J. A. J. M. Bakkeren

A NEW CHROMOSOMAL INSTABILITY DISORDER: THE NIJMEGEN BREAKAGE SYNDROME

ABSTRACT. Weemaes, C. M. R., Hustinx, T. W. J., Scheres, J. M. J. C, van Minister, P. J. J., Bakkeren, J. A. J. M. and Taalman, R. D. F. M. (Departments of Paediatrics and Human Genetics, University of Nijmegen, Nijmegen, The Netherlands.) Acta Paediatr Scand, 70:557,.–A 10‐year‐old boy with microcephaly, stunted growth, mental retardation, cafe‐au‐lait spots and immunodeficiency is described. An older brother of the patient had the same clinical symptoms and a more severe immunodeficiency. Cytogenetic studies in the proband revealed a typical form of chromosome instability with multiple rearrangements of chromosomes 7 and 14. Such abnormalities were also present, though in very low frequencies, in the father and three of the phenotypically normal sibs. The similarity of the symptoms in the two sibs, the close consanguinity of their parents and the results of the cytogenetic studies in the family favour the hypothesis that the disorder is an inherited one. The clinical features and the chromosome aberrations as present in the proband are usually found in chromosomal breakage syndromes, but it was possible to exclude each of the classical chromosomal breakage syndromes on clinical and/or cytogenetic grounds.

Disorders of the mitochondrial respiratory chain: clinical manifestations and diagnostic approach

The clinical identification of patients with defects in the mitochondrial respiratory chain is almost impossible. We describe screening tests that should be performed in order to select those patients in whom a skeletal muscle biopsy should be carried out for more specific biochemical assays. The importance of performing in vivo function tests is stressed. The biochemical diagnosis in disorders of the respiratory chain is presented and the application of immunological methods discussed.

Deficiency of cytochromes b and aa3 in muscle from a floppy infant with cytochrome oxidase deficiency

A girl was presented suffering from generalised weakness and cardiorespiratory insufficiency. She succumbed at the age of 5 months. Lactate levels were elevated in serum, cerebrospinal fluid and urine. Histopathological examination revealed a mitochondrial myopathy. In muscle tissue the cytochrome oxydase activity was strongly reduced. The content of cytochromes b and aa3 was very low. At autopsy a cardiomyopathy was found.

Clinical manifestations in selective IgA deficiency in childhood. A follow-up report.

ABSTRACT. Clinical manifestations in 40 children with selective IgA deficiency were studied during a follow‐up period of 2‐10 years. The patients were divided into two groups: group I consisted of 25 children with “sporadic” IgA deficiency and group II of 15 children with “familial” IgA deficiency. Respiratory tract infections including otitis media were frequent in both groups. Concomitant IgG,‐IgG, deficiency was found in two patients in group I. Longitudinal serum IgG levels were elevated significantly in both groups. Atopic complaints were observed in 10 children of the “sporadic” group, but only in two of the “familial” group. However, elevated serum IgE levels were more often found in group II. Two children of group I were mentally retarded and chromosomal examination showed abnormalities in both. Anti‐IgA antibodies were detected in one child in group I and three children in group II. These three patients had an IgA deficient mother with class‐specific anti‐IgA antibodies. Concomitant IgG4‐IgE deficiency was found in all four.

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 κ/λ ratio was measured and was found to be raised in all. However, the serum total light-chain ratio and IgG, IgA, and IgM κ/λ 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.

Deficiency of the α and β subunits of pyruvate dehydrogenase in a patient with lactic acidosis and unexpected sudden death

An infant with moderate muscular hypotonia and congenital lactic acidosis died suddenly at the age of 3 months. Autopsy revealed no abnormalities responsible for this unexpected death. Measurement of mitochondrial enzymes involved in energy production indicated a severely decreased total pyruvate dehydrogenase complex (PDHC) activity in muscle tissue (0.23 nmoles · min−1 · mg protein−1, control range 2.8–8.7) and moderately decreased PDHC activity in fibroblasts (0.27 nmoles · min−1 · mg protein−1, control range 0.37–2.32). The activity of the first component E1 (pyruvate dehydrogenase) in muscle tissue was 10 times lower than that of controls (0.008 nmoles · min−1 · mg protein−1, control range 0.10–0.25). The activities of dihydrolipoyl dehydrogenase (E3) and various other mitochondrial enzymes were normal. Immunochemical analysis in skeletal muscle tissue and fibroblasts demonstrated a decrease in the amount of the α and β subunits of E1. The features of this patient are compared with those of other patients reported in the literature with immunochemically confirmed combined E1 α and β deficiency.

Recovery of immune function after cessation of maintenance therapy in acute lymphoblastic leukemia (ALL) of childhood

In previously healthy children, serum immunoglobulin levels at diagnosis of acute lymphoblastic leukemia (ALL) were entirely in the normal range. After antileukemic therapy had been given for 26–27 months, serum immunoglobulin levels were low. In 32 children these parameters could be followed for periods up to 3 years after cessation of therapy, the patients remaining in unmaintained remission.At cessation of therapy serum immunoglobulin levels were at the tenth centile of the normal range or slightly below. IgG promptly returned to normal levels and then remained in the normal range. IgA levels were restored much more slowly. Most striking was the slow and incomplete return of serum IgM to normal levels. Even after a follow-up of 3 years the mean was still subnormal. This was not accompanied by clinical signs of disturbed immunity. Our study points out that in assessing the long-term immunosuppressive effects of anticancer therapy the follow-up period must be sufficiently long.

3-methylglutaconic aciduria in a patient with a disturbed mitochondrial energy metabolism

Sir: Three types of 3-methylglutaconic aciduria (McKusick 25095) can be distinguished [2]: 1. Patients with a massive excretion of 3-methylglutaconic acid (3-MGA) accompanied with 3-methylglutaric and 3-hydroxy-isovaleric acid, and a deficiency of 3-methylglutaconyl-CoA-hydratase (EC 4.2.1.18). 2. Patients with cardiomyopathy and retarded growth. 3. Patients with serious psychomotor retardation and neurological manifestations. In groups 2 and 3 3-methylglutaconic aciduria was variable and 3-methylglutaconyl-CoA-hydratase deficiency could not be established. Some patients showed lactic aciduria [1]. Haan et al. [3] found in their patients fibroblasts no enzyme defects in pyruvate metabolism, citric acid cycle or electron transport chain. We now report a patient with mild 3-methylglutaconic aciduria and severe neurological symptoms in whom an elevated concentration of lactate in CSF and blood gave rise to the suspicion of a defect in mitochondrial energy metabolism. The boy, the second child of healthy non-consanguineous parents, was admitted to our hospital at the age of 4 months because of developmental delay and failure to thrive. He was microcephalic (head circumference: 40.5 cm) with a height of 60 cm (10 th percentile) and weight of 5400 g (~0 tl~ percentile). There were no indications of cardiomyopathy. There was axial hypotonia with hypertonic muscles of the extremities. He had a convergent strabismus and a bilateral optic atrophy. He showed no reaction to auditory stimuli. There were frequent myoclonic jerks. Psychomotor development was at a very low level (0-1 month). Organic acid analysis in urine revealed only a mildly elevated excretion of 3-MGA. In blood and CSF no 3-MGA was detected, but the lactic acid concentration was increased (blood: 2.9 mmol/1; n < 1.8; CSF: 2.5 mmol/1; n < 1.9). Reduction of protein intake to 0.5 g/kg per day, supplied with a leucine-free amino acid mixture, resulted in a near normal 3-MGA excretion. After oral leucine loading the urinary 3-MGA excretion increased to levels found earlier in the patient. Lactic acid levels rose considerably both in blood (5.1 mmol/1) and urine (660 mmol/mol creatinine; n < 150). The clinical picture dominated by generalized encephalopathy, and the lactic acidaemia, pointed to a disordered mitochondrial energy metabolism. Subsequently, in a fresh muscle biopsy specimen the oxidation rates of several mitochondrial substrates were found to be markedly decreased. Oxidation of [1-14C] pyruvate in the presence of either malate or carnitine as acetyl-CoA acceptor was 20% and 40%, respectively, of the lower limit of the control range. Oxidation of [U-I4C] malate in the presence of either pyruvate or acetylcarnitine as acetyl-CoA donor was 15% and 17%, respectively. These findings can be explained by a defect in the respiratory chain. Measurement of separate parts of the electron transport chain revealed diminished activities of succinate:cytochrome c oxidoreductase and of NADH:O2 oxidoreductase (55% and 70%, respectively, of the lower limit of

Transient erythroblastopenia of childhood

In the period 1975–1983 22 patients, aged 4–36 months were seen with severe transient normochromic, normocytic anaemia caused by a transient erythroblastotopenia.In 20 patients bone marrow aspirations were obtained; they showed erythroblastopenia.In ten cases we observed young lymphoid cells, suggesting a diagnosis of acute lymphoblastic leukaemia. One patient suspected of a leukaemia, was studied in more detail.All patients showed reticulocytopenia. MCV and HbF were within normal range. During recovery reticulocytosis and higher levels of HbF were found. Except for blood transfusion in most patients, therapy (e.g. corticosteroids) was not necesssary. Spontaneous recovery is a feature of this kind of erythroblastopenia, contrasting with congenital hypoplastic anaemia.

Growth pattern of tumor xenografts in wistar rats after treatment with cyclophosphamide, total lymphoid irradiation and/or cyclosporin A

Wistar rats treated with cyclophosphamide, total lymphoid irradiation (TLI), and/or cyclosporin A (CSA) develop a state of immune suppression permitting the growth of tumor xenografts. Experiments were carried out on this newly developed model to investigate the growth patterns of a mouse osteosarcoma and a human colon adenocarcinoma. The combination of cyclophosphamide and CSA permitted a limited period of growth of the mouse osteosarcoma with a tumor take rate of 66%. No takes were observed with the human adenocarcinoma. The combination of cyclophosphamide and TLI resulted in a period of immunosuppression followed by recovery of the immune status. During the period of immunosuppression, tumor xenografts showed a 100% take rate. The most efficient immunosuppression was achieved by a combination of cyclophosphamide, TLI and CSA administered on alternate days. Wistar rats subjected to this treatment showed prolonged tolerance to mouse osteosarcoma and human adenocarcinoma xenografts. There was no alteration in the tumor doubling time or histological morphology of the xenografts in the adapted host as compared with those in the donor tumors. The tumor growth curve showed a pattern of initial growth, a period of stagnation, followed by a steady but slower growth phase. The significance of the results and the advantages of the rat model described in this paper for human tumor xenotransplantation are discussed.