Focus on genetic modifiers of polyglutamine diseases / 中华神经科杂志

Polyglutamine (PolyQ) diseases are a group of clinically and genetically heterogeneous neurodegenerative diseases, due to an expanded CAG repeat in a coding region of the respective genes leading to neurodegenerative phenotypes by selective neuronal loss. Overall, only part of variance (50%-70%) in age at onset is explained by (CAG)n length, suggesting genetic modifying factors independent of (CAG)n size may contribute to clinical heterogeneity. Here, the research history of genetic modifiers in polyQ diseases is reviewed, and the major findings and current research status are discussed.

The Analysis of Clinical Manifestations in a Large SCA3 Pedigree / 中国神经精神疾病杂志

Objective To analysis the clinical manifestations of a large Spinocerebellar Ataxia 3 pedigree to pro-vide the information for the early diagnosis of Ataxia 3. Methods SCA3/ATXN3 gene was determined by using Poly-merase Chain Reaction and fragment analysis in the large pedigree members and patients ’clinical data was collected. Five patients underwent MRI imaging and fundus examination. Results There were eighteen clinical patients and twelve ATXN3 carriers in this Pedigree . In addition to ataxia, three patients presented with intellectual disability, one with cer-vical spondylosis, one with dysmyotonia, one with disorder in visual system, and seven with abnormality in autonomic ner-vous system. The MRI revealed that pons and cerebellar atrophy in some patients inordinately. Undus examination did not reveal any obvious abnormality. Conclusions The symptoms of SCA3 are heterogeneous in the same pedigree. When patients present with symptoms of cerebellar system, visual system and autonomic nervous system, or cervical spondylosis and intellectual disability, SCA3 should be considered.

Non-Ataxic Phenotypes of SCA8 Mimicking Amyotrophic Lateral Sclerosis and Parkinson Disease

BACKGROUND: Spinocerebellar ataxia (SCA) type 8 (SCA8) is an inherited neurodegenerative disorder caused by the expansion of untranslated CTA/CTG triplet repeats on 13q21. The phenomenology of SCA8 is relatively varied when compared to the other types of SCAs and its spectrum is not well established. CASE REPORT: Two newly detected cases of SCA8 with the nonataxic phenotype and unusual clinical manifestations such as dopaminergic-treatment-responsive parkinsonism and amyotrophic lateral sclerosis (ALS) are described herein. Family A expressed good dopaminergic treatment-responsive parkinsonism as an initial manifestation and developed mild cerebellar ataxia with additional movements, including dystonic gait and unusual oscillatory movement of the trunk, during the disease course. The proband of family B presented as probable ALS with cerebellar atrophy on brain MRI, with a positive family history (a brother with typical cerebellar ataxia) and genetic confirmation for SCA8. CONCLUSIONS: Our findings support that the non-ataxic phenotypes could be caused by a mutation of the SCA8 locus which might affect neurons other than the cerebellum.

Erythrocyte Membrane Protein Alterations by SDS-PAGE and Underlying Clinical Heterogeneity in Hereditary Spherocytosis / 대한소아혈액종양학회지

BACKGROUND: Hereditary spherocytosis(HS) is a clinically and biochemically very heterogeneous disorder The purpose of this study is to detect erythrocyte membrane protein abnormalities by SDS-PAGE and to investigate the frequency of erythrocyte membrane protein defects in hereditary spherocytosis and correlation between some of the hereditary spherocytosis biochemical subsets and the selected clinical phenotype. METHODS: We evaluated the clinical and laboratory characteristics of 14 normal healthy persons and 23 hereditary spherocytosis patients and 8 their family members. The patients were divided into three groups based on clinical and hematological severity(mild, typical, severe). In addition to routine hematologic determlnatlons, osmotic fragility and autohemolysis, RBC membrane protein analysis were performed in all patients by densitometric tracing of SDS-PAGE(sodium dodecyl sulphate polyacrylamide gel electrophoresis) stained by Coomassle blue utilizing both the discontinuous buffer system of Laemmli with acrylamide linear gradient from 4% to 12% and the continuous buffer system of Fairbank with exponential gradient of acrylamide from 3.5% to 17%. RESULTS: 1) The patients could be seperated into three classes of different clinical severity as mild(3 cases), moderate(16 cases) and severe(4 cases) on the clinical feature. 2) Eighteen patients(82.6%) among 23 hereditary spherocytosis revealed abnormal erythrocyte membrane protein and we detected six patients(26.1%) with spectrin deficiency combined with ankyrin reduction, 4 patients(17.4%) with ankyrin deficiency, 4 patients(17.4%) with isolated spectrin deficiency and 3 patients(13.0%) with band 3 deficiency. Five HS patients(21.7%) showed normal RBC membrane protein. 3) Eight HS and their family members showed same RBC membrane protein deficiency. 4) The type and degree of RBC membrane protein reduction were variale with spectrin at 66~94%, with ankyrin at 48~82% of normal levels. These showed that each patient had different clinical severities according to different RBC membrane protein levels and type. CONCLUSION: RBC membrane protein abnormalities were observed in 82.6% of HS patients. The combined spectrin and ankyrin deficiency is the most common molecular defect in HS. The clinical severity and biochemical expression is heterogeneous. SDS-PAGE analysis of RBC membrane protein was provided the diagnosis of RBC membrane defects and basic molecular studies. We believed that the early identification of the biochemical defect responsible for HS is important because it is helpful starling point for the identification of the primary molecular defect, and it could help to anticipate the clinical outcome of the disease. For these reasons, we consider the SDS-PAGE of the red cell membrane to be of crucial importance for a complete evaluation of children with HS. Further studies with more cases would be to clarify the correlation between clinical and biochemical phenotypes.