Congenital zinc deficiency from mutations of the SLC39A4 gene as the genetic background of acrodermatitis enteropathica

Acrodermatitis enteropathica (AE) is an autosomal recessive disorder with the clinical triad of acral dermatitis, diarrhea and alopecia. AE is known to be caused by mutations of the SLC39A4 gene on the chromosome band 8q24.3, encoding the zinc transporter in human. An 8-month-old Korean boy presented with eczematous changes on the inguinal area and knees and was diagnosed with AE. Blood tests revealed a markedly decreased level of plasma zinc, and his symptoms improved on oral zinc replacement. To confirm the diagnosis of AE from congenital zinc deficiency, direct sequencing analysis of SLC39A4 was performed and revealed that he was compound heterozygous for a known missense mutation (Arg95Cys) and a novel splicing mutation in the donor site of intron 7 (c.1287+2T>C). Family study showed that his parents were heterozygous carriers of the mutations. To the best of our knowledge, this is the first report of genetically confirmed AE in Korea.     

Endovascular management of iliofemoral deep venous thrombosis due to iliac vein compression syndrome in patients with protein C and/or S deficiency

The purpose of this study was to evaluate the early outcome of endovascular management in patients with iliofemoral deep venous thrombosis (DVT) due to iliac vein compression syndrome (IVCS) and protein C and/or S deficiency. Between September 2000 and January 2003, catheter-directed thrombolysis was performed in 11 patients with a diagnosis of acute iliofemoral DVT: 7 with protein C and/or S deficiency and 4 without protein C and/or S deficiency. After thrombolysis, the diagnosis of IVCS was confirmed in 6 patients: 4 with protein C and/or S deficiency and 2 without protein C and/or S deficiency. Further intervention consisted of angioplasty and stent placement was performed. Four patients with IVCS and protein C and/or S deficiency were included in this study. The immediate technical and clinical success rates were 100% in all 4 patients. There were no complications or clinically detectable pulmonary emboli. This initial experience suggests that endovascular management of iliofemoral DVT due to IVCS in patients with protein C and/or S deficiency is safe and effective.     

Reduced half-life of holocarboxylase synthetase from patients with severe multiple carboxylase deficiency

Multiple carboxylase deficiency is a clinical condition caused by defects in the enzymes involved in biotin metabolism, holocarboxylase synthetase (HLCS) or biotinidase. HLCS deficiency is a potentially fatal condition if left untreated, although the majority of patients respond to oral supplementation of 10-20 mg/day of biotin. Patients who display incomplete responsiveness to this therapy have a poor long-term prognosis. Here we investigated cell lines from two such HLCS-deficient patients homozygous for the c.647T>G p.L216R allele. Growth of the patients' fibroblasts was compromised compared with normal fibroblasts. Also the patient cells were not sensitive to biotin-depletion from the media, and growth rates could not be restored by re-administration of biotin. The molecular basis for the HLCS deficiency was further investigated by characterisation of the p.L216R protein. The HLCS mRNA was detected in MCD and normal cell lines. However, protein and enzyme activity could not be detected in the patients' cells. In vitro kinetic analysis revealed that enzyme activity was severely compromised for recombinantly expressed p.L216R and could not be increased by additional biotin. Furthermore, the turn-over rate for the mutant protein was double that of wildtype HLCS. These results help provide a molecular explanation for the incomplete biotin-responsiveness of this p.L216R form of HLCS.     

Properdin deficiency associated with recurrent otitis media and pneumonia, and identification of male carrier with Klinefelter syndrome

Properdin is an initiator and stabilizer of the alternative complement activation pathway (AP). Deficiency of properdin is a rare X-linked condition characterized by increased susceptibility to infection with Neisseria meningitidis associated with a high mortality rate. We report properdin deficiency in a large Pakistani family. The index cases were found by screening for immunodeficiency due to a history of recurrent infections. This revealed absent AP activity, but normal classical and lectin pathway activity. Sequencing of the properdin gene (PFC) revealed a novel frameshift mutation. When all available relatives (n = 24) were screened for the mutation, four affected males, four female carriers and a male heterozygous carrier were identified. He was subsequently diagnosed with Klinefelter syndrome. A questionnaire revealed a striking association between properdin deficiency and recurrent otitis media (P = 0.0012), as well as recurrent pneumonia (P = 0.0017).This study is the first to show a significant association between properdin deficiency and recurrent infections.     

Mutation in subdomain G' of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle

The mitochondrial translation system is responsible for the synthesis of 13 proteins required for oxidative phosphorylation (OXPHOS), the major energy-generating process of our cells. Mitochondrial translation is controlled by various nuclear encoded proteins. In 27 patients with combined OXPHOS deficiencies, in whom complex II (the only complex that is entirely encoded by the nuclear DNA) showed normal activities, and mutations in the mitochondrial genome as well as polymerase gamma were excluded, we screened all mitochondrial translation factors for mutations. Here, we report a mutation in mitochondrial elongation factor G1 (GFM1) in a patient affected by severe, rapidly progressive mitochondrial encephalopathy. This mutation is predicted to result in an Arg250Trp substitution in subdomain G' of the elongation factor G1 protein and is presumed to hamper ribosome-dependent GTP hydrolysis. Strikingly, the decrease in enzyme activities of complex I, III and IV detected in patient fibroblasts was not found in muscle tissue. The OXPHOS system defects and the impairment in mitochondrial translation in fibroblasts were rescued by overexpressing wild-type GFM1, establishing the GFM1 defect as the cause of the fatal mitochondrial disease. Furthermore, this study evinces the importance of a thorough diagnostic biochemical analysis of both muscle tissue and fibroblasts in patients suspected to suffer from a mitochondrial disorder, as enzyme deficiencies can be selectively expressed.