Role of bacteria in the pathogenesis of short bowel syndrome-associated D-lactic acidemia.

Previously, we have demonstrated that short bowel syndrome (SBS) patients suffer daily from D-lactic acidemia; in these patients rather high amounts of (bacterial) D-lactate emerge in blood and urine with a circadian rhythm. The aim of this study was to establish the microbial basis of D-lactic acidemia in SBS. Therefore, faecal flora of (young and adult) SBS-patients was analysed qualitatively and quantitatively, and compared to that of controls. The isolated bacterial species were screened for massive D- and/or L-lactate production after in vitro growth. After introduction of oral feeding in SBS-infants shortly after the resection, lactobacilli increased from < or = 1% up to 60 +/- 5% of the faecal flora within 2-3 weeks. In the faeces of patients with oral feeding the lactate producers Lactobacillus acidophilus and Lactobacillus fermentum were the major resident bacteria (each with 10(10)-10(12) cfu/g faeces). During active growth in vitro these lactobacilli produced massive amounts of D- and L-lactic acid from glucose. Use of oral antibiotics in two SBS-children did not reduce the total numbers of lactobacilli, but caused shifts within the intestinal populations of at least lactobacilli. It is concluded that the strongly reduced intestinal capacity for carbohydrate absorption and the oral consumption of easily fermentable carbohydrates form the physiological basis for D-lactic acidemia in SBS, and that the fermentative D-lactate production by intestinal bacteria, especially the abundant, resident lactobacilli, forms its microbial basis. In these patients the antimicrobial and therapeutic effects of antibiotics are unpredictable.

Dihydropyrimidinase deficiency, a progressive neurological disorder?

A case of a child presenting with congenital abnormalities at birth is reported. The early development remained severely retarded and acquired skills minimally. The head circumference centile decreased. Magnetic resonance imaging showed progressive neuronal atrophy and secondary delay in myelination. Dihydropyrimidine concentrations in body fluids were quantitated by NMR spectroscopy. Enzymatic assay in the liver biopsy revealed total deficiency of dihydropyrimidinase (DHP) (5,6-dihydropyrimidine amidohydrolase; EC 3.5.2.2). As such, the patient is the first with enzymatically proven DHP deficiency. Thus far dihydropyrimidinuria has been reported in three other patients with a variety of neurological abnormalities. A relation of the enzyme deficiency with the neurodegenerative clinical course in our patient is suggested.

The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients.

OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.

The importance of immunoglobulin-breakdown supporting the growth of bacteria in oral abscesses.

Oral bacteria play an important rôle in the causation of oro-facial abscesses. However, they can also be involved in brain, liver and lung abscesses. To persist, it is essential that these bacteria can grow on those sites. The main source of nutrients for growth in abscesses is likely to be tissue exudate, which is rich in serum-derived proteins, and relatively poor in free amino acids and carbohydrates. Degradation of intact proteins seems a crucial step in providing the peptides necessary for energy generation. The aim of this study was to investigate the capacity of microorganisms from asscesses to degrade serum proteins, in particular immunoglobulins. To this end, samples were taken by aspiration from 16 odontogenic abscesses. It was found that pus from abscesses differed strongly in the concentration of viable bacterial cells. The ability of the abscess microflora to degrade serum proteins was investigated after growth of the sample in heat-inactivated human serum. The microflora from abscesses with a high concentration (n = 10) of bacteria strongly degraded immunoglobulins, whereas breakdown of immunoglobulins was virtually absent after growth of the microflora from low-bacterial concentration (n = 6) abscesses. Bacteriological analyses revealed the presence of at least one proteinase-producing species, like Porphyromonas, black-pigmented Prevotella species, or Actinomyces meyeri, in abscesses with a high density of bacteria, but not in those with low bacterial density. The results indicate that the capacity to degrade intact proteins, in particular immunoglobulins, is a major determinant of bacterial growth in abscesses.

CD4 deficiency in myelodysplastic syndrome with monosomy 7.

UNLABELLED: We describe a patient with myelodysplastic syndrome with monosomy 7 presenting with a T-cell defect. He suffered from infections from the age of 10 years, when a CD4 deficiency and impaired lymphoproliferative responses in vitro were found. The only symptom of a myelodysplastic syndrome at that time was thrombocytopenia with giant platelets. Monosomy 7 was found in the bone marrow cells. At the age of 11 years he developed other characteristics of monosomy 7 including splenomegaly and anaemia. Some months later leukaemia was diagnosed. CONCLUSION: In non-HIV CD4 deficiency myelodysplastic syndrome has to be considered.

A dysbalanced immune system in cryptogenic Lennox-Gastaut syndrome.

In children with cryptogenic Lennox-Gastaut syndrome we found a functionally impaired humoral immune response to a primary antigen (haemocyanin), despite signs of a triggered immune system consisting of elevated IgG concentrations. This combination of immunological findings, considered to be the expression of a dysbalanced-triggered as well as functionally impaired-immune system, has also been described in an auto-immune disease like systemic lupus erythaematodes in humans, and in genetically epilepsy-prone rats. The interactions between the immune system and the nervous system in Lennox-Gastaut syndrome will be discussed.

Altered immunoglobulin concentrations and light chain ratios in juvenile onset mixed connective tissue disease.

Immunological disturbances may result in altered immunoglobulin concentrations and kappa/lambda light chain (kappa/lambda) ratios. We measured the kappa/lambda ratios of total serum immunoglobulins and of polyclonal IgG, A, and M separately as well as concentrations of these immunoglobulins in fourteen patients with juvenile onset mixed connective tissue disease. When comparing the patient group with a reference group the mean serum IgG and IgA concentrations were respectively 2.98 G/L (p = 0.0012) and 0.79 G/L (p = 0.0114) higher in the group of patients with juvenile onset mixed connective tissue disease. The mean IgM concentration was 0.39 G/L (p = 0.0002) lower. The mean kappa/lambda ratios of total serum immunoglobulins, serum IgG, and serum IgA were respectively 0.20 (p = 0.0226), 0.28 (p = 0.0016) and 0.10 (p = 0.0732), higher in the group of patients with mixed connective tissue disease as compared with the reference group. Mean serum IgM kappa/lambda ratio, however, was 0.21 (p = 0.0046) lower. The alterations of the serum immunoglobulin concentrations and of the kappa/lambda ratios reflect immunological disturbances in patients with juvenile onset mixed connective tissue disease. The increased concentration of serum IgG and raised IgG kappa/lambda ratio and decreased concentration of serum IgM with decreased IgM kappa/lambda ratio indicate that the synthesis of kappa-bearing immunoglobulins mainly is affected.

Degradation of immunoglobulin G by periodontal bacteria.

Several subgingival microorganisms were tested for their ability to utilize human immunoglobulin G (IgG) as a substrate for growth. This was done using a protein-free chemically defined medium, supplemented with IgG. Stimulation of growth was observed for Capnocytophaga ochracea, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Prevotella intermedia, Prevotella oralis, Lactobacillus catenaforme and Streptococcus intermedius. Immunoelectrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and a protein assay demonstrated that P. intermedia and P. endodontalis completely degraded the protein chains of IgG. Partial breakdown of IgG was observed for P. asaccharolytica and C. ochracea, whereas P. oralis cleaved the IgG heavy chain, yielding Fc and Fab fragments. All these bacteria utilized IgG as a substrate for growth. Binding studies using an enzyme-linked immunosorbent assay, revealed complete loss of in vitro antigen-antibody binding capacity after incubation of specific IgG with P. endodontalis and partial loss of binding with P. intermedia, P. gingivalis, C. ochracea or Fusobacterium nucleatum. Degradation or inactivation of IgG by oral bacteria is thought to be important in the causation of polymicrobial infections.

Light chain ratios and concentrations of immunoglobulins G, A, and M in childhood common acute lymphoblastic leukemia.

The light chain ratios and the concentrations of immunoglobulin G (IgG), IgA, and IgM were measured before, during, and after antileukemic therapy in 10 patients with common acute lymphoblastic leukemia. The concentrations of IgG, IgA, and IgM decreased substantially during treatment but recovered slowly after cessation of the therapy. The light chain ratios were not systematically affected, but at diagnosis the kappa/lambda ratios of total serum Igs, IgG, and in particular IgM were somewhat lower in the patient group compared with an age-matched reference group. It is concluded that, despite a decrease in serum Ig concentrations, virtually normal kappa/lambda ratios are preserved, indicating that kappa and lambda syntheses are affected to the same extent. These ratios remained normal for age during the recovery of the serum Ig concentrations; the features as described for the development of the light chain ratios in childhood were not observed.

Antibody deficiency and isolated growth hormone deficiency in a girl with Mulibrey nanism.

A combination of humoral immunodeficiency and isolated growth hormone deficiency was observed in a girl with Mulibrey nanism. The humoral immunodeficiency consisted of subnormal concentration of serum IgG, in particular IgG2 and IgG4, and low concentration of serum IgM. Serum IgA and IgD were elevated, IgE was absent. Antibody response in vivo was very low or absent and opsonization in vitro was defective. Total B-cell number was low. In addition, the serum kappa/lambda light chain ratios within the immunoglobulin classes G, A, and M were abnormal. The defective antibody response may be linked to the abnormal kappa/lambda light chain ratios. Endocrine functions were normal except for isolated growth hormone deficiency. Therapy with human growth hormone resulted in increased growth velocity but did not improve humoral immune functions.

Variants of Nijmegen breakage syndrome and ataxia telangiectasia.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by telangiectasia, progressive ataxia, sinopulmonary infections and a combined immunodeficiency (usually consisting of IgA deficiency, IgE deficiency, IgG2 and IgG4 deficiency and a disturbed T cell immunity). The alpha-fetoprotein level is elevated. Cytogenetic studies reveal a very specific chromosome instability with multiple chromosome 7 and/or 14 rearrangements (preferential breakpoints 14q32, 14q12, 7q35 and 7p12). X-ray hypersensitivity is one of the hallmarks of the disease. Nijmegen Breakage Syndrome (NBS), an autosomal recessive disorder with some features of AT, was first reported in 1981. At this moment at least 19 patients have been recognized. Clinical symptoms are microcephaly from birth, a peculiar face, growth retardation, repeated respiratory tract infections and renal abnormalities. Immunological, cytogenetic and cell-biological findings in NBS are identical to AT. However, alpha-fetoprotein levels are not increased. A tendency toward malignancy has been demonstrated in both syndromes. Recently, we encountered three patients with variants of these syndromes.

Light chain ratios and concentrations of serum immunoglobulins in children with epilepsy.

Serum immunoglobulin G, A and M concentrations and their respective kappa/lambda (kappa/lambda) light chain ratios were studied in 26 children with epilepsy. Fifteen had cryptogenic West syndrome or Lennox-Gastaut syndrome and 11 had other forms of childhood epilepsy. The results were compared to the data of a reference group of healthy children. The mean serum IgG and IgM concentrations were respectively 2.2 g/l (P = 0.007) and 0.4 g/l (P = 0.016) higher in the 26 children with epilepsy compared to the reference group. The kappa/lambda ratios of total serum immunoglobulins, IgG and IgM were respectively 0.10 (P = 0.057), 0.20 (P = 0.001) and 0.14 (P = 0.005) lower in the children with epilepsy than in the reference group. IgA concentration and IgA kappa/lambda ratio were not affected. There were no significant differences between the kappa/lambda ratios of the West and Lennox-Gastaut epilepsy and the other types of childhood epilepsies. The results are further evidence of reciprocal interaction between the nervous system and the immune system in childhood epilepsy.

Immunological studies in the hyper-immunoglobulin D syndrome.

Five patients with hyper-immunoglobulin D syndrome (hyper-IgD syndrome) were followed up for 3 to 8 years. In all patients studied, serum IgG3 was high. IgM decreased during the follow-up in all patients. In four of the patients serum IgA was elevated. In four patients the serum IgD kappa/lambda ratio was measured and was found to be raised in all. However, the serum total light-chain ratio and IgG, IgA, and IgM kappa/lambda ratios separately were virtually normal. In two of the patients, clinical symptoms preceded the increase in serum IgD. All patients had a history of severe reactions on immunizations in early childhood. We conclude that in hyper-IgD syndrome, other immunoglobulins may also be affected, in particular, IgA, IgM, and IgG3. The IgD light-chain ratio is also disturbed. We emphasize that clinical symptoms may herald immunological changes. This may be the result of an underlying factor causing both the clinical symptoms and, later, the increasing serum IgD levels.

Immunoglobulin G, A, and M light chain ratios in some humoral immunological disorders.

The total kappa/lambda immunoglobulin light chain ratio and the kappa/lambda ratios within each of the serum immunoglobulin classes G, A, and M were measured in thirteen patients with humoral immunological disorders. Of those patients, eight had common variable immunodeficiency whereas five patients had other forms of humoral immunological deficiencies. Eleven patients had abnormal antibody response in vivo. All but three of the thirteen patients had clearly abnormal light chain ratios in one or more of the immunoglobulin classes. We conclude that humoral immunological disorders, usually characterized by abnormal heavy chain production and a disturbed antibody response, may frequently have a concomitant abnormal synthesis of the light chains resulting in an abnormal kappa/lambda light chain ratio.

Immunoglobulin levels during follow-up of children with selective IgA deficiency.

Longitudinal serum immunoglobulin levels were studied in 36 children with selective IgA deficiency during a median follow-up period of 5 years. Twenty-five children were 'sporadic' cases, and 11 were 'familial'. Serum and saliva IgA levels in 23 children remained below 2 mg/l. Eight children with IgA levels above 2 mg/l showed considerable intra-individual variance in serum IgA, but remained IgA deficient. Five children at various ages developed IgA levels above 50 mg/l with detectable secretory IgA in saliva. In most of the children IgG subclass levels were found to be rather high, including at younger ages. There were no obvious differences between 'sporadic' and 'familial' cases except an association between IgD deficiency and serum IgA levels below 2 mg/l, and between serum levels of IgD above 1 IU/ml and of IgA above 2 mg/l, which was found to be significant in the 'sporadic' group but not in the 'familial' group.

Immunoglobulin G, A and M light chain ratio in children.

Values for the kappa/lambda light chain ratio in immunoglobulins G, A and M and the total kappa/lambda ratio, measured by enzyme linked immunosorbent assay, were evaluated in serum samples from different age groups (114 children, aged from 1 month to 15 years, and 20 adults). The IgG kappa/lambda ratio decreased in the first 6 months and subsequently increased slowly during childhood towards the adult value of 2.0. The IgM kappa/lambda ratio increased at a greater rate than IgG kappa/lambda ratio in the first years of life and thereafter rose slightly throughout childhood to reach an adult value of 1.7. A decreasing IgA kappa/lambda ratio was found from 1 month of age onwards to an adult value of 1.1. The pattern of total kappa/lambda ratio was similar to the IgG kappa/lambda ratio with an adult value of 2.0.

Iatrogenic IgG2 deficiency in a leukaemic child. A case report.

A girl with acute non-lymphoblastic leukaemia was treated with immunosuppressive chemotherapy. After cessation of therapy she had three consecutive episodes of infection due to Streptococcus pneumoniae from which she recovered and was shown to have developed a combined deficiency of both IgG2 and IgG4. The patient eventually relapsed and died 3 years after the initial diagnosis. The importance of measuring IgG subclasses in patients treated with immunosuppressive chemotherapy is discussed.