Bilateral optic pathway glioma with intracranial calcification: Magnetic resonance imaging and magnetic resonance spectroscopy findings

Optic nerve glioma is the most common primary neoplasm of the optic nerve in childhood. It can extend intracranially along the optic pathway (optic pathway glioma). The lesion tends to present with decreased visual acuity in the affected eye, but can cause additional symptoms when it is large. Local involvement within the orbit can be characterized using CT, but MRI is superior in showing the intracranial extent of the lesion. Intracranial calcification in optic pathway glioma is rare. We present a rare case of optic pathway glioma with calcification in the intracranial component. Also, we describe MR spectroscopy (MRS) findings in this case.     

Hepatic Met‐enkephalin immunoreactivity is enhanced in primary biliary cirrhosis

Abstract: Background/aims: In contrast to the normal adult liver, the fetal human and rat livers, and the liver of rats with cholestasis secondary to bile duct resection (BDR) express the preproenkephalin (ppENK) mRNA, which codes for the endogenous opioid peptide Met‐enkephalin. In addition, Met‐enkephalin immunoreactivity (MEIR) is detected in hepatocytes and in proliferating bile ductules in the cholestatic rat liver. These data suggest that cholestasis is associated with the resurgence of cells that produce Met‐enkephalin. To explore further the status of opioids in cholestasis, we studied the expression of MEIR in liver tissue. Methods: The MEIR was sought in paraffin‐preserved liver tissues from patients with primary biliary cirrhosis (PBC) (n = 10). Results: The MEIR was detected in all the PBC livers. Its intensity varied from weak to strong on hepatocytes and bile ducts and the strongest expression appeared as coarse granules. The MEIR was either absent or only faintly expressed by some hepatocytes from disease and nondisease control biopsies, but absent from bile ducts. Conclusion: These results suggest that the human liver in cholestasis may be a source of endogenous opioids.     

Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutations

Spondylocostal dysostoses (SCD) are a heterogeneous group of disorders of axial skeletal malformation characterized by multiple vertebral segmentation defects and rib anomalies. Sporadic cases with diverse phenotypes, sometimes including multiple organ abnormalities, are relatively common, and monogenic forms demonstrating autosomal recessive (AR) and, more rarely, autosomal dominant (AD) inheritance have been reported. We previously showed that mutations in delta-like 3 (DLL3), a somitogenesis gene that encodes a ligand for the notch signaling pathway, cause AR SCD with a consistent pattern of abnormal segmentation. We studied an SCD family previously reported to show AD inheritance, in which the phenotype is similar to that in AR cases. Direct DLL3 sequencing of individuals in two generations identified the affected father as homozygous for a novel frameshift mutation, 1440delG. His two affected children were compound heterozygotes for this mutation and a novel missense mutation, G504D, the first putative missense mutation reported in the transmembrane domain of DLL3. Their two unaffected siblings were heterozygotes for the 1440delG mutation. Pseudodominant inheritance has been confirmed, and the findings raise potential consequences for genetic counseling in relation to the SCD disorders.     

Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age- related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G- >T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G- >A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.      

The Mitochondrial Genome And Human Mitochondrial Diseases

To date, more than 100 point mutations and several hundreds of structural rearrangements of mitochondrial DNA (mtDNA) are known too be connected with characteristic neuromuscular and other mitochondrial syndromes varying from those causing death at the neonatal stage to diseases with late ages of onset. The immediate cause of mitochondrial disorders is a defective oxidative phosphorylation. Wide phenotypic variation and the heteroplasmy phenomenon, which some authors include in mutation load, are characteristic of human mitochondrial diseases. As the numbers of cases identified and pedigrees described increase, data on the genotype-phenotype interaction and the structure and frequency of pathogenic and conditionally pathogenic mtDNA mutations in human populations are rapidly accumulated. The data on the genetics and epidemiology of mitochondrial diseases are not only important for differential diagnosis and genetic counseling. Since both neutral and mildly pathogenic mutations of mtDNA are progressively accumulated in maternal phyletic lines, molecular analysis of these mutations permits not only reconstruction of the genealogical tree of modern humans, but also estimation of the role that these mutations play in natural selection.     

Population pharmacokinetics of enfuvirtide in HIV-1-infected pediatric patients over 48 weeks of treatment

The objective of this study was to characterize the population pharmacokinetics of enfuvirtide in HIV-1-infected children and adolescents. HIV-infected patients received combination antiretroviral therapy, including enfuvirtide 2.0 mg/kg subcutaneously, twice daily. Serial and trough blood samples were collected up to 48 weeks. NONMEM was used for population pharmacokinetic analysis. Enfuvirtide exposure was calculated from individual parameter estimates derived from the final model. A total of 218 samples from 43 patients were included in the analysis. Enfuvirtide plasma concentration-time data were described by a 1-compartment model with first-order absorption and elimination. The addition of each subject's actual body weight as a covariate affected CL/F but not V/F or K(a). The population CL/F, V/F, and K(a) for a 33-kg reference patient was 1.31 L/h, 2.31 L, and 0.105 h(-1), respectively. The final model was CL/F (L/h) = 1.31 . (body weight/33 [kg])(0.721). Age did not affect enfuvirtide exposure. These results confirm the appropriateness of body weight-based pediatric enfuvirtide dosing.