Autosomal dominant spinocerebellar ataxias ad infinitum?
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Genotype↗
Biomedical subjects
S H Subramony
Publications and source records attributed to S H Subramony.
A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy.
BACKGROUND: Central core disease (CCD) and nemaline rod myopathy are generally considered two genetically and histologically distinct disorders. CCD is defined by the presence of well-demarcated round cores within most myofibers. Nemaline rod myopathy is distinguished by the presence of characteristic nemaline bodies within myofibers. The simultaneous occurrence of both cores and rods in the same muscle biopsy has been described, but no gene mutations have been reported yet for this condition. OBJECTIVE: To describe a family containing 16 affected individuals in six generations with an autosomal dominant congenital myopathy that shows clinical and histologic features of both CCD and nemaline myopathy, and to determine the genetic etiology and protein composition of the cores/rods in this family. METHODS AND RESULTS: The results of linkage analyses excluded involvement of the two autosomal dominant nemaline myopathy loci on chromosome 1, but were consistent with a localization of the disease gene at the CCD locus on chromosome 19q13.1 (ryanodine receptor). SSCP analysis and DNA sequencing identified a novel Thr4637Ala mutation in the transmembrane region of the ryanodine receptor protein. Immunofluorescence studies of patient muscle biopsies showed the central cores to stain for ryanodine receptor. CONCLUSIONS: These data suggest that the occurrence of nemaline bodies can be a secondary feature of CCD, and that genetic studies on previously reported core/rod families should be targeted to the ryanodine receptor locus. The results of the immunofluorescence studies suggest that the cores contain excess abnormal ryanodine receptor protein.
Adolescent↗
Relationship between ataxin-1 nuclear inclusions and Purkinje cell specific proteins in SCA-1 transgenic mice.
Spinocerebellar ataxia-1 (SCA-1), like other polyglutamine diseases, is associated with aggregation of mutant protein ataxin-1 in the nuclei of susceptible neurons. The role of ataxin-1 aggregates in the pathogenesis of susceptible neurons, especially cerebellar Purkinje cells, is unknown. The present study was initiated to determine the temporal relationship between ataxin-1 aggregation and the sequence of specific biochemical changes in Purkinje cells in SCA-1 transgenic mice (TM). Earlier, we demonstrated that SCA-1 TM with no Purkinje cell loss and no alterations in home cage behavior show decreased expression of calcium-binding proteins calbindin-D28k (CaB) and parvalbumin (PV) in Purkinje cells. To determine if increased expression of mutant ataxin-1 in TM is also associated with earlier biochemical changes in Purkinje cells, both heterozygous and homozygous (B05 line of SCA-1) TM were used. The age of onset of ataxia in SCA-1 TM was at 12 weeks in heterozygotes and 6 weeks in homozygotes. In 6 week old heterozygous TM, Western blot analysis of growth associated protein 43 (GAP-43) and synaptophysin revealed no significant alterations as compared with the age-matched nontransgenic mice (nTM), whereas CaB was significantly reduced. beta-III-Tubulin was used as a specific Purkinje cell marker protein, immunohistochemical localization showed strong beta-III-tubulin immunoreactivity (IR) in Purkinje cells in 6 week old heterozygous TM, whereas CaB and PV IR were markedly reduced in the same neurons (double immunofluorescence staining). Most Purkinje cells from heterozygous (12 weeks old) and homozygous (6 weeks old) TM contained ataxin-1 nuclear inclusions (NIs). Cells with and without visible NIs revealed reduced PV and CaB IR; however, the changes were overtly more severe in cells with visible NIs. In contrast, the same cells were strongly immunoreactive to beta-III-tubulin. CaB, which is also present in the nucleus, colocalized with ataxin-1 and ubiquitin positive NIs. Further, RT-PCR analysis of CaB mRNA in the cerebellum in 6 week old heterozygous TM demonstrated a significant decrease in mRNA in comparison with the aged-matched nTM. These data suggest that there are selective alterations in the expression of CaB and PV in Purkinje cells which possibly occur earlier than ataxin-1 aggregation. Further, we speculate that ataxin-1 aggregates may not be toxic in general; however, they may deplete specific proteins essential for Purkinje cell viability in SCA-1 TM.
Animals↗
Dominantly inherited ataxias.
Molecular genetic studies in the past decade have demonstrated the enormous genetic heterogeneity among the dominantly inherited ataxias. Mutations at several distinct loci give rise to the progressive dominant ataxias and at least 2 different mutations cause episodic ataxias with dominant inheritance. The well-established genotypes for progressive dominant ataxias have all involved expansions of repeated CAG sequences. Clinically these patients present with progressive cerebellar deficits as well as signs relating to pathology in other neural systems in a variable fashion. Some of these other signs serve as diagnostic clues to the underlying genotype, but the identification of the genotype from the clinical phenotype alone is usually difficult. The CAG expansions involved usually are unstable with intergenerational expansions as well as contractions of the repeat size. Phenotypic features such as age of onset and to a lesser extent disease progression rate and the presence of specific clinical signs depend on the CAG repeat size. Identification of the mutations has allowed precise genotypic diagnosis in several families allowing more accurate genetic counseling, including predictive testing of at risk individuals when sought. Also, increasing information about the gene products and their abnormal distributions in disease brain is rapidly giving rise to rational ideas about the pathogenesis of neuronal degeneration in these diseases and raising hope for meaningful treatment strategies.
Ataxia↗
The effects of calbindin D-28K and parvalbumin antisense oligonucleotides on the survival of cultured Purkinje cells.
The role of calcium binding proteins, calbindin D-28k (CaB) and parvalbumin (PV) in Purkinje cell survival was investigated using oligonucleotide antisense strategy. Purkinje cell enriched cultures were prepared from the cerebella of 0-1 day old Balb/c mouse pups. Purkinje cells were identified by size, asymmetric arbors, immunoreactivity to CaB and PV, uptake of gamma-aminobutyric acid (GABA) and failure to express glial fibrillary acidic protein. The cells at different days in vitro were treated with antisense or mismatched antisense phosphorothioate oligonucleotides for CaB and PV mRNA (complexed with lipofectin). Neuronal specific [3H]-GABA uptake was used as a measure of Purkinje cell survival. The cultures treated for 24 h with antisense oligos (CaB+PV) showed a significant decrease in [3H]-GABA uptake as compared with the cultures treated with lipofectin alone or with lipofectin + mismatched antisense oligos to CaB and PV mRNA. The results of the present study suggest that the expression of calcium buffering proteins CaB and PV may have a significant involvement in Purkinje cell viability.
Animals↗
Lethal neonatal autosomal recessive axonal sensorimotor polyneuropathy.
Peripheral neuropathy is an uncommon cause of generalized hypotonia and weakness in infancy. It occurs as a part of the clinical syndrome in some neurodegenerative disorders of infancy, but seldom causes respiratory failure or swallowing difficulties. We report a lethal autosomal recessive axonal polyneuropathy with neonatal onset in a large kindred from Northern Mississippi. One patient was studied in detail at our medical center and the information on 12 other affected infants in this large family were gathered from medical records and by interviewing the family members. Patients were symptomatic for the polyneuropathy before birth and died in the first year of life from respiratory complications. Thirteen babies were affected by this clinical phenotype in four generations of this family with a high frequency of consanguinity. Affected babies were of both sexes and were born to healthy consanguineous parents. The clinical phenotype of polyneuropathy in our index patient and other affected babies in this family was similar, and represents a unique form of hereditary neonatal polyneuropathy.
Age of Onset↗
Reduced immunoreactivity to calcium-binding proteins in Purkinje cells precedes onset of ataxia in spinocerebellar ataxia-1 transgenic mice.
Earlier we have shown alterations in immunoreactivity (IR) to the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CaB) in surviving Purkinje cells of patients with spinocerebellar ataxia-1 (SCA-1). In the present study we determined PV and CaB expression (by immunohistochemical and immunoblot analyses) in Purkinje cells of transgenic mice (TM) expressing the human SCA-1 gene with an expanded (line B05) and normal (line A02) CAG tract, as well as in age-matched nontransgenic mice (nTM). Heterozygotes in the B05 line develop progressive ataxia beginning around 12 weeks of age. A02 animals are phenotypically indistinguishable from wild-type (nontransgenic) animals. In the cerebella of 8-, 9-, and 12-week-old TM-B05 there was a progressive decrease in PV IR in Purkinje cells compared with nTM and TM-A02. Parvalbumin immunostaining in interneurons was well preserved in all groups. A progressive decrease was also observed in CaB IR in Purkinje cells of 8-, 9-, and 12-week-old TM-B05. Cerebellar Purkinje cells of 6-week-old TM-B05, which exhibit no ataxia and even lack demonstrable Purkinje cell loss, also revealed reduction in PV IR. This change was matched by a significant decrease in the amount of cerebellar PV in 6-week-old TM-B05 as determined by Western blot analysis. Calbindin D-28K immunohistochemistry did not detect any marked changes in CaB IR within Purkinje cells at 4 weeks. However, at 6 weeks immunostaining and immunoblot analysis revealed a significant decrease in CaB in TM-B05 compared with controls. These data suggest that decreased levels of calcium-binding proteins in Purkinje cells in SCA-1 transgenic mice may cause alteration in Ca2+ homeostasis.
Alleles↗
International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology.
Despite the involvement of cerebellar ataxia in a large variety of conditions and its frequent association with other neurological symptoms, the quantification of the specific core of the cerebellar syndrome is possible and useful in Neurology. Recent studies have shown that cerebellar ataxia might be sensitive to various types of pharmacological agents, but the scales used for assessment were all different. With the long-term goal of double-blind controlled trials-multicentric and international-an ad hoc Committee of the World Federation of Neurology has worked to propose a one-hundred-point semi-quantitative International Cooperative Ataxia Rating Scale (ICARS). The scale proposed involves a compartimentalized quantification of postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders, in order that a subscore concerning these symptoms may be separately studied. The weight of each symptomatologic compartment has been carefully designed. The members of the Committee agreed upon precise definitions of the tests, to minimize interobserver variations. The validation of this scale is in progress.
Cerebellar Ataxia↗
Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3.
The mechanism of neurodegeneration in CAG/polyglutamine repeat expansion diseases is unknown but is thought to occur at the protein level. Here, in studies of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), we show that the disease protein ataxin-3 accumulates in ubiquitinated intranuclear inclusions selectively in neurons of affected brain regions. We further provide evidence in vitro for a model of disease in which an expanded polyglutamine-containing fragment recruits full-length protein into insoluble aggregates. Together with recent findings from transgenic models, our results suggest that intranuclear aggregation of the expanded protein is a unifying feature of CAG/polyglutamine diseases and may be initiated or catalyzed by a glutamine-containing fragment of the disease protein.
Glutamine↗
Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel.
A polymorphic CAG repeat was identified in the human alpha 1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21-27) compared to the number of repeats (4-16) in 475 non-ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human alpha 1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human alpha 1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
Alleles↗
Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or Dentato-Rubro-Pallido-Luysian atrophy locus.
The dominantly inherited ataxias are characterized both by phenotypic variability (phenotypic heterogeneity) within the same genotype and overlapping phenotypes from different genotypes (genotypic heterogeneity). Therefore it is important to characterize specific clinical-neuropathologic phenotypes as precisely as possible at the genetic level. We describe a family with dominantly inherited ataxia of late adult onset with relatively "pure" cerebellar signs. Neuropathologic examination in two individuals from this family revealed findings consistent with cerebello-olivary atrophy, suggesting that this neuropathologic phenotype many run true within f families. Mutations at the spinocerebellar ataxia-I, Machado-Joseph disease, and dentatorubropallidoluysian atrophy loci were excluded by direct DNA analysis on the leukocytes of one living affected member. Thus we provide evidence that these mutations are not responsible for this particular phenotype of dominantly inherited ataxia.
Adult↗
Intrafamilial variability in Machado-Joseph disease.
Dominantly inherited ataxias resulting from different gene mutations are difficult to distinguish based on clinical phenotypes. We believe the phenotypic variability within families can be a clue to clinical diagnosis. We illustrate the range of phenotypes extending from levodopa-responsive extrapyramidal disease to more purely ataxic syndromes seen in two families with molecularly proven Machado-Joseph disease.
Adult↗
A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness.
In 1960, progressive sensorineural deafness (McKusick 304,700, DFN-1) was shown to be X-linked based on a description of a large Norwegian pedigree. More recently, it was shown that this original DFN-1 family represented a new type of recessive neurodegenerative syndrome characterized by postlingual progressive sensorineural deafness as the first presenting symptom in early childhood, followed by progressive dystonia, spasticity, dysphagia, mental deterioration, paranoia and cortical blindness. This new disorder, termed Mohr-Tranebjaerg syndrome (referred to here as DFN-1/MTS) was mapped to the Xq21.3-Xq22 region2. Using positional information from a patient with a 21-kb deletion in chromosome Xq22 and sensorineural deafness along with dystonia, we characterized a novel transcript lying within the deletion as a candidate for this complex syndrome. We now report small deletions in this candidate gene in the original DFN-1/MTS family, and in a family with deafness, dystonia and mental deficiency but not blindness. This gene, named DDP (deafness/ dystonia peptide), shows high levels of expression in fetal and adult brain. The DDP protein demonstrates striking similarity to a predicted Schizosaccharomyces pombe protein of no known function. Thus, is it likely that the DDP gene encodes an evolutionarily conserved novel polypeptide necessary for normal human neurological development.
Abnormalities, Multiple↗
Decreased parvalbumin immunoreactivity in surviving Purkinje cells of patients with spinocerebellar ataxia-1.
The distribution of two calcium-binding proteins, calbindin D28k (CaBP) and parvalbumin (PV), was investigated by immunohistochemistry in the brains of three individuals dying of nonneurologic illness and three patients with spinocerebellar ataxia-1 (SCA-1). SCA-1 has recently been proven to be due to an unstable CAG repeat mutation on chromosome 6. In the cerebellum of control individuals the Purkinje cells showed strong immunoreactivity to CaBP. Other cells were CaBP-negative. Parvalbumin was highly localized to Purkinje, basket, stellate, and Golgi cells. All surviving Purkinje cells in SCA-1 were strongly immunoreactive to CaBP. The number of PV-immunoreactive Purkinje cells was markedly reduced in SCA-1. In addition, there was a significant decrease in the intensity of PV immunostaining within the individual Purkinje cells compared with controls. However, in the hippocampus, temporal cortex, and lateral geniculate scattered PV-positive neurons were seen in SCA-1 patients, similar to those in controls. The present results suggest that the decreased PV-immunoreactivity in the surviving Purkinje cells in SCA-1 may reflect biochemical alterations preceding Purkinje cell degeneration.
Humans↗
Genotypes and phenotypes.
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Cerebellar Ataxia↗
Treatment of hereditary ataxia with the levorotatory form of hydroxytryptophan.
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5-Hydroxytryptophan↗
Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease.
The autosomal dominant spinocerebellar ataxias are clinically and genetically a heterogeneous group of neurodegenerative disorders. Genetic studies have classified some of these disorders based on the mapping of their respective genes. The gene for Machado-Joseph disease, one type of spinocerebellar ataxia, has been mapped to the long arm of chromosome 14q24.3-ter. The gene for another spinocerebellar ataxia, which is clinically distinct from Machado-Joseph disease, has been also localized to the same region on 14q and has been named type 3 spinocerebellar ataxia. Recently, expansions of a CAG trinucleotide repeat in a novel gene on chromosome 14q32.1 were shown in 11 patients affected with Machado-Joseph disease. In this study, we analyzed the DNA samples from 103 individuals representing 42 independent families with dominantly inherited ataxia to determine whether any had the Machado-Joseph disease mutation. The Machado-Joseph disease CAG expansion was detected in 5 of these 42 families. Sixteen affected individuals displayed a normal allele containing 14 to 31 CAG repeats and an expanded allele ranging between 66 and 79 CAG repeats. Seven asymptomatic individuals showed an allele ranging between 67 and 80 CAG repeats. Two of these families had a phenotype consistent with Machado-Joseph disease while the other 3 had clinical features of type 3 spinocerebellar ataxia. These data suggest that a single locus at 14q32.1 is responsible for two forms of spinocerebellar ataxia, spinocerebellar ataxia type 3 and Machado-Joseph disease, and that this locus may account for approximately 11% of this group of dominantly inherited ataxias.
Adolescent↗
Lupus transverse myelopathy: better outcome with early recognition and aggressive high-dose intravenous corticosteroid pulse treatment.
Seven patients with transverse myelopathy (TM) were found to have systemic lupus erythematosus (SLE). Four patients had no prior diagnosis of SLE. All patients had positive antinuclear antibody (ANA). All patients had a spinal syndrome which progressed to TM with cervical or thoracic levels. The diagnosis of TM was confirmed with neurological tests and neuro-radiographic studies. Delay in diagnosis and treatment resulted in a poor outcome. Four patients died and one remained wheelchair-bound. Only two patients who received high-dose IV pulse steroid within 1 week of onset of TM had a good outcome, with full ability to ambulate without assistance. Our experience suggests that early diagnosis with early treatment using high-dose IV steroid affects the mortality and improves the outcome.
Adolescent↗