A nutritional basis for lead pica

Lead pica is a puzzling behavioral phenomenon involving the continued voluntary ingestion of a toxic substance. Calcium deficiency produced an elevated proportion of lead ingestion while magnesium and zinc deficiency produced proportional levels of lead ingestion intermediate to control and calcium deficient rats. Partrial restoration of calcium did not eliminate the increased proportion of lead ingestion while full calcium restoration did. Calcium deficient rats offered lead to drink gained more weight than deficient rats not offered lead. Control animals showed a reduction in their intake of novel solutions ingested following intubation of lead acetate while calcium deficient animals did not. Rats deficient in calcium, iron and zinc also showed elevated proportional levels of quinine sulfate ingestion compared to controls suggesting that a pica may be a general response to nutritional deficiency. The increased proportion of lead ingestion by calcium, zinc and magnesium deficient rats and the failure of calcium deficient rats to form a learned aversion to lead acetate, suggests that mineral deficiency may be a major factor in producing lead pica.     

Deficiency of Biotinyl-AMP Synthetase Activity in Fibroblasts of Patients with Holocarboxylase Synthetase Deficiency

A simple, rapid assay was developed to diagnose holocarboxylase synthetase deficiency. Holocarboxylase synthetase first catalyzes the formation of biotinyl-AMP from biotin and ATP, an activity designated as biotinyl-AMP synthetase. In the second step of the reaction, biotin is transferred from biotinyl-AMP to the enzymatically inactive apocarboxylase to form an active holocarboxylase. The assay for holocarboxylase synthetase activity therefore requires a protein apocarboxylase substrate which is not readily available. In the assay for biotinyl-AMP synthetase, hydroxylamine reacts nonenzymatically with the product of the enzymatic reaction, biotinyl-AMP, to form biotinylhydroxamate. At the end of the reaction, unreacted radioactive biotin substrate, which is negatively charged at neutral pH, is bound to an anion-exchange resin and a neutral radioactive biotinylhydroxamate product in the supernatant is counted. In fibroblasts from 11 patients with proven holocarboxylase synthetase deficiency, the mean biotinyl-AMP synthetase activity at 25 nM biotin was 4% of the control mean with a range of 0.2 to 8%. This is an improved assay because it does not require preparation of an apocarboxylase substrate and is suitable for the diagnosis of patients with holocarboxylase synthetase deficiency.     

Selective partial IgM deficiency: Functional assessment of T and B lymphocytesin vitro

Seven patients with selective IgM deficiency (SIgMD) were studied for cell surface immunoglobulin (SmIg), T-cell subpopulations, and immunoglobulin (Ig) synthesisin vitro by peripheral blood lymphocytes (PBL). Serum IgM levels were less than 25 mg/dl, while IgA, IgG, and IgD were within normal levels. The patients had respiratory or urinary tract infections and two were diagnosed as having systemic lupus erythematosus (SLE). T/B-cell ratios in PBL were within normal ranges. Percentage ratios of B cells bearing SmIg were normal in five patients and decreased in two; however, normal values were seen after 7 days of culture in the presence of PWM. OKT4/OKT8 ratios decreased in five of seven patients, in whom two were due to a decrease in OKT4 and two to an increase in OKT8 cells. One showed a decrease in OKT4 and an increase in OKT8. Analysis of lymphocyte function for Ig synthesisin vitro, using a coculture of counterpart T and B cells from healthy individuals and patients with SIgMD, revealed that the increased function of IgM isospecific suppressor T cells (Ts) was responsible for the IgM deficiency in all seven patients.     

209例6个月～2岁儿童铁营养调查与分析

目的 研究婴幼儿早期缺铁的临床指标，为缺铁的早期诊断提供理论依据。方法 选取209例在门诊进行健康体检的婴幼儿，年龄6月～2岁，按不同月龄分为6月～1岁，1岁～2岁各2组，测定其末梢血系列，主要包括RBC、Hb、MCV、MCH、MCHC、RDW指标，资料应用SPSS12．5软件进行Х^2检验。结果 （1）RBC、Hb、MCHC的均值均在正常范围内；（2）MCV、MCH、RDW均数均低于正常值范围，其中MCH值在两组间有显著性差异（P〈0．05）。结论 （1）本组RDW、MCV、MCH的异常是诊断缺铁的重要指标，它的异常较其它指标出现要早。（2）婴幼儿辅食添加情况可直接决定其体内铁营养的状况。     

Truly selective primary IgM deficiency is probably very rare

Isolated decreased serum‐immunoglobulin (Ig)M has been associated with severe and/or recurrent infections, atopy and autoimmunity. However, the reported high prevalence of clinical problems in IgM‐deficient patients may reflect the skewed tertiary centre population studied so far. Also, many papers on IgM deficiency have included patients with more abnormalities than simply IgM‐deficiency. We studied truly selective primary IgM deficiency according to the diagnostic criteria of the European Society for Immunodeficiencies (ESID) (true sIgMdef) by reviewing the literature (261 patients with primary decreased serum‐IgM in 46 papers) and analysing retrospectively all patients with decreased serum‐IgM in a large teaching hospital in 's‐Hertogenbosch, the Netherlands [1 July 2005–23 March 2016; n = 8049 IgM < 0·4 g/l; n = 2064 solitary (IgG+IgA normal/IgM < age‐matched reference)]. A total of 359 of 2064 (17%) cases from our cohort had primary isolated decreased serum‐IgM, proven persistent in 45 of 359 (13%) cases; their medical charts were reviewed. Our main finding is that true sIgMdef is probably very rare. Only six of 261 (2%) literature cases and three of 45 (7%) cases from our cohort fulfilled the ESID criteria completely; 63 of 261 (24%) literature cases also had other immunological abnormalities and fulfilled the criteria for unclassified antibody deficiencies (unPAD) instead. The diagnosis was often uncertain (possible sIgMdef): data on IgG subclasses and/or vaccination responses were lacking in 192 of 261 (74%) literature cases and 42 of 45 (93%) cases from our cohort. Our results also illustrate the clinical challenge of determining the relevance of a serum sample with decreased IgM; a larger cohort of true sIgMdef patients is needed to explore fully its clinical consequences. The ESID online Registry would be a useful tool for this.     

A novel SLC5A6 homozygous variant in a family with multivitamin-dependent neurometabolic disorder: Phenotype expansion and long-term follow-up

The sodium-dependent multivitamin transporter (hSMVT) encoded by the SLC5A6 gene is required for the intestinal absorption of biotin, pantothenic acid and lipoate, three micronutrients essential for normal growth and development. Systemic deficiency of these elements, either occurring from nutritional causes or genetic defects, is associated with neurological disorders, growth delay, skin and hair changes, metabolic and immunological abnormalities. A few patients with biallelic variants of SLC5A6 have been reported, exhibiting a spectrum of neurological and systemic clinical features with variable severity. We describe three patients from a single family carrying a homozygous p.(Leu566Valfs*33) variant of SLC5A6 disrupting the frame of the C-terminal portion of the hSMVT. In these patients, we documented a severe disorder featuring developmental delay, sensory polyneuropathy, optic atrophy, recurrent infections, and repeated episodes of intestinal pseudo-obstruction. Two patients who did not receive multivitamin supplementation therapy died in early infancy. In a third patient, early supplementation of biotin and pantothenic acid stabilized the clinical picture changing the course of the disease. These findings extend genotype-phenotype correlations and show how a timely and lifelong multivitamin treatment may be crucial to reduce the risk of life-threatening events in patients with pathogenic variants of the SLC5A6 gene.     

Association of autoimmunity with IgG2 and IgG4 subclass deficiency in a growth hormone-deficient child

An association between humoral immune deficiency and childhood autoimmune disease has been previously established. We describe a 7-year-old male with severe autoimmune disease, recurrent infections, a marked deficiency of IgG2 and IgG4, and an inability to respond to polysaccharide antigens. This child was also found to have isolated growth hormone (GH) deficiency. Laboratory results included a positive anti-smooth muscle antibody, a positive Raji-cell assay for immune complexes, and normal levels of IgG, IgM, and IgA. IgG subclasses revealed an IgG1 of 1225 (normal for age, 280–1120 mg/dl), IgG2 of <10 (30–630 mg/dl), IgG3 of 36 (40–250 mg/dl), and IgG4 of <4 (11–620 mg/dl). No increase in antibody titer was noted to either Pneumovax or unconjugatedHaemophilus influenzae vaccine. Numbers of circulating B cells (CD19) were markedly diminished (<0.5%). Liver biopsies have shown chronic active hepatitis. Somatomedin C was 0.28 U/ml (normal for age, 0.5–2.06 U/ml). Challenge with eitherl-dopa or clonidine produced a peak GH response of 2.3 ng/ml (normals = >7 ng/ml). Children with autoimmune disorders should be evaluated for IgG subclass deficiencies and ability to make antibody in response to antigen challenge regardless of the serum immunoglobulin levels. Growth failure in immune-deficient children should not be assumed to be due to chronic illness or recurrent infections. Other etiologies for growth failure should be sought.     

Asymptomatic and late-onset ornithine transcarbamylase (OTC) deficiency in males of a five-generation family, caused by an A208T mutation

In a large five-generation Polish family, late-onset ornithine transcarbamylase (OTC) deficiency in males segregated with the missense mutation Ala208Thr (A208T), and all heterozygous females were asymptomatic. No other mutations were found in the coding sequences and intron-exon boundaries of the OTC gene. Surprisingly, the mutation originated from the great-grandfather of the index patient who died at age 59 of liver carcinoma. He never had dietary restrictions or hyperammonemic spells throughout life and appears to be the oldest male reported with OTC deficiency. The index patient had a severe OTC deficiency (3% of normal). Eight males died suddenly at ages 4 months to 23 years (average 14 years) after a foudroyant episode triggered by a common infection. The patients remained undiagnosed for 28 years because a metabolic defect was not considered to be the cause of the acute episodes. Recognition of the familial pattern of inheritance was initially unnoticed since the patients were admitted to eight different hospitals. DNA analysis predicted that two 'healthy' boys also had OTC deficiency, which was confirmed by abnormal results of allopurinol challenge tests. Initial suspicion of OTC deficiency in such families is complicated, since symptoms can develop at any age, or even remain absent. This obscures the typical pattern of X-linked inheritance in small families.     

Laryngeal Spasm Mimicking Asthma and Vitamin D Deficiency

We present a woman with heterozygous carnitine palmitoyl transferase 2 (CPT-2) deficiency who in the last 6 months suffered from episodic dyspnea and choking. Symptoms could not be attributed to her muscular energy defect, since heterozygous CPT-2 deficiency is usually asymptomatic or causes only mild muscle fatigability. Myopathy is usually triggered by concurrent factors, either genetic (additional muscle enzymes defects) or acquired (metabolic stress). The patient was referred to our respiratory clinic for suspect bronchial asthma. Spirometry showed mild decrease in inspiratory flows. Methacholine challenge was negative. Dyspnea was triggered by hyperventilation-induced hypocapnia, which produced marked decrease in airflow rates, particularly in inspiratory flows, consistent with laryngospasm. Nutritional assessment of the patient showed low serum level of calcium and vitamin D, attributable to avoidance of milk and dairy products for lactose intolerance and to insufficient sunlight exposure. After calcium and vitamin D supplementation episodic laryngospasm disappeared and hypocapnic hyperventilation test induced very mild change in airflow rates. Calcium and vitamin D deficiency may favour laryngeal spasm mimicking asthma, particularly in subjects with underlying myopathy.     

Changes in lymphoid organs and blood lymphocytes induced by vitamin A deficiency and Newcastle disease virus infection in chickens

The effect of vitamin A deficiency in the presence or absence of Newcastle disease virus infection (NDV, La Sota strain) on weight of lymphoid organs and on the number and type of circulating white blood cells (WBC) was investigated in chickens. Day-old chickens with limited vitamin A reserves were fed purified diets containing either marginal (ad libitum) or adequate (pair-fed) levels of vitamin A and at 21–28 days of age; half the chickens in each group were infected with NDV. Vitamin A deficiency resulted only in significantly lower absolute and relative weights of bursa of Fabricius and after infection both weights of bursa and thymus were significantly lower. Relative weight of spleen was significantly higher after infection irrespective of vitamin A status. Liver weights were not affected by vitamin A status and/or NDV infection. Both vitamin A deficiency and NDV infection resulted in lymphopenia, while the lowest number of WBC were observed in vitamin A-deficient chickens during the acute phase of NDV (5 days after infection). Subsequent to lymphopenia due to NDV infection, a marked lymphocytosis was observed in controls and to a lesser extent in vitamin A-deficient birds. These results indicate that vitamin A deficiency, which is aggravated by concomitant NDV infection, affects lymphoid cell systems.     

Novel mutations in 3‐phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics

Three‐phosphoglycerate dehydrogenase (3‐PGDH) deficiency is a rare recessive inborn error in the biosynthesis of the amino acid L‐serine characterized clinically by congenital microcephaly, psychomotor retardation, and intractable seizures. The biochemical abnormalities associated with this disorder are low concentrations of L‐serine, D‐serine, and glycine in cerebrospinal fluid (CSF). Only two missense mutations (p.V425M and p.V490M) have been identified in PHGDH, the gene encoding 3‐PGDH, but it is currently unclear how these mutations in the carboxy‐terminal regulatory domain of the protein affect enzyme function. We now describe five novel mutations in five patients with 3‐PGDH deficiency; one frameshift mutation (p.G238fsX), and four missense mutations (p.R135W, p.V261M, p.A373T, and p.G377S). The missense mutations were located in the nucleotide binding and regulatory domains of 3‐PGDH and did not affect steady‐state expression, protein stability, and protein degradation rates. Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations. In transient overexpression studies in HEK293T cells, the p.A373T, p.V425M, and p.V490M mutations resulted in almost undetectable enzyme activities. Molecular modeling of the p.R135W and p.V261M mutations onto the partial crystal structure of 3‐PGDH predicted that these mutations affect substrate and cofactor binding. This prediction was confirmed by the results of kinetic measurements in fibroblasts and transiently transfected HEK293T cells, which revealed a markedly decreased V_max and an increase in K_m values, respectively. Taken together, these data suggest that missense mutations associated with 3‐PGDH deficiency either primarily affect substrate binding or result in very low residual enzymatic activity. Hum Mutat 0, 1–8, 2009. © 2009 Wiley‐Liss, Inc.     

Challenges in investigating patients with isolated decreased serum IgM: The SIMcal study

The clinical consequences of isolated decreased serum immunoglobulin (Ig)M are not sufficiently known. Therefore, it is difficult to determine the clinical policy following such a finding. Only few reported IgM‐deficient patients fulfil the European Society for Immunodeficiencies (ESID) diagnostic criteria for selective IgM deficiency (true sIgMdef), or their diagnosis is uncertain due to insufficient laboratory data (possible sIgMdef). Decreased serum IgM is often incidentally found in asymptomatic adults. The objective of our study was to further characterize true sIgMdef and to compare the European data collected through the ESID Registry community (tertiary centres) to our previously published Dutch cohort (secondary centre). Fifteen centres (12 countries) participated with 98 patients. Patients were excluded if serum IgM was only determined once (n = 14), had normalized (n = 8), or if they also had other immunological abnormalities (n = 15). Ten patients (5 adults) completely fulfilled the ESID criteria for true sIgMdef. Age‐matched cut‐off values varied widely between centres; when using the ESID diagnostic protocol reference values, only six patients (five adults) had true sIgMdef. Because of these small numbers, further analyses were performed in patients with true or possible sIgMdef (13 adults, 48 children). Respiratory infections were commonly reported at presentation (adults 54%, children 60%). Symptomatic adults had lower serum IgM levels (mean 0.27 g/L, 95% CI 0.22‐0.31) than those without symptoms (mean 0.33 g/L, 95% CI 0.30‐0.36; P = 0.02). To be able to explore the clinical consequences of true sIgMdef, we should fully analyse and accurately describe those patients in whom a decreased serum IgM is found.     

The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments

The Progressive Familial Intrahepatic Cholestasis (PFIC) disease spectrum encompasses a variety of genetic diseases that affect the bile production and the secretion of bile acids. Typically, the first presentation of these diseases is in early childhood, frequently followed by a severe course necessitating liver transplantation before adulthood. Except for transplantation, treatment modalities have been rather limited and frequently only aim at the symptoms of cholestasis, such as cholestatic pruritus. In recent years, progress has been made in understanding the pathophysiology of these diseases and new treatment modalities have been emerging. Herewith we summarize the latest developments in the field and formulate the current key questions and opportunities for further progress.     

Immunoglobulin prophylaxis in patients with antibody deficiency syndromes and anti-IgA antibodies

Sera from three hundred five patients with immunoglobulin deficiencies were analyzed for the presence of anti-IgA antibodies by using indirect agglutination and enzyme-linked immunosorbent assay (ELISA). Anti-IgA antibodies were observed in 15 of 68 (22%) patients with hypogammaglobulinemia and 53 of 185 (29%) patients with selective IgA deficiency, both groups having serum IgA<0.05 g/liter. The highest frequency, 6 of 10 or 60%, was noted for patients with a combined IgA-IgG2 deficiency. No anti-IgA antibodies were detected in 25 patients with serum IgA between 0.05 and 0.27 g/liter and normal amounts of serum IgM and IgG or in 17 patients with hypogammaglobulinemia who had serum IgA of 0.05–0.7 g/liter. The anti-IgA antibodies were primarily of the IgG class, but IgD and IgM anti-IgA were occasionally found. IgE anti-IgA antibodies could not be detected with the presently used technique. The IgG anti-IgA antibodies were mainly of the IgG1 subclass but occasionally also of the subclasses IgG2, IgG3, and IgG4. Of eight patients with anti-IgA antibodies, seven tolerated Ig prophylaxis with a commercial immunoglobulin preparation low in IgA when given either intramuscularly or intravenously. The titers of anti-IgA in the sera of these patients did not rise in relation to the prophylaxis. Only one of the eight patients had a history of previous anaphylactic reactions to IgA-containing blood products. He tolerated six Ig infusions during 5 months with the IgA-depleted preparation without any adverse effects but showed increasing levels of anti-IgA antibodies and ultimately experienced a near-fatal reaction at the seventh infusion.     

Ultrastructural pathology in congenital defects of the urea cycle: Ornithine transcarbamylase and carbamylphosphate synthetase deficiency

Summary Inborn defects of urea synthesis, leading to hyperammonemia, are complex inherited disorders, whose structural sequelae in different tissues and organs have not yet been studied in detail. Ultrastructural investigations have been performed on two cases of deficiencies of two consecutive enzymes of the urea cycle, carbamylphosphate synthetase and ornithine transcarbamylase, and the findings are compared with previously reported results. With regard to liver pathology it appeared that 1). Hepatocytes in CPS deficiency mainly exhibited changes of SER and mitochondrial compartments, whereas 2). OTC deficiency was characterized by regressive liver cell change, with abnormal configuration of the RER, formation of telolysosomes and peribiliary vesiculation. It is suggested that the mitochondrial disorder in the CPS defect is directly related to the lack of a major enzyme protein in this organelle, resulting in structural damage. The leading renal change in CPS deficiency is foot process fusion of glomerular podocytes. Brain alteration in this disorder is similar to that reported for other hyperammonaemic urea cycle defects.     

Carence en fer et troubles digestifs

Iron deficiency anemia still remains problematic worldwide. Iron deficiency without anemia is often undiagnosed. We reviewed, in this study, symptoms and syndromes associated with iron deficiency with or without anemia: fatigue, cognitive functions, restless legs syndrome, hair loss, and chronic heart failure. Iron is absorbed through the digestive tract. Hepcidin and ferroportin are the main proteins of iron regulation. Pathogenic micro-organisms or intestinal dysbiosis are suspected to influence iron absorption.     

Linkage of IgA deficiency to Gm allotypes; the influence of Gm allotypes on IgA-IgG subclass deficiency

IgA deficiency (IgAD) is the most common immunodeficiency, characterized by an arrest in B cell differentiation. It has a sporadic occurrence or variable inheritance pattern, and is also linked to the HLA genes. IgA deficiency is sometimes associated with IgG subclass deficiency. In this study the Gm allotypes, as genetic characteristics of the IgG1, IgG2 and IgG3, were analysed in 83 Caucasian IgAD individuals. Half of the patients presented with IgG4 < 0·01 g/l compared with 5% (P < 0·001) in a healthy population. Three of the 83 had significantly low IgG2 and four had significantly low IgG3 levels. Gm allotype frequencies in IgAD deviated compared with a normal population. Of the 83 patients, 44 (53%) showed homozygous G2m(“,”) expression on the IgG2 locus (33% in controls, P < 0·01). In IgAD the Gm(a, g) haplotype was more frequent (43%) compared with controls (31%, P < 0·01). The Gm homozygous phenotype Gm(a', g/a', g) was most common, found in 20 of 83 patients (24%, P < 0·05) compared with controls (14%). On the other hand the Gm(f,n,b) haplotype of IgAD was rare (28%) compared with controls (45%, P < 0·001). The low IgG4, < 0·01 g/l, found in 50% of the patients, was even more frequent (56–69%) among the G2m(“,”) phenotypes. IgG subclass levels were given for different Gm phenotypes of the IgAD group and compared with controls. Significantly low IgG4 was revealed in the Gm(a,“,g/a,”,g) phenotype (P < 0·01) and significantly low IgG2 in the Gm(a,“,g/f,”,b) phenotype (P < 0·01). The Gm(a,“,g/f,”,b) phenotype contained the three patients found with IgG2 levels < - 2 s.d., and the four patients with IgG3 levels < -2 s.d. were present among those with the homozygous Gm(a,“,g/a,”,g) phenotype; both phenotypes with G2m(“,”) on the IgG2 locus. The ‘compensatory’ increase of IgG was significant for both IgG1 and IgG3 in all Gm phenotypes, but in the Gm(a,“,g/f,”,b). Thus, the susceptibility of IgAD with the additional IgG antibody deficiencies, down-regulated IgG4 and IgG2/IgG3, is associated with Gm allotypes, especially the homozygous G2m(“,”) expression on the IgG2 locus.