due to biallelic mutations of the fumarase hydratase () gene. Several pathogenic mutations have been published. The article describes an infant with failure to thrive, microcephaly, axial hypotonia, and developmental retardation with increased excretion of fumarate, no activity of fumarase and a homozygous mutation of the gene, which was until recently only known as a variant of unknown significance.

Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete.

Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency.

Systemic carnitine deficiency is a potentially lethal, autosomal recessive disorder characterized by cardiomyopathy, myopathy, recurrent episodes of hypoketotic hypoglycemia, hyperammonemia, and failure to thrive. This form of carnitine deficiency is caused by a defect in the active cellular uptake of carnitine, and the gene encoding the high affinity carnitine transporter OCTN2 has recently been shown to be mutated in patients suffering from this disorder. Here, we report the underlying molecular defect in three unrelated patients.

Prenatal diagnosis of purine nucleoside phosphorylase deficiency in the first and second trimesters of pregnancy.

Prenatal diagnosis was performed in two successive pregnancies of a mother with a previous child with purine nucleoside phosphorylase (PNP) deficiency. In one pregnancy, an affected fetus was diagnosed in the 18th week of gestation after the demonstration of PNP deficiency in cultured amniotic fluid cells. Also an abnormal purine nucleoside profile was found in the amniotic fluid.

Suppression of antigraft immunity by preimmunization. V. Characterization of suppressor T memory cells.

We have previously shown that after intravenous (i.v.) immunization of mice with allogeneic spleen cells, two populations of suppressor T (Ts) cells may occur that can suppress delayed-type hypersensitivity (DTH) to alloantigens: Ts effector cells that transiently occur in the spleen, and long-lived, recirculating Ts cells that occur in thoracic duct lymph and can be transferred by parabiosis.

Generation of suppressor T cells after local immunization with histocompatibility antigens.

Subcutaneous (sc) hind-foot immunization (HFI) of mice with allogeneic spleen cells can induce a state of delayed-type hypersensitivity (DTH) as well as a state of suppression of DTH. This paper deals with the suppression induced by HFI. The state of suppression could be adoptively transferred by spleen cells and lymph node cells between Days 3 and 7 after HFI only.

Lipopolysaccharide-induced suppression of DTH-reactivity to histocompatibility antigens. I. Kinetic aspects and specificity.

The effects of bacterial lipopolysaccharide (LPS) on the development of DTH-reactivity to alloantigens in mice were investigated. DTH to a particular set of alloantigens could be suppressed by treatment of responder mice with a single intravenous (i.v.

Prenatal diagnosis of Fabry's disease by direct analysis of chorionic villi.

Six pregnancies of three carriers for X-linked Fabry's disease, were monitored by chromosome and enzyme analysis. Two affected male fetuses were detected by the demonstration of alpha-galactosidase deficiency in amniotic fluid cells and chorionic villi respectively. The use of chorionic villi enabled a diagnosis within a few hours after sampling in the ninth week of pregnancy whereas the use of amniotic fluid cells in the earlier case required two weeks of culturing after amniocentesis in the 16th week.

Suppression of antigraft immunity by preimmunization. III. Characterization of suppressor T cells involved in suppression of the efferent phase of DTH against alloantigens.

Suppressor T (Ts) cells that can suppress delayed type hypersensitivity (DTH) against histocompatibility (H) antigens can be isolated from spleen and lymph nodes a few days after i.v. immunization of mice with irradiated allogeneic spleen cells.

Suppression of antigraft immunity by preimmunization. IV. Persistence by long-lived recirculating suppressor T cells.

Delayed-type hypersensitivity (DTH) against histocompatibility (H) antigens in mice, which normally arises after s.c. immunization, can be prevented by i.

Secondary delayed type hypersensitivity to H-2 subregion-coded alloantigens.

Secondary type delayed type hypersensitivity (DTH) in mice against class I alloantigens or non-H-2 alloantigens is characterized by an earlier appearance of DTH reactivity after booster immunization compared with the development of DTH reactivity after primary immunization. In contrast to the primary and secondary DTH against class I or non-H-2 alloantigens, the development of secondary DTH against class II alloantigens or a set of alloantigens that includes class II alloantigens is not faster than the development of primary DTH. Thus, primary and secondary immunization with class II alloantigens prevents secondary type DTH reactivity to simultaneously administered class I alloantigens and non-H-2 alloantigens.

Characterization of suppressor T cells in graft-versus-host reactions.

Intravenous (i.v.) immunization of mice with irradiated (2000 rads) allogeneic lymphoid cells induces the generation of suppressor T cells.

Differential influence of 2'-deoxyguanosine on the induction and expression of suppressor T lymphocytes in vivo.

Subcutaneous (sc) immunization of mice with allogeneic spleen cells can induce delayed-type hypersensitivity (DTH) to histocompatibility antigens. Intravenous immunization with irradiated allogeneic spleen cells, on the other hand, induces suppressor T (Ts) lymphocytes. These Ts cells are capable of suppressing the host-versus-graft (HvG) DTH reactivity which normally arises after sc immunization.

The long-lasting state of specific nonresponsiveness induced by intravenous immunization with alloantigens is due to the generation of recirculating suppressor T cells.

We investigated whether the long-lasting state of nonresponsiveness that is induced by intravenous immunization with alloantigens is mediated by suppressor T cells, or is caused by inactivation or deletion of the relevant alloreactive T cell clones. The data from parabiosis and thoracic duct drainage experiments suggest that the state of nonresponsiveness depends on recirculating non-proliferating Ts memory cells.

Suppression of antigraft immunity by preimmunization. II. Characterization of the suppressor cells.

Immunization of mice with irradiated (20 Gy) or non-irradiated allogeneic spleen cells i.v. induces delayed-type hypersensitivity (DTH)-reactive T cells, as well as suppressor T cells, against histocompatibility antigens.

Synergism of T lymphocyte subsets in the response to Mls-locus coded antigens during graft-versus-host reaction.

After transplantation of lymphoid cells into lethally irradiated (semi)allogeneic mice specific anti-host directed effector T cells are generated. This can be demonstrated using a delayed type hypersensitivity (DTH) assay. In H-2 compatible combinations, Mls-locus antigens, but no other minor histocompatibility antigens, can induce the generation of such effector T cells.

Restricted recognition of H-2 subregion coded alloantigens in delayed-type hypersensitivity.

Subcutaneous (sc) immunization of mice with H-2K, I, or D incompatible spleen cells induces a state of host-versus-graft (HvG) delayed-type hypersensitivity (DTH). The DTH reaction is elicited by challenging the immunized mice in a hind foot with similar allogeneic spleen cells and is measured as the subsequent foot swelling. DTH effector T cells specific for H-2I-coded alloantigens, but not for H-2K/D-coded alloantigens, can be induced in a graft-versus-host (GvH) model as well.

Suppression of delayed-type hypersensitivity to third party "bystander" alloantigens by antigen-specific suppressor T cells.

Delayed-type hypersensitivity (DTH) against alloantigens can be induced by sc immunization with allogeneic cells. The induction of DTH can be suppressed by iv preimmunization of the mice with similar allogeneic spleen cells, provided the cells are irradiated before injection. This suppression is mediated by T cells.

Secondary delayed-type hypersensitivity to sheep red blood cells and minor histocompatibility antigens in mice: transfer of memory by recirculating thoracic duct lymphocytes.

Secondary delayed-type hypersensitivity (DTH) in mice to sheep red blood cells (SRBC) and minor histocompatibility (H) antigens is dependent on long-lived memory T cells. In this paper we investigated whether these memory T cells recirculate. It was shown that late phase "immune' thoracic duct lymphocytes (TDL) from mice which were immunized with SRBC or non-H-2-incompatible spleen cells several weeks previously could adoptively transfer secondary DTH to these antigens.

Nonspecific suppression of anti-graft immunity by antigen-specific T suppressor cells.

The specificity of T suppressor cells induced by intravenous administration of irradiated allogeneic spleen cells was studied in mice by means of a delayed type hypersensitivity (DTH) assay. T suppressor cells induced by either H-2K, H-2I or H-2D incompatible cells were found to be specific for the inducing alloantigen. Such antigen specific T suppressor cells can suppress the response to another H-2 alloantigen, provided it is administered together with the alloantigen that had induced the T suppressor cells.