A common PEX1 frameshift mutation in patients with disorders of peroxisome biogenesis correlates with the severe Zellweger syndrome phenotype.

Peroxisome biogenesis disorders are a heterogeneous group of human neurodegenerative diseases caused by peroxisomal metabolic dysfunction. At the molecular level, these disorders arise from mutations in PEX genes that encode proteins required for the import of proteins into the peroxisomal lumen. The Zellweger syndrome spectrum of diseases is a major sub-set of these disorders and represents a clinical continuum from Zellweger syndrome (the most severe) through neonatal adrenoleukodystrophy to infantile Refsum disease. The PEX1 gene, which encodes a cytoplasmic AAA ATPase, is the responsible gene in more than half of the Zellweger syndrome spectrum patients, and mutations in PEX1 can account for the full spectrum of phenotypes seen in these patients. In these studies, we have undertaken mutation analysis of PEX1 in skin fibroblast cell lines from Australasian Zellweger syndrome spectrum patients. A previously reported common PEX1 mutation that gives rise to a G843D substitution and correlates with the less severe disease phenotypes has been found to be present at high frequency in our patient cohort. We also report a novel PEX1 mutation that occurs at high frequency in Zellweger syndrome spectrum patients. This mutation produces a frameshift in exon 13, a change that leads to the premature truncation of the PEX1 protein. A Zellweger syndrome patient who was homozygous for this mutation and who survived for less than two months from birth had undetectable levels of PEX1 mRNA. This new common mutation therefore correlates with a severe disease phenotype. We have adopted procedures for the detection of this mutation for successful prenatal diagnosis.

Cefotaxime therapy of neonatal gram-negative bacillary meningitis.

Seven neonates were treated with cefotaxime during eight episodes of Gram-negative bacillary meningitis and sepsis. The causative organisms were Escherichia coli in six cases and Klebsiella pneumoniae and Enterobacter sakazakii in one each. After identification of the pathogen cefotaxime was used alone in six instances. Two patients with brain abscesses received adjunctive therapy with another antibiotic. The sterility of cerebrospinal fluid was documented after a mean of 3.3 days of therapy. Mean cerebrospinal fluid bactericidal titer was 1:64. All patients recovered with good neurologic outcome. Cefotaxime in a dosage of 150 mg/kg/day divided every 6 hours intravenously seems safe and effective therapy for neonatal Gram-negative bacillary meningitis.

The immunogenicity of K99 antigen in whole cell bacterins of Escherichia coli.

K99 antigen in Escherichia coli whole cell bacterins was immunogenic in rabbits and mice. Mice vaccinated subcutaneously and bled three weeks later had a serum antibody response which was dose dependent. The dose response on dilution of bacterins was shown to be mainly due to dilution of K99 antigen, rather than the reduction in adjuvant or bacterial cell concentration. The procedure appears to be a satisfactory one for immunogenicity testing of bacterins containing K99 antigen.