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In a patient with celiac disease, folate and iron deficiency, and epilepsy, CT over a 4-month period showed parietoocipital calcifications in the corticomedullary junctions. The calcification was progressive, but it and the seizures stabilized after institution of a gluten-free diet and iron and folic acid supplements.
Autosomal dominant guanosine triphosphate cyclohydrolase I (GCH-I) deficiency (Segawa disease) is a dopa-responsive dystonia caused by mutation of the GCH-I gene located on 14q22.1-q22.2. Neurohistochemical examination revealed a decrease of the tyrosine hydroxylase protein as well as its activity in the striatum and decrease of dopamine content, particularly in its ventral portion rich in D1 receptors (striatal direct pathways). Neuroimaging, clinical neurophysiological, and biochemical studies showed preservation of the structure and function of the terminal of the nigrostriatal DA neuron. Clinical neurophysiological studies showed no progressive decrement of DA activities. As the enzymatic activity of pteridine metabolism is highest in the early developmental course, it may modulate dopamine receptors maturing early in the developmental course. Its product, tetrahydrobiopterin, has higher affinity to tyrosine hydroxylase among hydroxylases. Thus, partial deficiency of tetrahydrobiopterin caused by heterozygous mutation of the GCH-I gene decreases dopamine activity rather selectively. This affects the DA receptors that mature early and demonstrates characteristic symptoms age-dependently along with the developmental decrement of the tyrosine hydroxylase activities at the terminals and the maturational processes of the projecting neurons of the basal ganglia. A difference in the ratio of mutant/wild-type GCH-I mRNA that depends on the locus of mutation may explain intrafamilial and interfamilial variation of phenotype.
We report three new mutations in patients with myophosphorylase deficiency (McArdle disease). A splice-junction mutation (G-to-A transition at the 5' end of intron 14) and a missense mutation (CTG to CCG at codon 291, changing an encoded leucine to a proline) were identified in Caucasian patients who were heterozygous for a common mutation reported elsewhere (CGA [Arg] to TGA [stop]) at codon 49. The splice-junction mutation destroyed the consensus sequence at the 5' splice site, and a cryptic splice site 67 bp upstream was recognized instead. As a result, there was a 67-bp deletion in the 3'-terminal region of exon 14 in the transcript, resulting in a frameshift with premature translation termination. A deletion of a single codon, 708/709 (TTC, specifying phenylalanine) was identified in Japanese patients. Two affected siblings were homozygotes, and their parents were heterozygotes. A third, unrelated patient was heterozygous for the same mutation, while the myophosphorylase gene on the other allele was only faintly expressed.
Four cases are described of multi-system immunologically-mediated disease (systemic lupus erythematosus (two cases), polymyositis, and sarcoidosis) in association with thyroid autoimmunity. In all patients there was evidence of T lymphocyte deficiency, namely poor response of peripheral blood lymphocytes (PBL) to T cell mitogens (four cases) and failure or decreased ability to become sensitized to dinitrochlorobenzene (three cases), although two patients were ill and two were being treated with steroids. There was also evidence of B lymphocyte deficiency since PBL of no patient responded normally to pokeweed mitogen, a B and T lymphocyte mitogen. In two patients there was evidence of cell-mediated immunity to human thyroid antigens. Although thyroid stimulating antibody was not detected in the one patient with Graves' disease tested, significant titres of thyroid antibodies were detected in all cases. Possible relationships between T lymphocyte deficiency, organ-specific autoimmune disease and immunologically-mediated multi-system disorders are discussed.
Fifty-five children with CID and known ADA status were studies at a workshop held in Albany, New York. Erythrocyte ADA determinations were performed in 22 of the 55 patients, 13 of whom were ADA negative. The ADA defect appears to be transmitted as an autosomal recessive trait. Some patients with CID and ADA deficiency have characteristic radiologic abnormalities of the skeleton, which are not found in other illnesses. The thymus glands of all patients with CID and ADA deficiency who could be examined have evidence of thymic involution manifested by presence of Hassall's corpuscles and differentiated germinal epithelium; this is in contrast to "classic" thymus findings in CID with normal ADA. Adenosine deaminase probably plays an important, although as yet undefined, role in lymphocyte development and/or function. The deficiency of ADA in CID is the first enzyme defect observed in a deficiency disease of specific immunity.
Malnutrition, infectious and toxic stress, hormonal and enzymatic deficiencies as well as graft versus host reactions during the last trimester of pregnancy and during the first six months of life lead to persistent depressions of cell mediated immunity. The subsequent imbalance between the cell mediated and humoral system of immunity leads to differences in disease prevalence in poor and rich populations. Particularly leprosy, tuberculosis, viral disease as for instance frequently fatal measles and diseases due to complexes between humoral antibody and bacterial components as for example acute rheumatic fever occur with increased frequency in B (+) T (-) populations. Desturbances of immune surveillance due to suppression of specific cell mediated immune function leads to an increased frequency of neoplasia, particularly B-cell lymphoma and gastrointestinal tumors. Populations in which the T-cell system can mature without interference show a trend towards diseases in which excessive T-cell response plays a major role, as for instance rheumatoid arthritis, Sjögren syndrome, terminal ileitis, autoimmune angiopathies, multiple sclerosis and possibly also disseminated lupus erythematodes.
Main causes for metal taste may be deficiency diseases (especially deficiency of zinc), medication or dental restorations. Saliva of probationers with partial dentures was analyzed for their nickel contents. The solubility behavior in saliva of the alloys studied was related to metal taste and burning sensation. For most alloys the frequency of metal taste was in accordance with the nickel solubility in saliva.
We identified a family with lysosome-associated membrane protein-2 deficiency (Danon disease) associated with a novel 883 ins-T mutation in the lysosome-associated membrane protein-2 gene located at Xq24. Although the affected son and daughter carried the same mutation, it was not detected in their mother's peripheral blood or buccal cells; this indicated germline mosaicism. This is the first molecular evidence for germline mosaicism in Danon disease and has important implications for genetic counseling.
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Deficient information regarding placental pathology has compromised epidemiological investigations of cerebral palsy, mental retardation, and other diseases. This article reviews light microscopic signs of low placental blood flow, fetal nucleated red blood cells, villitis (villous inflammatory lesions), chorangiosis (placental villous capillary hypervascularity), meconium staining, and chorioamnionitis. These findings can be used with data of birth weight, head circumference, and length to document the duration of fetal disease. The article includes pathophysiological considerations; for example, chorioamnionitis and fetal meconium discharge may cause autacoids to produce fetal hypoperfusion of the fetal brain and other vital organs.
Deficient activity of the lysosomal enzyme beta-mannosidase leads to widespread tissue accumulation of oligosaccharides in caprine beta-mannosidosis, an autosomal recessive neurovisceral storage disease. Severe thyroid morphologic abnormalities found in a previous light microscopic survey of tissues from neonatal affected goats suggested the possibility of impairment of function. Since considerable evidence indicates that thyroid hormone plays an important role in regulation of myelination, thyroid hormone deficiency, if present during central nervous system development, could be a factor in the hypomyelination seen in affected animals. Thus, this study was designed to characterize thyroid structure and function in beta-mannosidosis. To investigate developmental aspects of structural abnormalities, thyroids from six pairs of affected and control animals ranging in age from 96/150 days gestation to 3 days postnatal were analyzed by light and electron microscopy. Major findings in thyroids from affected animals, as early as 96/150 days gestation, included follicle irregularities and pronounced presence of lysosomal storage vacuoles in all cell types, particularly in follicular cells. The degree of cytoplasmic vacuolation increased with advancing age. To assess thyroid function, thyroid hormone concentrations were determined in six age-matched, neonatal pairs of affected and control goats. Significantly decreased thyroid hormone concentrations were present in affected animals. It is hypothesized that thyroid hormone deficiency plays a role in the pathogenesis of hypomyelination in affected animals. This study comprises, to our knowledge, both the most complete description of developmental abnormalities and the first report of abnormal function in an endocrine organ in a lysosomal storage disease. Further, this report suggests that systemic perturbations induced by a genetically determined deficiency of a lysosomal hydrolase could be a factor in the pathogenesis of central nervous system lesions.
Multiple acyl-CoA dehydrogenase deficiency (MADD) is considered an autosomal recessive disorder; yet, recent findings suggest up to 10% of cases may result from heterozygous electron transfer flavoprotein dehydrogenase (ETFDH) variants exhibiting dominant or dominant-like effects. Here, a novel heterozygous ETFDH variant (c.1798A>C, p.Asn600His) was identified within a three-generation family. The grandfather presented with muscular weakness at age 35, and the father developed similar symptoms at 19 following a tonsillectomy. Both were diagnosed with MADD based on muscle biopsies revealing neutral lipid accumulation and acylcarnitine profiles and responded fully to riboflavin therapy (150 mg/day). The two siblings, aged 8 and 10, carry the same mutation and show increased acyl-carnitine levels but remain asymptomatic due to early riboflavin treatment. Skin fibroblasts from affected individuals were immortalized and subjected to normal and reduced riboflavin levels. Gene expression analysis demonstrated unchanged ETFDH RNA but reduced protein levels in mutant cells, particularly under low riboflavin. Structural modelling suggested the Asn600His substitution destabilizes the protein, diminishing its mitochondrial function. Proximity ligation assays indicated a decreased interaction with mitochondrial complex III, while oxygen consumption via fatty acid oxidation was impaired, especially at reduced riboflavin. The novel ETFDH variant found in this family gives a possible dominant pattern of inheritance for MADD, where a single mutant allele impairs the mitochondrial metabolism, particularly under riboflavin-deficient conditions, and highlights the importance of early riboflavin supplementation in preventing clinical symptoms.
A 60-year-old homozygous patient with familial high density lipoprotein deficiency (Tangier disease) was examined by coronary angiography and intravascular ultrasound because of typical angina pectoris. We found a normal left ventricular function, moderately diffuse coronary sclerosis without stenosis, and no critical stenosis of peripheral arteries. Intravascular ultrasound revealed normal thickness and the three-layer appearance of the arterial intima, media, and adventitia within the peripheral arteries, and showed a single, discrete arteriosclerotic lesion in one iliac artery segment. The lack of severe atherosclerosis was remarkable insofar as massive foam cell formation in reticuloendothelial tissues and the virtually complete absence of circulating HDL is characteristic of Tangier disease and had been previously demonstrated in this patient.
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Deficient erythropoietin (EP) production is thought to be a key factor in the pathogenesis of the anemia of end-stage renal disease. We describe the interrelationships between radioimmunoassayed plasma EP levels, reticulocyte counts corrected for anemia (CRC) and hematocrit (HCT) under challenge by hemorrhage, transfusions and hemodialysis in 32 chronically-hemodialyzed patients. Spontaneous hemorrhage resulted in a decrease in HCT (P = 0.001) and increases in both EP (P = 0.006) and CRC levels (P = 0.0065). Transfusions of two units of packed red cells into each of 16 patients suppressed EP (P = 0.0004) and CRC (P less than 0.0001) after about 28 and 42 hours, respectively. Repeat transfusions after one to 27 days resulted in similarly significant suppressions of both EP and CRC, except the CRC remained on higher levels for prolonged periods of times. Within a few hours after each transfusion of 2,3-diphosphoglycerate-poor red cells, both EP (P = 0.009) and CRC (P = 0.007) increased temporarily between one to 18 and three to 38 hours, respectively. Hemodialysis resulted in alkalinization (P = 0.008) of blood but not in changes of EP or CRC counts. The data show that, with the EP-HCT feedback loop persisting, increased endogenous hormone levels elicit erythropoietic responses, and that the regulation of EP levels may involve determinants such as oxy-deoxyhemoglobin interactions.
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