Biomarkers in lysosomal storage diseases: a review

A biomarker is generally an analyte that indicates the presence or extent of a biological process, which is itself directly linked to the clinical manifestations and outcome of a particular disease. An ideal biomarker provides indirect but ongoing and specific determinations of disease activity. These characteristics emphasize the value of surrogate biomarkers for non-invasive and detailed monitoring to demonstrate the efficacy of orphan drugs in clinical trials. The emergence of novel laboratory methods has facilitated the search for biomarkers in lysosomal storage diseases (LSDs), by allowing the systematic identification of molecules whose expression is altered as a result of the primary storage pathology. In Gaucher disease, for example, a chemokine, CCL18, has been identified as a biomarker for clinical development that reflects disease severity and response to treatment.
Conclusion: New methods for the identification of novel biomarkers have the potential to provide mechanistic insights into the molecular pathogenesis of LSDs, including Fabry disease and Gaucher disease.     

A Pro51Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects

We analysed a Dutch family with autosomal dominant non-syndromic progressive sensorineural hearing loss and mapped the underlying gene defect by genetic linkage analysis to a 11.0 cM region overlapping the DFNA9 interval on chromosome 14q12-q13. Clinically, the Dutch family differs from the original DFNA9 family by a later age at onset and a more clearly established vestibular impairment. A gene that is highly and specifically expressed in the human fetal cochlea and vestibule, COCH (previously described as Coch5B2 ), was mapped to the DFNA9 critical region. Sequence analysis revealed a 208C-->T mutation in the COCH gene, resulting in a Pro51Ser substitution in the predicted protein in all affected individuals of the family but not in unaffected family members and 200 control individuals. The same mutation was also identified in three apparently unrelated families with a similar phenotype, suggesting the presence of a Dutch founder mutation. The function of COCH is unknown but several characteristics of the protein point to a structural role in the extracellular matrix. The mutant serine at position 51 is situated between cysteines and possibly interferes with proper COCH protein folding or its interaction with extracellular matrix proteins.      

Regulatory and methodologic challenges to tocolytic development

The development of tocolytic medications faces challenges common to all drug development programmes, principally related to evolving understanding of the pathophysiology. There are unique impediments to drug development for pregnancy-related conditions in general and for tocolysis in particular. The purpose of this brief overview is to familiarise the obstetrician with the current challenges to drug development, focusing in particular on the problems of tocolytic development. A strategy for encouraging drug development for preterm labour and for pregnancy-related problems in general is presented.     

Gastric trichobezoar: sonographic findings

Ultrasonographic diagnosis of trichobezoar may be relatively specific. A broad band of high-amplitude echoes can be seen superficially, with complete sonic shadowing behind. The authors describe a patient in whom the diagnosis was made prior to conventional barium studies and in whom the question of trichobezoar had not been raised clinically.     

Nontuberculous mycobacterial infection in AIDS: clinical, pathologic, and radiographic features

The medical records, radiographs, and pathologic specimens of ten patients with the diagnoses of nontuberculous mycobacterial infection and acquired immunodeficiency syndrome (AIDS) were examined. The radiographic findings of alveolar or nodular infiltrates and adenopathy were relatively nonspecific but in most cases led to bronchoscopic study or open-lung biopsy, which established the diagnosis. Bronchoscopic washings or sputum cultures, which frequently provided the first confirmation of infection, were always followed by positive blood or tissue cultures. In contrast to nontuberculous infection in immunocompetent hosts, disseminated infection was common, with evidence of extrapulmonary involvement in nine patients. On the basis of these findings, we recommend that any AIDS patient with sputum or bronchoscopic washings demonstrating nontuberculous mycobacterial organisms be tentatively classified as having disseminated infection while being evaluated with blood, bone-marrow, stool, and urine cultures, even if the chest radiograph shows no disease.