Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019214 (hepatosplenomegaly)
 4,408 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the baso-lateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.
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PMID:Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. 1008 Jan 82

Lysinuric protein intolerance (LPI, MIM 222700) is an autosomal recessive multisystem disorder found mainly in Finland and Italy. On a normal diet, LPI patients present poor feeding, vomiting, diarrhoea, episodes of hyperammoniaemic coma and failure to thrive. Hepatosplenomegaly, osteoporosis and a life-threatening pulmonary involvement (alveolar proteinosis) are also seen. LPI is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine. Metabolic derangement is characterized by increased renal excretion of CAA, reduced CAA absorption from intestine and orotic aciduria. The gene causing LPI was assigned using linkage analysis to chromosome 14q11.2 near the T-cell receptor alpha/delta chains locus, and a critical region has been defined. We have identified two new transcripts (SLC7A8 and SLC7A7) homologous to amino acid transporters, highly expressed in kidney and mapping in the LPI critical region. Mutational analysis of both transcripts revealed that SLC7A7 (for solute carrier family 7, member 7) is mutated in LPI. In five Italian patients, we found either an insertion or deletion in the coding sequence, which provides evidence of a causative role of SLC7A7 in LPI. Furthermore, we detected a splice acceptor change resulting in a frameshift and premature translation termination in four unrelated Finnish patients. This mutation may represent the founder LPI allele in Finland.
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PMID:SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. 1008 Jan 83

We studied the auditory brainstem response (ABR) and neuropathology in a female infant who died at six months of age because of typical infantile Gaucher's disease. The patient was hospitalized for hepatosplenomegaly and failure to thrive. Her ABR showed only waves I and II. The neuropathological study disclosed that: (1) Gaucher's cells were found in the perivascular region of the cerebrum and anterior ventral nucleus of the thalamus. (2) Gliosis was found in the dorsal part of the brainstem rather than the ventral part. (3) Neuronal cells in the superior olivary nucleus were lost, and marked gliosis was found in the cochlear nucleus. The disappearance of wave III and later waves of ABR could be supported by these pathological findings.
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PMID:Brainstem pathology of infantile Gaucher's disease with only wave I and II of auditory brainstem response. 1019 47

Lysinuric protein intolerance (LPI) is characterized by defective cellular transport of the dibasic amino acids, secondary dysfunction of the urea cycle, aversion to dietary protein, failure to thrive, hepatosplenomegaly and osteoporosis. Because several patients have suffered from recurrent respiratory infections and/or severe generalized varicella, and a few have developed systemic lupus, vasculitis or other autoimmune diseases, we have now evaluated the function of patients' immune systems. Serum concentrations of one to three IgG subclasses were decreased in 10 of the 12 patients studied. Antibody titres against diphtheria, tetanus and Haemophilus influenzae (Hib) were below the detection limit of the assay in four, three and eight of the 11 patients examined, respectively. (Re)vaccination of these 11 patients led to satisfactory responses against tetanus, but two patients still failed to develop measurable antibodies against diphtheria, two against Hib and six against one or more of the three serotypes of 23-valent pneumococcus vaccine. The proportions of T cells of all lymphocytes and the proliferative responses of the peripheral blood mononuclear cells were normal. In conclusion, humoral immune responses in some patients with LPI are defective and these patients may benefit from intravenous immunoglobulin therapy.
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PMID:B and T cell immunity in patients with lysinuric protein intolerance. 1036 Dec 30

Mevalonic aciduria is a rare autosomal recessive metabolic disorder, characterized by psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. The disorder is caused by a deficient activity of mevalonate kinase due to mutations in the encoding gene. Thus far, only two disease-causing mutations have been identified. We now report four different missense mutations including three novel ones, which were identified by sequence analysis of mevalonate kinase cDNA from three mevalonic aciduria patients. All mutations affect conserved amino acids. Heterologous expression of the corresponding mutant mevalonate kinases as fusion proteins with glutathione S -transferase in Escherichia coli showed a profound effect of each of the mutations on enzyme activity. In addition, immunoblot analysis of fibroblast lysates from patients using specific antibodies against mevalonate kinase identified virtually no protein. These results demonstrate that the mutations affect not only the activity but also the stability of the mutant proteins.
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PMID:Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis. 1040 Oct 1

Bone marrow transplantation (BMT) has been used for a wide variety of lysosomal storage diseases with encouraging results. We report a 3-year 5-month-old girl with Niemann-Pick type C disease (NPC) who received an allogeneic BMT. The patient presented with repeated lower respiratory tract infections, hepatosplenomegaly, failure to thrive, and developmental delay. Chest computed tomography (CT) revealed diffuse interstitial lung infiltration. Bone marrow and liver biopsies revealed abundant lipid-filled foamy macrophages. Skin fibroblast sphingomyelinase assay revealed partial deficiency. The ability of her skin fibroblasts to esterify cholesterol was very low, and the cells stained brightly for free cholesterol. She received BMT from a healthy HLA-identical male sibling donor at the age of 2 year 6 months. Full engraftment was evidenced by repeated bone marrow sex chromosome studies. Regression of the hepatosplenomegaly, markedly reduced foamy macrophage infiltration in bone marrow, and decreased interstitial lung infiltration was noted 6 months after BMT. Her neurological status, however, deteriorated. Follow-up magnetic resonance image (MRI) revealed progressive, diffuse brain atrophy. We conclude that resolution occurred in the liver, spleen, bone marrow and lung following successful engraftment. Such a response is remarkable since the underlying problem involves a membrane receptor for cholesterol. This positive response might be due to replacement of the monocyte-phagocytic system or it may imply the existence of cross-correction in the NPC membrane receptor defect by BMT approach. Since BMT did not halt the neurological deterioration, it is unlikely to be an adequate treatment for NPC.
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PMID:Niemann-Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation. 1043 44

We studied a cohort of children with the human immunodeficiency virus (HIV) infection in Barbados in order to determine the prevalence of HIV infection, the clinical course including morbidity and mortality and the magnitude of the health care and social problems. Forty-seven children were diagnosed with HIV infection during the study period. The number of HIV infected children increased from 5 during 1981-85, to 14 during 1986-90, and to 21 during the 1991-95 period. The majority (91.5%) of infections resulted from perinatal transmission. Six (12.8%) cases remained asymptomatic and 41 (87.2%) were symptomatic with 19(46.3%) presenting in infancy, while 22 (53.5%) presented post-infancy. The median age at diagnosis (class P-2) was 13 months. Generalized lymphadenopathy (47.5%), hepatosplenomegaly (40.0%), failure to thrive (27.5%), persistent recurrent diarrhoea (15.0%), oral candidiasis (37.5%), Pneumocystis carinii pneumonia (37.5%), lymphoid interstitial pneumonia (12.5%) and progressive neurological disease (10.0%) were common HIV related conditions. Two children developed non-hodgkin's lymphoma. The median age at death for 23 children was 12 months, whereas the median survival after diagnosis was 4 months. Mortality was higher among those diagnosed in infancy (73.7%) as compared to those diagnosed post-infancy (42.8%). Pneumocystis carinii pneumonia was the most common (65.2%) cause of death. Paediatric HIV infection is rising and contributes considerably to infant mortality. In this study, children took longer to be symptomatic when compared to other reports. However, once symptomatic, they died early.
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PMID:HIV infection among children in Barbados. 1078 51

A 29 day old male infant presented with a history of fever, cough, increasing respiratory distress and abdominal distension from the 10th day of life. Examination revealed failure to thrive, marked tachypnea, pallor, hepatosplenomegaly and harsh vesicular breath sounds. Chest skiagram showed extensive broncho-pneumonic changes. As the infant did not respond to antibiotics, he was investigated for tuberculosis. The gastric aspirate smear showed plenty of acid fast bacilli (AFB) and culture showed M. tuberculosis growth. Endometrial biopsy of the mother showed tuberculous granuloma and acid fast bacilli and culture of the aspirate from endometrium grew M. tuberculosis. The need for endometrial biopsy of mothers of infants with congenital tuberculosis is highlighted.
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PMID:Congenital tuberculosis. 1079 50

The detection of neurodegenerative and neurometabolic diseases in children relies on a high index of suspicion as most will present as common paediatric problems such as recurrent vomiting, feeding problem, failure to thrive, sepsis, or developmental delay. Alternatively, children may present with an acute encephalopathy or with a chronic progressive encephalopathy. Clinical clues suggestive of neurometabolic disorders include encephalopathic features such as microcephaly, macrocephaly, developmental regression, developmental arrest, change in sensorium, seizures, hypotonia, hypertonia, abnormal eye signs; also extrapyramidal or cerebellar signs and systemic features like abnormal respiration, hepatosplenomegaly, abnormal hair, liver dysfunction, renal tubular dysfunction, cardiomyopathy, and feeding difficulties or growth problems. Initial screening include tests for acidosis, ketosis, hyperlacticemia, and hyperammonemia. Further investigations should amino acid chromatography, assays of organic acids, specific enzyme assay of white cell or fibroblast culture, and histopatholgy of cell and tissue biopsy (white blood cell, skin, muscle, conjunctiva, bone marrow, liver, rectum, or brain). The correct diagnosis holds implications for targeted therapeutic intervention, genetic counselling, and possibly, prenatal diagnosis.
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PMID:Neurodegenerative diseases in children. 1184 61

Glycogen storage disease (GSD) is a rare autosomal-recessive disorder characterized by hypoglycemia, hepatosplenomegaly, seizures, and failure to thrive in infants. Neutropenia and/or neutrophil dysfunction develops in GSD1b, but not in other types. GSD1b results from a deficiency of the glucose-6-phosphate translocase enzyme and the genetic defect maps to chromosome 11q23. Patients with GSD1b are susceptible to recurrent bacterial infections, commonly involving the perirectal area, ears, skin, and urinary tract, although life-threatening infections, such as septicemia, pneumonia, and meningitis occur less frequently. Although the exact mechanism of neutropenia in patients with GSD1b is not known, treatment with recombinant human granulocyte colony-stimulating factor (G-CSF) has reduced the incidence of infections and has improved the quality of life of these patients. Defects in neutrophil chemotaxis and intracellular bacterial killing have been described and appear to be corrected by the use of G-CSF. To date, no cases of myelodysplasia or acute myeloid leukemia have been observed in patients with GSD1b treated with G-CSF. A significant complication of cytokine therapy is the development of hypersplenism, requiring either a reduction in the dosage of G-CSF or splenectomy.
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PMID:Glycogen storage disease. 1195 92


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