Bengt Kristiansson

Progressive Increase of the Mutated Mitochondrial DNA Fraction in Kearns-Sayre Syndrome

ABSTRACT: We have performed morphologic and biochemical studies in three pediatric cases of Kearns-Sayre syndrome. All cases had heteroplasmy with a high percentage of mitochondrial DNA (mtDNA) with deletion in muscle. The deletions were mapped to the same region of mtDNA but were of different sizes. The same type of deletion could also be detected in fibroblasts from all cases but the percentage was considerably lower. In two cases, an increase with time of the mutated mtDNA fraction in muscle was found and this increase paralleled the progression of the disease. Oximetric evaluation of respiratorychain function in isolated muscle mitochondria showed a complex I deficiency in one case and was normal in the two other cases. Comparison of the fractional concentration of mtDNA with deletion in muscle and isolated mitochondria showed that the isolated mitochondria were not representative of the mitochondrial population in muscle. Mitochondria with high percentage of mtDNA with deletion were selectively lost. The finding of different mitochondrial populations is in good agreement with the morphology. One case spontaneously recovered from an infantile sideroblastic anemia before the development of Kearns-Sayre syndrome. The anemia was of the same type as that in Pearsons syndrome, a mitochondrial disorder with high amounts of mtDNA with deletion in blood cells. These findings indicate that the phenotype of a mtDNA deletion disorder can change with time and is governed by the fractional concentration of mtDNA with deletion in different tissues.

Longitudinal growth in children and adolescents with inflammatory bowel disease.

SummaryWeight and height were followed longitudinally from birth to adulthood in children with inflammatory bowel disease living in a defined area of Sweden, 1983 through 1987; 124 children out of a possible 128 were studied. During the year preceding diagnosis, height growth velocity was significantly reduced in both ulcerative colitis and Crohns disease. At the time of diagnosis, weight-for-height was subnormal in both children with ulcerative colitis (p < 0.05) and those with Crohns disease (p < 0.001), while height was reduced only in children with Crohns disease (p < 0.05). Weight for height was normalized within one year in ulcerative colitis, after the initiation of medical therapy. In Crohns disease, weight-for-height improved during the years following diagnosis but height remained subnormal. Children with ulcerative colitis reached puberty at the normal time and their final heights became normal. In children with Crohns disease, puberty was delayed (p < 0.001) and final height was reduced (p < 0.01). The impact of inflammatory bowel disease on growth was substantial, but it was smaller in this study than in many other published studies. The possible reasons for this difference include use of population-based material and a relatively short interval between the first symptoms and the start of treatment. Our findings indicate that, although final height was significantly reduced in children with Crohns disease, delayed puberty reduced the negative effects on permanent adult height, to a certain extent compensating for the period of poor growth earlier in life.

CARNITINE DEFICIENCY INDUCED BY PIVAMPICILLIN AND PIVMECILLINAM THERAPY

Short-term administration of pivampicillin and pivmecillinam resulted in a reduction of serum carnitine concentration and an increase in excretion of acylcarnitine in urine. These changes persisted for more than ten days after cessation of therapy. In seven girls on long-term treatment with a mixture of pivampicillin and pivmecillinam the mean total serum carnitine concentration fell to 15% (7-27%) of pretreatment values. The acylcarnitine fraction was 11-57% of total carnitine, compared with less than 2% before treatment. Muscle carnitine concentrations in two girls treated with the antibiotics for 22 and 30 months were only 10% of the mean reference value. These concentrations in serum and muscle are in the range encountered in patients with carnitine deficiencies of other aetiologies in which life-threatening metabolic crises may arise. The risk of adverse effects from prodrugs that give rise to pivalic acid should be seriously considered, particularly in patients under metabolic stress.

Carbohydrate-deficient glycoprotein syndromes: peculiar group of new disorders.

A new group of metabolic disorders, the carbohydrate-deficient glycoprotein (CDG) syndromes, is reviewed with emphasis on the key condition, the CDG syndrome type I. This disease, an autosomal-recessive multisystem condition, has now been diagnosed in 45 Scandinavian patients. It is characterized by carbohydrate deficiencies of a number of glycoproteins, including uniform changes in transferrin. The transferrin alterations provide a distinct biologic marker and a practical and simple laboratory diagnostic means employing analysis of serum or blood spots from Guthrie-type filter paper. The syndrome presents differently through various life periods. A four-stage grouping system by age has been constructed and is presented. During infancy, internal organ symptoms are dominant; some may be life-threatening. In later childhood and adolescence, static mental deficiency, cerebellar ataxia, slowly progressive lower limb neuropathy, and pigmentary retinal degeneration, as well as secondary skeletal deformities, are the most prominent findings. Two very recently described clinical and biologic variants, CDG syndromes II and III, are summarized and compared to CDG type I.

Mitochondrial encephalomyopathies in childhood. I. Biochemical and morphologic investigations

During a 4-year period (1984 to 1988), 50 children referred with manifestations of central nervous system or neuromuscular disease combined with hyperlactatemia were subjected to investigations that aimed to identify and characterize children with mitochondrial disorders. Biochemical and morphologic investigations of quadriceps muscle biopsy tissue were done, including oximetric and spectrophotometric analysis of the respiratory chain function, enzyme histochemistry, electron microscopy, and analysis of mitochondrial DNA. A diagnosis of mitochondrial disease was based on the presence of at least two of five criteria: (1) abnormal results of oximetry, (2) abnormal results of spectrophotometry, (3) enzyme histochemical evidence of cytochrome x oxidase deficiency, (4) deletions or point mutations of mitochondrial DNA, and (5) abundant ultrastructurally abnormal mitochondria. With the combined biochemical and morphologic investigation, 20 of the children were found to have mitochondrial disorders. In an additional 10 children a mitochondrial disorder was neither excluded nor verified. Mitochondrial disorders are thus an important cause of central nervous system and neuromuscular disease in children with hyperlactatemia.

Biochemical Characteristics and Diagnosis of the Carbohydrate-deficient Glycoprotein Syndrome

29 patienxts with a new inherited complex developmental deficiency syndrome—the carbohydrate‐deficient glycoprotein syndrome—were studied biochemically. The most striking biochemical abnormality in these patients is the presence of secretory glycoproteins, that are deficient in their carbohydrate moieties. Serum transferrin shows the most pronounced carbohydrate defect, both quantitatively and qualitatively. Half of this glycoprotein is apparently missing two or four of its terminal trisaccharidcs—sialic acid, galactose and N‐acetylglucosamine—while the carbohydrate core appears to be intact. The abnormal transferrin is also present in the liver. This biochemical alteration is a highly specific marker of the syndrome, which can be diagnosed either qualitatively by isoelectric focusing of serum transferrin or quantitatively by the “carbohydrate‐deficient transferrin” (CDT) assay. In the CDT assay all of these patients have values approximately ten times above the reference level. The unique carbohydrate defect in secretory glycoproteins indicates that this disorder represents a new type of inborn error of glycoprotein metabolism. Studies of eleven enzymes in glycoprotein synthesis and catabolism have not revealed any deficiency of glycosidases or glycosyltransferases. The nature of the transferrin change and the cathepsin assays performed to date may suggest an as yet unidentified degradation abnormality.

Genome-wide Linkage Analysis of Scandinavian Affected Sib-pairs Supports Presence of Susceptibility Loci for Celiac Disease on Chromosomes 5 and 11

Celiac disease (CD) is a common chronic inflammatory disorder of the small intestine with a multifactorial aetiology. HLA is a well-known risk factor, but other genetic factors also influence disease susceptibility. To identify the genes involved in this disorder, we performed a genome-wide scan on 106 well-defined Swedish and Norwegian families with at least two affected siblings. We investigated familial segregation of 398 microsatellite markers, and utilised non-parametric linkage analysis. The strongest linkage with disease was found to the HLA locus (6p) (P<0.000006). There were eight regions besides HLA with a point wise P value below 0.05. Among these eight regions were 11q and 5q, both of which have been suggested in several linkage studies of independent celiac disease families. We also performed a stratification analysis of families according to their HLA genotypes. This resulted in significant differences on chromosome 2q. These results indicate that 11q, 5q and possibly also 2q are true susceptibility regions in CD.

Mitochondrial encephalomyopathies in childhood. II. Clinical manifestations and syndromes

During a 4-year period 1984 to 1988, 20 children referred with manifestations of central nervous system or neuromuscular disease combined with hyperlactatemia were found to have a mitochondrial disease. Each diagnosis was based on the results of thorough biochemical and morphologic investigations. The patients were separated into one series with mainly encephalopathy (n = 14) and another with mainly myopathy (n = 6). The patients with encephalopathy had the following syndromes: Kearns-Sayre (n = 2), MERRF (myoclonus epilepsy and ragged red fibers; n = 2), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; n = 3), Alpers (n = 3), Leigh (n = 1), and other variants (n = 3). In patients with myopathy, three had hypertrophic nonobstructive cardiomyopathy. Ultrastructural abnormalities of mitochondria were the most common morphologic changes in the muscle biopsies. Complex I deficiency was most common in the patients with encephalopathy. All of the patients with myopathy had complex IV deficiency. Mutations of mitochondrial DNA were found in six patients with encephalopathy. We conclude that identification of defects at the DNA level and determination of the phenotypic expression with clinical, morphologic, and biochemical methods are fundamental for future rational classification of mitochondrial disorders.

Chronic inflammatory bowel disease in children and adolescents in Sweden

Summary: The incidence and prevalence of chronic inflammatory bowel disease (IBD) in children was established during 1984 and 1985 in a prospective study in Sweden. The patients with IBD were classified as having ulcerative colitis (UC), Crohns disease (CD), probable Crohns disease (PCD), and indeterminate colitis (IC) according to defined histopathologic, endoscopic, and radiologic criteria. The study covered 1.51 million children <16 years of age (93% of all children in Sweden). The incidence of IBD was 5.0 and 4.5 and the prevalence was 17.6 and 18.2 per 100,000 children during the 2 years, respectively. The mean prevalence of UC was 7.5 per 100,000 and of CD + PCD was 6.2 per 100,000. The prevalence of IC was 4.2 per 100,000, which corresponds to 23% of the children with IBD.

The influence of khat-chewing on birth-weight in full-term infants

The leaves of the shrub Catha edulis (khat) are widely chewed as part of social life in several countries around the Red Sea and in East Africa. The leaves possess stimulant properties and are also used by pregnant women. The effect of khat on birth-weight has been studied, It was found that healthy full-term, singletons, born after uneventful pregnancies and deliveries, had a significantly lower average birth-weight when the mothers were khat-chewers, either habitually or occasionally (P less than 0.001). Khat-chewing appears to be one of several maternal practices adverse to the fetus.