1/7. A novel 4-bp deletion creates a premature stop codon and dramatically decreases HEXB mRNA levels in a severe case of sandhoff disease.We present the molecular genetic analysis of an infantile-onset sandhoff disease patient. Genomic dna amplification, heteroduplex analysis, cloning and sequencing revealed a 4-bp deletion in exon 4 (497 DeltaAGTT). The result is a frameshift mutation that leads to a stop codon in exon 5. This mutation is associated with a dramatic decrease of HEXB mRNA levels.- - - - - - - - - - ranking = 1keywords = m, g, b (Clic here for more details about this article) |
2/7. Late-onset GM2 gangliosidosis presenting as burning dysesthesias.Two brothers with a painful neuropathy as a component of late-onset GM2 gangliosidosis of the Sandhoff type are presented. A dramatic response of the severe dysesthesias to amitriptyline and gabapentin is described. Symptomatic sensory neuropathy may be a component of late-onset GM2 gangliosidosis.- - - - - - - - - - ranking = 1777809.5074243keywords = gangliosidosis, m, g, b (Clic here for more details about this article) |
3/7. Molecular and structural studies of the GM2 gangliosidosis 0 variant.To determine the molecular basis of the GM2 gangliosidosis 0 variant, we constructed a three-dimensional structure of the human beta-hexosaminidase beta-subunit by homology modeling. It is composed of two domains, domains I and II, and has three disulfide bonds. C534 is located on an extra helix in domain II and forms a disulfide bond with C551. The extra helix is structurally located near domain I. C534Y, identified in a patient with the infantile form of the disease, was deduced to cause disruption of the disulfide bond, which results in a large conformational change of the extra helix, stabilizing the two domains. The drastic change in the protein structure results in a deficiency of the mature beta-subunit, and deficient activities of beta-hexosaminidases A (abeta) and B (betabeta), followed by abundant accumulation of GM2 ganglioside in the patient's cells. R505 is located on the eighth helix of domain II. R505Q, found in a patient with the chronic form of the disease, is predicted to influence the surface structure of the beta-subunit, although it does not affect the active site. The amino acid substitution causes a partial processing defect and decreased enzyme activities, which result in moderate accumulation of GM2 ganglioside in the patient's cells. The structural defects well reflect biochemical and phenotypic abnormalities of the disease.- - - - - - - - - - ranking = 1509728.9277313keywords = gangliosidosis, hexosaminidase, deficiency, m, g, b (Clic here for more details about this article) |
4/7. GM2 gangliosidosis variant B1 neuroradiological findings.Variant B1 is a rare type of GM2 gangliosidosis. Clinically, it shows a wide spectrum of forms ranging from infantile to juvenile. We report the first magnetic resonance imaging (MRI) findings from three patients affected by GM2 gangliosidosis variant B1, two presenting with the infantile form and one with the juvenile form. The MRI appearances of the two patients with the infantile form disease are congruent with those reported for the early-onset type of both Tay-Sachs and Sandhoff diseases, and are characterized by early involvement of the basal ganglia and thalamus with cortical atrophy appearing later. In contrast, the patient with the juvenile form of variant B1 showed progressive cortical and white-matter atrophy of the supratentorial structures and, to a lesser extent, the infratentorial structures. No basal ganglia or thalamic anomalies were observed. Because in the adult forms of both Tay-Sachs and Sandhoff diseases a progressive cerebellar atrophy represents the only abnormality detectable, it appears that an MRI pattern peculiar to GM2 gangliosidosis can be defined. This pattern ranges from the basal ganglia injury associated with the early and severe demyelination process noted in the infantile form of the disease, to cerebellar atrophy with no supratentorial anomalies in the adult form. An "intermediate" MRI picture, with cortical atrophy and mild cerebellar atrophy, but without basal ganglia impairment, can be observed in the juvenile form. In addition, our investigations suggest that MRI abnormalities in GM2 gangliosidosis correlate with the clinical form of the disease rather than with the biochemical variant of the enzymatic defect.- - - - - - - - - - ranking = 2370413.9687212keywords = gangliosidosis, m, g, b (Clic here for more details about this article) |
5/7. Unusual presentation of GM2 gangliosidosis mimicking a brain stem tumor in a 3-year-old girl.We report a case of GM2 gangliosidosis revealed by MR imaging of an isolated brain stem abnormality in a 3-year-old girl referred for gait difficulties related to ataxia and pyramidal signs. Brain MR imaging displayed a brain stem lesion with high signal intensity on fluid-attenuated inversion recovery and T2-weighted images, suggesting either a tumor or an inflammatory process. Stereotactic biopsy findings showed the presence of swollen neurons with storage material in lysosomes. Enzyme study revealed deficiency of hexosaminidase a, variant B1. gangliosidoses should be considered in the differential diagnosis of isolated infiltrating brain stem lesions in childhood.- - - - - - - - - - ranking = 1495619.5293411keywords = gangliosidosis, hexosaminidase, deficiency, m, g, b (Clic here for more details about this article) |
6/7. Severe subacute GM2 gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mRNA.We have characterized the molecular basis of beta-hexosaminidase a (HEX A) deficiency in a patient ascertained through an ophthalmologic examination that revealed cherry red spots on his retina. The absence of neurological deficit in this child until 3 3/4 years of age indicated residual HEX A must be present. Three HEXA mutations, 10T > C (S4P) and 972T > A (V324V) on the maternal allele, and 1A > T (M1L) on the paternal allele were identified. The effects of the amino acid substitutions on HEX A expressed in COS-7 cells were analyzed; as expected, no HEX A activity was associated with the M1L mutation but surprisingly, the S4P mutation resulted in 59% of the HEX A activity expressed by the wild type cDNA. The effect of the S4P change was much less than that of another HEXA mutation, G269S, associated with an adult onset form of G(M2) gangliosidosis. This indicated that the S4P change was not the cause of disease and suggested that one of the mutations on the maternal allele, 10T > C or 972T > A, had its effect at the mRNA level. This was confirmed by Northern blot analysis that showed only 7% of the normal level of HEXA mRNA in proband fibroblasts. Analysis of the residual mRNA by RT/PCR and sequencing revealed normal transcripts from both the maternal and paternal allele, as well as a low abundance aberrant transcript from the maternal allele. Sequencing of this aberrant transcript revealed a new exon 8 donor site created by the 972T > A mutation that resulted in a 17 bp deletion and destabilization of the resulting abnormal transcript. The remaining normal mRNA produced from the 972T > A allele must account for the delayed onset of clinical symptoms in this child.- - - - - - - - - - ranking = 1495620.0007829keywords = gangliosidosis, hexosaminidase, deficiency, m, g, b (Clic here for more details about this article) |
7/7. The natural history of cognitive dysfunction in late-onset GM2 gangliosidosis.BACKGROUND: Late-onset GM2 gangliosidosis (LGG) is a rare disease that is often considered in the differential diagnosis of adolescents and young adults who present with multiple realms of neurologic dysfunction. Cognitive disturbances are common but have not been systematically studied. OBJECTIVE: To determine the natural history of cognitive dysfunction in patients with LGG. DESIGN: Case series and literature review. SETTING: Urban tertiary referral clinic. patients: Individuals with hexosaminidase a deficiency as the origin of LGG. MAIN OUTCOME MEASURES: Cognitive dysfunction, psychiatric symptoms, and cerebellar, upper motor neuron, lower motor neuron, or extrapyramidal symptoms and signs. RESULTS: Historical and examination data from 62 patients were found. Forty-four percent of LGG patients had some degree of cognitive dysfunction. Cognitive dysfunction was associated with a greater number of other elemental neurologic deficits. In 21 patients with acceptable longitudinal information, 8 (38%) had a static cognitive disorder, whereas progressive dementia was evident in 13 patients (62%), including 2 of our cases with serial neuropsychological testing. neuroimaging often showed nonspecific cerebellar and/or cerebral atrophy. CONCLUSIONS: Cognitive dysfunction is a frequent manifestation of LGG. patients who experience cognitive dysfunction are more likely to have a greater number of other neurologic manifestations of the disease. Cognitive dysfunction may take the form of static encephalopathy, but progressive dementia is more often encountered. The pathogenesis of cognitive dysfunction in this disease is unknown, highlighting the need for further study.- - - - - - - - - - ranking = 1495619.5937153keywords = gangliosidosis, hexosaminidase, deficiency, m, g, b (Clic here for more details about this article) |