Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome.

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is an autosomal recessive disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Diagnostic hallmark of HIDS is a constitutively elevated level of serum immunoglobulin D (IgD), although patients have been reported with normal IgD levels. To determine the underlying defect in HIDS, we analysed urine of several patients and discovered increased concentrations of mevalonic acid during severe episodes of fever, but not between crises. Subsequent analysis of cells from four unrelated HIDS patients revealed reduced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all patients. Expression of the mutant cDNAs in Escherichia coli showed that all three mutations affect the activity of the encoded proteins. Moreover, immunoblot analysis demonstrated a deficiency of MK protein in patient fibroblasts, indicating a protein-destabilizing effect of the mutations.

The success of dietary protein restriction in alkaptonuria patients is age-dependent.

Alkaptonuria is characterized by an increased urinary excretion of homogentisic acid, pigmentation of cartilage and connective tissues, and ultimately the development of inflammatory arthropathy. Various diets low in protein have been designed to decrease homogentisic acid excretion and to prevent the ochronotic pigmentation and arthritic lesions. However, limited information is available on the long-term beneficial effects of these diets. We reviewed the medical records of 16 patients aged 3-27 years (4 > 18 years) to ascertain the age of diagnosis, growth, development, social behaviour, signs of complications and longitudinal dietary compliance. The diagnosis of alkaptonuria was made at an average age of 1.4 years (2 months-4 years); following the diagnosis all patients were prescribed a diet with a protein content of 1.5 g/kg per day. All patients showed normal growth and development, and no major complications of the disease. Behavioural problems associated with poor dietary compliance emerged as the main problem. Dietary compliance decreased progressively with age. The effect of dietary protein restriction in homogentisic acid excretion was studied by fixing the amounts of protein in the diet at 1 g/kg per day and 3.5-5 g/kg per day during 8 days. Twelve patients, aged 4-27 years, participated in the investigation. Protein restriction resulted in a significantly lower excretion of homogentisic acid in the urine of children younger than 12 years (p < 0.01), whereas this effect was less obvious for adolescent and adult patients. The results suggest that restriction of protein intake may have a beneficial effect on alkaptonuric children; but continuation of this regimen to older age seems questionable and not practical.

Persistent low plasma vitamin E levels in premature infants surviving respiratory distress syndrome.

Plasma vitamin E levels were determined serially in preterm infants surviving respiratory distress syndrome (RDS) and in premature infants without RDS (control). Vitamin E intakes of the RDS and control infant group were not significantly different. The results of the study show that preterm infants surviving RDS have a persistent low plasma vitamin E level throughout the first 8 weeks of life. In contrast, in premature infants without RDS the plasma vitamin E level gradually increases to the adult level throughout the first 8 weeks of life. It is concluded that data on plasma vitamin E levels in premature infants with and without RDS should not be pooled together to obtain reference values. It is further suggested that premature infants with RDS might need more supplemental vitamin E than premature infants without RDS.

The cerebro-costo-mandibular syndrome: third report of familial occurrence.

Two male sibs with cerebro-costo-mandibular syndrome and spina bifida are described. The parents are physically and radiologically normal. A short review of the pertinent literature is given with special emphasis on the mode of inheritance.

The use of diclofenac sodium (Voltaren) suppositories as an antipyretic in children with fever due to acute infections: a double-blind, between-patient, placebo-controlled study.

In a placebo-controlled double-blind, between-patient trial the antipyretic effect of diclofenac sodium (voltaren) was studied in forty-three children ranging from 2-10 years of age. All patients were hospitalized because of acute illness associated with fever (38.5 degrees C-40.4 degrees C; mean 39.3 degrees C) due to viral or bacterial infections. The trial medication was given in the form of suppositories containing 25 mg of diclofenac sodium or as matching placebo to children aged from 2-5 years. The children aged from 6-10 years received a 50 mg diclofenac sodium suppository or placebo. Body temperature and pulse rate were measured at the time of administration and after 1/2, 1, 2, 4, and 6 hours. The results showed a return to normal temperature values after 2 hours in all patients receiving diclofenac sodium, whereas in the placebo group only minimal changes were observed. No unwanted effects were reported.

Application of enzymehistochemical methods to isolated subcellular fractions and to sucrose-ficoll density gradients. A contribution to the comparison of histochemical and biochemical data.

To compare histochemical and biochemical determinations of enzyme activities, enzymehistochemical procedures are applied to sections of pellets of subcelluar fractions. These investigations are of value to determine the subcellular localization of histochemically demonstrable enzyme activities and to test the homogeneity of an isolated fraction. In homogenating duckling liver a great part of the endothelial cells is not destructed and consequently is found in the nuclear fraction. Kupffer cell lysosomes land in the heavy mitochondrial fraction, whereas hepatocyte lysosomes are chiefly found in the light mitochondrial fraction. beta-Glucuronidase activity shows a preferentially microsomal localization. Application of enzymehistochemical staining reactions to discontinuous gradients and comparison with biochemical data provides additional information about the validity of an enzymehistochemical reaction. In rat liver the tetrazolium reductases show a distinctly dual localization: activity in the mitochondrial band and in microsomal bands. As to their localization in different bands of the gradients non-specific esterases demonstrate a clear pH-dependency.

Biochemical and ultrastructural aspects of the inhibited phagocytosis by neutrophil granulocytes in acute brain-damaged patients.

In a study of 60 head-injured patients inhibition of phagocytosis by neutrophil granulocytes was observed over a period of up to 5 weeks. This inhibition of phagocytosis could be correlated with the severity of head injury as well as with the state of unconsciousness at the time of the investigation. No correlation was found between neutrophil granulocyte counts and the inhibition of phagocytosis. A good correlation could be demonstrated between the level of lumbar CSF 5-HIAA and the inhibition of phagocytosis. After in vitro incubation with albumin the cells showed a recovery of phagocytosis. Electron micrographs of the cells showed ultrastructural appearances suggesting a changed permeability of the plasma membrane and, in addition, alterations in the cytoplasmic region beneath the plasma membrane. It is suggested that head injury may influence the pituitary-adrenal system and the autonomic nervous system, giving changes of neutrophil function and of neurotransmitter metabolism; these changes may represent an adaptation mechanism.