F. A. Beemer

Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency

Abstract Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, including 2 deletions [295–298delTCAT, 1897delC], 1 splice-site mutation [IVS14+1G>A)] and 4 missense mutations (85T>C, 703C>T, 2658G>A, 2983G>T). Analysis of the prevalence of the various mutations among DPD patients has shown that the G→A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations. A clear correlation between the genotype and phenotype has not been established. An altered β-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.

Combined deficiency of xanthine oxidase and sulphite oxidase: a defect of molybdenum metabolism or transport?

A child is described who presented in the neonatal period with feeding difficulties, severe neurological abnormalities, lens dislocation of the eyes and dysmorphic symptoms of the head. Routine laboratory investigations revealed a decreased serum urate and a positive sulphite reaction of the urine. Subsequent chromatographic examinations showed xanthinuria and increased excretion ofS-sulphocysteine and taurine to be present. In addition, high thiosulphate and low sulphate excretions in the urine were observed. Xanthine oxidase deficiency was demonstrated in a jejunal biopsy specimen, whereas the excretion of sulphur containing substances was considered to be characteristic of sulphite oxidase deficiency.This new combination of defects may be the result of malfunctioning of both enzymes, possibly caused by alterations in the essential molybdenum containing active centre of the enzymes, which they share in common.

Dihydropyrimidine Dehydrogenase Deficiency Leading to Thymine-uraciluria. An Inborn Error of Pyrimidine Metabolism

Three unrelated patients with excessive thymine-uraciluria due to dihydropyrimidine dehydrogenase deficiency are described. Excretory values (mmol/g creatinine) were: uracil 2.0-10.5, thymine 2.3-7.5, 5-hydroxymethyluracil 0.2-0.9. Orally administered (index patient) uracil and thymine were excreted for the greater part whilst dihydrouracil and S-dihydrothymine were mainly metabolised. Dihydropyrimidine dehydrogenase activities (nmol X h-1 X mg-1 protein) in leucocytes were 0.04, 0.01 and less than 0.01 in the patients, 0.31-1.66 in their parents, and 1.01-4.46 in controls (n = 4). The patients presented with a non-specific clinical picture of cerebral dysfunction.

Osteogenesis imperfecta in childhood: treatment strategies.

Osteogenesis imperfecta (OI) is a skeletal disorder of remarkable clinical variability characterized by bone fragility, osteopenia, variable degrees of short stature, and progressive skeletal deformities. Additional clinical manifestations such as blue sclerae, dentinogenesis imperfecta, joint laxity, and maturity onset deafness are described in the literature. OI occurs in about 1 in 20,000 births and is caused by quantitative and qualitative defects in the synthesis of collagen I. Depending on the severity of the disease, a large impact on motor development, range of joint motion, muscle strength, and functional ability may occur. Treatment strategies should primarily focus on the improvement of functional ability and the adoption of compensatory strategies, rather than merely improving range of joint motion and muscle strength. Surgical treatment of the extremities may be indicated to stabilize the long bones to optimize functional ability and walking capacity. Surgical treatment of the spine may be indicated in patients with progressive spinal deformity and in those with symptomatic basilar impression.

Spinal complications in osteogenesis imperfecta: 47 patients 1-16 years of age

We examined in a cross-sectional study, 47 children (mean age 7.7 (1-16) years) with osteogenesis imperfecta (OI) to find the prevalence of spinal deformities and to correlate these observations with anthropometry. The associations between dentinogenesis imperfecta, joint hypermobility and spinal deformities were also studied. Disproportion in stature in OI type I and type IV was mainly caused by spinal involvement, as evidenced by a greater decrease in body height than in leg length. In OI type I, the decrease in sitting height was mainly caused by platyspondyly, whereas in OI types III and IV, it was also caused by progressive scoliosis and kyphosis. Scoliosis was present in 22 children, and pathological kyphosis in 18, mainly in the severe OI types. Basilar impression was observed in 10 children, mainly in type III. Children with dentinogenesis imperfecta seemed to be prone to develop scoliosis, pathological kyphosis and basilar impression. Children with generalized joint hypermobility were less prone to develop scoliosis and basilar impression. Our observations may contribute to a better understanding of the risk factors for progressive spinal deformities in OI.

Genetic basis of peroxisome-assembly mutants of humans, Chinese hamster ovary cells, and yeast: identification of a new complementation group of peroxisome-biogenesis disorders apparently lacking peroxisomal-membrane ghosts.

We thank K. Hori for technical assistance, M. Ohara for helpful comments, and K. Kamijo for human PMP70 cDNA and an anti-ALDP antibody. This study was supported in part by a grant-in-aid for scientific research (08670870) from the Ministry of Education, Science, Sports, and Culture of Japan, by a research grant from the National Center of Neurology and Psychiatry of the Ministry of Health and Welfare of Japan, and by a research grant from Ono Medical Research Foundation.

Absence of hepatic molybdenum cofactor: An inborn error of metabolism leading to a combined deficiency of sulphite oxidase and xanthine dehydrogenase

Five patients with a combined deficiency of xanthine dehydrogenase, sulphite oxidase and, probably, also of aldehyde oxidase are described. This remarkable coincidence of three inborn errors of metabolism in a single individual was demonstrated to result from a deficiency of the ‘molybdenum cofactor’, an essential constituent of all three enzymes. The main biochemical findings in these patients included: hypouricaemia, xanthinuria, an increased excretion of sulphite, thiosulphate andS-sulphocysteine and a decreased excretion of inorganic sulphate. Plasma molybdenum was normal. The ultimate diagnosis was made by the measurement of ‘molybdenum cofactor’ in a liver biopsy specimen in three out of five patients.The clinical hallmarks in these patients were: feeding difficulties, mental retardation, neurological symptoms, lens dislocation, an abnormal muscle tone, myoclonia and an abnormal physiognomy. The majority of these were already present in the neonatal period. So far, attempts at treatment have been unsuccessful.

Cerebral gigantism (Sotos syndrome). Compiled data of 22 cases

An in depth study on growth, bone age, cranial CT scans and plasma somatomedin activity (SM-act) was made of 22 children with Sotos syndrome. In addition to the known characteristics of the syndrome, thin and brittle nails were found in three adolescent patients. The mean body stature, expressed as standard deviation score, increased from 2.2–2.8 in the 1st year of life, followed by a fall to 2.0 in the 2nd year. Thereafter the SDS increased slowly to values of 3.0 at 10 years of age. At least two subjects have reached an exceptionally tall final stature. After the age of 2 years, Δ SDS/year remained very stable (−0.1–0.2), concurring with growth velocities in the upper normal range. Bone age was advanced in all patients. Cranial CT scans showed ventricular widening, mid-line cava and Sylvian anomalies in nine, six, and three patients respectively. SM-act dropped from high or normal values in the 1st year, to below normal from 1–5 years, and returned thereafter to the lower half of normal or below the normal range.

Bone Dysplasia Associated with Phytanic Acid Accumulation and Deficient Plasmalogen Synthesis: A Peroxisomal Entity Amenable to Plasmapheresis

The diagnosis of inborn errors of peroxisomal metabolism is based on a number of clinical and biochemical characteristics. The combination of skeletal abnormalities and peroxisomal dysfunction is seen in the rhizomelic form of chondrodysplasia punctata (RCDP) and in Zellweger syndrome (Wanders et al 1988). Recently two patients were described with a new type of chondrodysplasia punctata associated with the characteristic peroxisomal abnormalities observed in RCDP: (1) accumulation of phytanic acid in plasma, (2) a defect in plasmalogen synthesis, and (3) presence of the unprocessed form of peroxisomal thiolase protein (Pike et al 1990; Poll-The et all 1991)

Functional Outcome in Osteogenesis Imperfecta: Disability Profiles Using the Pedi

The purpose of this study was to determine if the severity of osteogenesis imperfecta (Ol) in childhood might have any influence on functional outcome. In a cross-sectional study, the functional outcome of 61 children with Ol was related to the three subtypes of the disease. Functional outcome was m