ABSTRACT
We have identified three mutations in the beta-hexoseaminidase A (HEXA) gene in a juvenile Tay-Sachs disease (TSD) patient, which exhibited a reduced level of HEXA mRNA. Two mutations are novel, c.814G>A (p.Gly272Arg) and c.1305C>T (p.=), located in exon 8 and in exon 11, respectively. The third mutation, c.1195A>G (p.Asn399Asp) in exon 11, has been previously characterized as a common polymorphism in African-Americans. Hex A activity measured in TSD Glial cells, transfected with HEXA cDNA constructs bearing these mutations, was unaltered from the activity level measured in normal HEXA cDNA. Analysis of RT-PCR products revealed three aberrant transcripts in the patient, one where exon 8 was absent, one where exon 11 was absent and a third lacking both exons 10 and 11. All three novel transcripts contain frameshifts resulting in premature termination codons (PTCs). Transfection of mini-gene constructs carrying the c.814G>A and c.1305C>T mutations proved that the two mutations result in exon skipping. mRNAs that harbor a PTC are detected and degraded by the nonsense-mediated mRNA decay (NMD) pathway to prevent synthesis of abnormal proteins. However, although NMD is functional in the patient's fibroblasts, aberrant transcripts are still present. We suggest that the level of correctly spliced transcripts as well as the efficiency in which NMD degrade the PTC-containing transcripts, apparently plays an important role in the phenotype severity of the unique patient and thus should be considered as a potential target for drug therapy.
Subject(s)
Alternative Splicing , Hexosaminidase A/genetics , RNA Stability/genetics , Tay-Sachs Disease/genetics , Adolescent , Adult , Child , Child, Preschool , Exons , Female , Humans , Point MutationSubject(s)
Aged , Health Education , Health Promotion , Chicago , Female , Humans , Male , Social Work Department, HospitalABSTRACT
Legg-Calvé-Perthes disease affects children, mostly boys, in the age range of 3 to 12 years. Severity and duration are quite variable. Catterall's classification of disease according to degree of femoral head involvement is of real prognostic value. Other factors of prognostic importance are loss of motion, metaphyseal cysts, subluxation and extrusion, and involvement of the epiphyseal plate, all of which are associated with poor results. Patients with Catterall group I involvement require no specific treatment as long as motion is normal. For patients under 6 years of age with group II involvement, specific efforts to contain the femoral head do not appear to bb indicated. In all other patients, maximum effort should be made to achieve containment of the femoral head and maintain full range of motion. Surgery has been used for reconstruction and as an alternative method of containment.
Subject(s)
Legg-Calve-Perthes Disease , Osteochondritis , Bed Rest , Child , Child, Preschool , Female , Femur Head/physiopathology , Follow-Up Studies , Humans , Legg-Calve-Perthes Disease/diagnostic imaging , Legg-Calve-Perthes Disease/physiopathology , Legg-Calve-Perthes Disease/therapy , Male , Orthopedic Fixation Devices , Osteochondritis/diagnostic imaging , Osteotomy , Radiography , Sex Factors , TractionABSTRACT
Catterall's classification of Legg-Calvé-Perthes disease is of prognostic value. When indicated, early energetic treatment in the form of containment and achievement of a full range of motion significantly decreases the percentage of poor results.
Subject(s)
Legg-Calve-Perthes Disease/therapy , Osteochondritis/therapy , Child , Female , Humans , Legg-Calve-Perthes Disease/classification , Legg-Calve-Perthes Disease/diagnosis , Legg-Calve-Perthes Disease/physiopathology , Male , Movement , Orthopedic Fixation Devices , Prognosis , Rest , TractionABSTRACT
Seven cases of osteochondritis dissecans following Legg-Calvé-Perthes disease are presented and the literature is reviewed. This complication could not be predicted during the early stages of the Legg-Calvé-Perthes process. A high index of suspicion is necessary to recognize the lesion. Conservative treatment is suggested.