Kegg Pathway: Dentatorubropallidoluysian atrophy (DRPLA)

Arch Neurol. 2004 Jun; 61(6): 946-9
Muñoz E, Campdelacreu J, Ferrer I, Rey MJ, Cardozo A, Gómez B, Tolosa E

BACKGROUND: The pathophysiology of white matter involvement in Dentatorubropallidoluysian atrophy (DRPLA) is controversial. Moreover, the clinical repercussions and evolution of these lesions have not been well documented. OBJECTIVE: To describe a case of DRPLA with severe cerebellar white matter involvement. DESIGN: Case report. Patient A 62-year-old woman with DRPLA. RESULTS: When the genetic diagnosis was made, the patient manifested severe ataxia, slight dysarthria, and subcortical cognitive impairment. Cranial magnetic resonance imaging showed atrophy of the cerebellum and brainstem and moderate high-intensity signal alterations in the periventricular cerebral white matter in T2-weighted sequences. In the following 5 years, she developed uncontrolled head movements associated with severe bruxism and tetraparesis, and became deeply demented. New magnetic resonance imaging showed severe diffuse cerebral white matter alterations in T2 sequences with only slight progression of brainstem and cerebellar atrophy. After her death at 67 years of age, the autopsy study showed diffuse myelin pallor, axonal preservation, and reactive astrogliosis in the cerebral white matter, with only mild atherosclerotic changes, and moderate neuronal loss in the cerebellum and brainstem. CONCLUSIONS: Leukoencephalopathy could be a prominent finding in some patients with DRPLA, explaining, at least in part, their clinical evolution. In our case, the disproportion between the severity of white matter damage and vascular changes does not support a cardinal role for ischemic mechanisms in leukoencephalopathy.

Cornea. 2004 Mar; 23(2): 210-4
Jung DS, Lee JH, Lee JE, Park HJ, You HW, Lee JS

OBJECTIVE: To present a rare case of patient diagnosed with Dentatorubropallidoluysian atrophy (DRPLA) accompanied by corneal endothelial cell loss. METHODS: A 37-year-old man with choreoathetoid movement and cerebellar ataxia was diagnosed with DRPLA based on a DNA analysis compared with that of healthy control subjects. We examined the best corrected visual acuity, color vision, light reflex, topography, corneal thickness, fundus, fluorescein angiograpic findings, the visual field, ERG, specular microscopy as well as MRI and serologic tests. RESULTS: The best corrected visual acuity was 20/20 in both eyes by Snellen chart, and the other ocular findings were within normal limits except for a significantly decreased corneal endothelial cell density, 876 cells/mm in the right eye and 941 cells/mm in the left eye. CONCLUSIONS: A patient with neurodegenerative disorders such as choreathetoid movement, myoclonic seizure, cerebellar ataxia, and dementia should be examined specifically by specular microscopy because corneal endothelial cell loss is the only clinical diagnostic indicator of DRPLA.

Clin Genet. 2004 Mar; 65(3): 209-14
Wu YR, Lin HY, Chen CM, Gwinn-Hardy K, Ro LS, Wang YC, Li SH, Hwang JC, Fang K, Hsieh-Li HM, Li ML, Tung LC, Su MT, Lu KT, Lee-Chen GJ

DNA tests in normal subjects and patients with ataxia and Parkinson's disease (PD) were carried out to assess the frequency of spinocerebellar ataxia (SCA) and to document the distribution of SCA mutations underlying ethnic Chinese in Taiwan. MJD/SCA3 (46%) was the most common autosomal dominant SCA in the Taiwanese cohort, followed by SCA6 (18%) and SCA1 (3%). No expansions of SCA types 2, 10, 12, or Dentatorubropallidoluysian atrophy (DRPLA) were detected. The clinical phenotypes of these affected SCA patients were very heterogeneous. All of them showed clinical symptoms of cerebellar ataxia, with or without other associated features. The frequencies of large normal alleles are closely associated with the prevalence of SCA1, SCA2, MJD/SCA3, SCA6, and DRPLA among Taiwanese, Japanese, and Caucasians. Interestingly, abnormal expansions of SCA8 and SCA17 genes were detected in patients with PD. The clinical presentation for these patients is typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. This study appears to be the first report describing the PD phenotype in association with an expanded allele in the TATA-binding protein gene and suggests that SCA8 may also be a cause of typical PD.

Eur J Hum Genet. 2003 Oct; 11(10): 808-11
Martins S, Matamá T, Guimarães L, Vale J, Guimarães J, Ramos L, Coutinho P, Sequeiros J, Silveira I

Dentatorubropallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by a variable combination of progressive ataxia, epilepsy, myoclonus, choreoathetosis and dementia. This disease is caused by a (CAG)(n) expansion in the DRPLA gene, on chromosome 12p13. DRPLA is prevalent in Japan, but several families of non-Japanese ancestry have already been published. To identify the origin of expanded alleles in Portuguese families with DRPLA, we studied two previously reported intragenic SNPs in introns 1 and 3, in addition to the CAG repeat of the DRPLA gene. The results showed that all four Portuguese DRPLA families shared the same haplotype, which is also common to that reported for Japanese DRPLA chromosomes. This haplotype is also the most frequent in Japanese normal alleles, whereas it was rare in Portuguese control chromosomes. Thus, our findings support that a founder DRPLA haplotype of Asian origin was introduced in Portugal, being responsible for the frequency of the disease in this country.

Am J Med Genet. 2002 Jul 8; 114(5): 578-83
Maruyama H, Izumi Y, Morino H, Oda M, Toji H, Nakamura S, Kawakami H

Expansions of trinucleotide repeats have been discovered in spinocerebellar ataxia (SCA) types 1, 2, 6, 7, 12, and 17, Machado-Joseph disease (MJD/SCA3), and Dentatorubropallidoluysian atrophy (DRPLA). However, the frequency of familial SCA in Japan remains unclear. The number of trinucleotide repeats was determined for 1,286 patients. Three hundred and thirty families (523 cases) were autosomal dominant group (A), and 165 families were positive for family history but not autosomal dominant group (B), while the remaining 598 cases were the sporadic group (C). The frequency of SCA subtypes in autosomal dominant group was: 1) 5.5% for SCA1; 2) 2.4% for SCA2; 3) 27.6% for MJD/SCA3; 4) 25.5% for SCA6; 5) 0.3% for SCA17; and 6) 7.3% for DRPLA. Abnormal expansion of SCA12 was not detected. Another 31.5% of the patients in the autosomal dominant group had unknown genetic abnormalities. Within group B, SCA6 was the most prominent and within the sporadic group MJD/SCA3 and SCA6 were the most common subtypes observed. The disease-free survival curve of SCA6 was different from that of other SCAs and the mean age at onset for SCA6 was found to be later than that of the other types. Regional differences were observed in the relative rate of SCA subtypes. MJD/SCA3 appears more common in the Kanto and Kyushu districts of Japan, whereas SCA6 is most common in the Chugoku district. In order to establish an effective social welfare system for SCA patients, clinical course and regional differences in the prevalence of SCA subtypes must be taken into consideration.

Eur Neurol. 2002; 47(4): 222-3
Ono S, Kaneda K, Suzuki M, Tagawa A, Shimizu N

We describe a Japanese family with molecularly confirmed DRPLA associated with chronic renal failure of unclear etiology on hemodialysis. The clinical symptoms and laboratory data show that the renal failure in our DRPLA patients is not associated with known familial renal diseases. Thus, we suggest a possible unifying hypothesis that the coexistence of DRPLA and chronic renal failure may be caused by the same etiology.

Arch Neurol. 2002 Apr; 59(4): 623-9
Silveira I, Miranda C, Guimarães L, Moreira MC, Alonso I, Mendonça P, Ferro A, Pinto-Basto J, Coelho J, Ferreirinha F, Poirier J, Parreira E, Vale J, Januário C, Barbot C, Tuna A, Barros J, Koide R, Tsuji S, Holmes SE, Margolis RL, Jardim L, Pandolfo M, Coutinho P, Sequeiros J

BACKGROUND: Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood. OBJECTIVE: To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA. PATIENTS AND METHODS: We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification. RESULTS: Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for Dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. CONCLUSIONS: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)(n) expansions at the TBP gene may cause SCA17.

Arch Neurol. 2001 Nov; 58(11): 1905-8
Lee IH, Soong BW, Lu YC, Chang YC

BACKGROUND: Dentatorubropallidoluysian atrophy (DRPLA) is a rare, autosomal dominant neurodegenerative disease characterized by a range of clinical manifestations, including cerebellar ataxia, epilepsy, myoclonus, choreoathetosis, and dementia. Outside the Japanese population, the prevalence is extremely low worldwide. The reason for different ethnic prevalences of DRPLA is unclear. A previous assumption was that large normal alleles contribute to generation of expanded alleles and the relative frequencies of DRPLA. OBJECTIVES: To describe the clinical, radiological, and genetic features of the first reported Chinese family with DRPLA, to our knowledge, and to compare the size distribution of normal alleles at the DRPLA locus in healthy Chinese individuals with that of other ethnic groups. PATIENTS AND METHODS: Of 80 Chinese kindreds with autosomally dominant spinocerebellar ataxias, 1 pedigree with 2 affected patients was found by polymerase chain reaction to carry the characteristic DRPLA mutation. The allele frequencies of different CAG repeat lengths at the DRPLA locus in 225 healthy Chinese individuals were also analyzed and compared with Japanese, white, and African American distributions. RESULTS: The clinical presentations of the 2 Chinese patients affected with DRPLA are similar to those described in Japanese patients, except that the affected father exhibited myoclonus but not chorea. Although the normal DRPLA allele size is distributed similarly in Chinese and Japanese populations, DRPLA in Chinese individuals is rare. Thus far, to our knowledge, only 1 intermediate-sized allele containing more than 30 CAG repeats has been reported among healthy Chinese individuals, in contrast to 3 among Japanese populations. CONCLUSION: The ethnic prevalence of DRPLA seems to be correlated with the prevalence of intermediate-sized alleles in individual populations.

J Neurol Sci. 2000 Sep 15; 178(2): 153-8
Onodera Y, Aoki M, Tsuda T, Kato H, Nagata T, Kameya T, Abe K, Itoyama Y

Autosomal dominant cerebeller ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders that differ in both the clinical manifestations and modes of inheritance. At present, eight different genes causing ADCAs have been found: spinocerebeller ataxia type 1 (SCA1), SCA2, SCA3/Machado-Joseph disease (MJD), SCA6, SCA7, SCA8, SCA12 and Dentatorubropallidoluysian atrophy (DRPLA). The relative prevalence of each mutation varies according to race and native place. We studied 117 unrelated ADCA families that originated from the Tohoku District in the northernmost part of Honshu Island in Japan (mainly Miyagi Prefecture in the central part of Tohoku District). The SCA1 mutation was the most frequent among the known disorders (24.8% of all such families). The relative prevalence of SCA1 in the Tohoku District is very high compared with the values already reported from other regions in the world. Because the population of this area had seldom moved, the alleles with SCA1 mutations (including alleles with an intermediate CAG repeat number) are assumed to have been present in this area for a long time.

Eur Neurol. 2000; 44(1): 31-6
Filla A, Mariotti C, Caruso G, Coppola G, Cocozza S, Castaldo I, Calabrese O, Salvatore E, De Michele G, Riggio MC, Pareyson D, Gellera C, Di Donato S

Two hundred and forty-eight patients from 116 Italian families with dominant ataxia were studied for CAG expansion within SCA1, 2, 3, 6, 7 (spinocerebellar ataxia) and DRPLA (Dentatorubropallidoluysian atrophy) genes. Fifty-six percent of the families originated from Southern, 19% from Central and 25% from Northern Italy. SCA2 was the commonest mutation, accounting for 47% of the families, followed by SCA1 (24%), SCA6 (2%), SCA7 (2%) and DRPLA (1%). No SCA3 family was found. Twenty-four percent of the families carried a still unidentified mutation. When occurrence of mutations was evaluated according to the geographic origin, SCA1 was the commonest in Northern (72%), whereas SCA2 was prevalent (63%) in Southern Italy. The number of CAG repeats in SCA1 normal alleles was higher in Northern than in Central-Southern Italy.

Ann Neurol. 2000 Jul; 48(1): 72-6
Lodi R, Schapira AH, Manners D, Styles P, Wood NW, Taylor DJ, Warner TT

We studied in vivo muscle energy metabolism in patients with Huntington's disease (HD) and Dentatorubropallidoluysian atrophy (DRPLA) using 31P magnetic resonance spectroscopy (MRS). Twelve gene-positive HP patients (4 presymptomatic patients) and 2 gene-positive DRPLA patients (1 presymptomatic patient) were studied. 31P-MRS at rest showed a reduced phosphocreatine-to-inorganic phosphate ratio in the symptomatic HD patients and DRPLA patient. Muscle adenosine triphosphate/(phosphocreatine + inorganic phosphate) at rest was significantly reduced in both groups of symptomatic and presymptomatic HD subjects and was below the normal range in the 2 DRPLA subjects. During recovery from exercise, the maximum rate of mitochondrial adenosine triphosphate production was reduced by 44% in symptomatic HD patients and by 35% in presymptomatic HD carriers. The maximum rate of mitochondrial adenosine triphosphate production in muscle was also reduced by around 46% in the 2 DRPLA subjects. Our findings show that HD and DRPLA share a deficit of in vivo mitochondrial oxidative metabolism, supporting a role for mitochondrial dysfunction as a factor involved in the pathogenesis of these polyglutamine repeat-mediated neurodegenerative disorders. The identification of 31P-MRS abnormalities may offer a surrogate biochemical marker by which to study disease progression and the effects of treatment in HD and DRPLA.

Arch Neurol. 2000 Apr; 57(4): 540-4
Tang B, Liu C, Shen L, Dai H, Pan Q, Jing L, Ouyang S, Xia J

OBJECTIVE: To assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, and DRPLA (Dentatorubropallidoluysian atrophy) CAG trinucleotide repeat expansions [(CAG)n] among persons diagnosed with hereditary SCA from Chinese families. PATIENTS AND METHODS: Spinocerebellar ataxia type 1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA (CAG)n mutation were detected with the polymerase chain reaction, highly denaturing polyacrylamide gel electrophoresis, and silver staining technique in 167 patients with autosomal dominant SCA from 85 Chinese families and 37 patients with sporadic SCA. RESULTS: Spinocerebellar ataxia type 1 (CAG)n mutation in 7 patients from 4 kindreds (4.70%) was expanded to 53 to 62 repeats. Spinocerebellar ataxia type 2 (CAG)n mutation in 12 patients from 5 kindreds (5.88%) was expanded to 42 to 47 repeats. Spinocerebellar ataxia type 3/Machado-Joseph disease (CAG)n mutation in 83 patients from 41 kindreds (48.23%) was expanded to 68 to 83 repeats. Sixty-five patients from 35 kindreds (41.19%) and 37 patients with sporadic SCA did not test positive for SCA1, SCA2, SCA3/MJD, SCA6, SCA7, or DRPLA. There was a predictable inverse relationship between the number of CAG repeats and the age at onset for SCA3/MJD and SCA2. Clinically, dementia and hyporeflexia were more frequent in patients with SCA2, while spasticity, hyperreflexia, and Babinski signs were more frequent in patients with SCA3/ MJD, and those might be helpful in clinical work to primarily distinguish patients with SCA3/MJD and SCA2 from others with different types of SCA. CONCLUSIONS: The frequency of SCA3/MJD is substantially higher than that of SCA1 and SCA2 in patients with autosomal dominant SCA from Chinese kindreds, who are non-Portuguese. Clinical expressions of the various types of SCAs overlap one another; therefore, for clinical study it is important to make a gene diagnosis and genetic classification for patients with SCA.

J Neurol Neurosurg Psychiatry. 1999 Dec; 67(6): 811-4
Muñoz E, Milà M, Sánchez A, Latorre P, Ariza A, Codina M, Ballesta F, Tolosa E

The object was to describe the clinical, radiological, pathological, and genetic findings in a Spanish family with Dentatorubropallidoluysian atrophy (DRPLA). This is an inherited neurodegenerative disease, well recognised in Japan, but with few cases reported from Europe and America and no cases published from Spain. The clinical misdiagnosis of Huntington's disease is not infrequent. Pedigree analysis and clinical data of a family were collected. A genetic study was performed in two patients. Pathological information was obtained from the necropsy of one patient. RESULTS: Pedigree analysis showed an autosomal dominant pattern of inheritance. Age at onset varied from 5 to 55 years. Ataxia and chorea were present in most of the members. Some of these had a long course disease with late dementia. Four patients had seizures and early mental impairment. In one patient, cranial MRI showed cortical, brain stem and cerebellar atrophy, and white matter changes. In another patient, necropsy showed atrophy of the globus pallidus and lipofuscin deposits in dentate and pallidal neuronal cells. Genetic study showed an abnormal CAG triplet expansion in the B37 gene on chromosome 12. As in other cases previously reported, Spanish cases of DRPLA show intrafamilial phenotypic heterogeneity. Clinical and MRI data could differentiate DRPLA from Huntington's disease but definitive diagnosis requires molecular studies. Pathological studies are still necessary to correlate DRPLA brain involvement with the clinical and molecular findings.

J Biol Chem. 1999 Mar 26; 274(13): 8730-6
Ellerby LM, Andrusiak RL, Wellington CL, Hackam AS, Propp SS, Wood JD, Sharp AH, Margolis RL, Ross CA, Salvesen GS, Hayden MR, Bredesen DE

Dentatorubropallidoluysian atrophy (DRPLA) is one of eight autosomal dominant neurodegenerative disorders characterized by an abnormal CAG repeat expansion which results in the expression of a protein with a polyglutamine stretch of excessive length. We have reported recently that four of the gene products (huntingtin, atrophin-1 (DRPLA), ataxin-3, and androgen receptor) associated with these open reading frame triplet repeat expansions are substrates for the cysteine protease cell death executioners, the caspases. This led us to hypothesize that caspase cleavage of these proteins may represent a common step in the pathogenesis of each of these four neurodegenerative diseases. Here we present evidence that caspase cleavage of atrophin-1 modulates cytotoxicity and aggregate formation. Cleavage of atrophin-1 at Asp109 by caspases is critical for cytotoxicity because a mutant atrophin-1 that is resistant to caspase cleavage is associated with significantly decreased toxicity. Further, the altered cellular localization within the nucleus and aggregate formation associated with the expanded form of atrophin-1 are completely suppressed by mutation of the caspase cleavage site at Asp109. These results provide support for the toxic fragment hypothesis whereby cleavage of atrophin-1 by caspases may be an important step in the pathogenesis of DRPLA. Therefore, inhibiting caspase cleavage of the polyglutamine-containing proteins may be a feasible therapeutic strategy to prevent cell death.

Acta Neuropathol. 1998 Nov; 96(5): 502-8
Tsuchiya K, Oyanagi S, Arima K, Ikeda K, Akashi T, Ando S, Kurosawa T, Ikeuchi T, Tsuji S

This report concerns a clinicopathological study including a quantitative pathological study on the nucleus basalis of Meynert (nbM) of seven Japanese autopsy cases (four male, three female) of Dentatorubropallidoluysian atrophy (DRPLA) with special reference to the clinicopathological correlation of dementia in DRPLA. In each case the pattern of the inheritance was consistent with that of an autosomal dominant trait. The neurological examination revealed that all seven individuals had cerebellar signs. Six patients had epilepsy and choreoathetoid involuntary movement; myoclonus was evident in five patients. Dementia was noted in all seven patients. Degeneration of the globus pallidus (particularly the lateral segment) and of the dentate nucleus was the principal pathological feature. Brain weights at autopsy ranged from 1020 to 1400 g (average 1241 g: male 1320 g, female 1135 g). The quantitative evaluation revealed no significant loss of neurons in the nbM as compared with a control group. There was no clinicopathological correlation between dementia and involvement of the nbM. We suggest that the dementia of DRPLA is due not to the involvement of the nbM, but to - as yet - unidentified pathology elsewhere.

J Neurol Neurosurg Psychiatry. 1998 Sep; 65(3): 396-9
Yoshii F, Tomiyasu H, Shinohara Y

The white matter lesions in a patient with late adult onset Dentatorubropallidoluysian atrophy (DRPLA) were studied in detail by MRI using the fluid attenuation inversion recovery (FLAIR) technique. The patient was a 60 year old woman with a family history of DRPLA, in whom the number of CAG repeats in the DRPLA gene on chromosome 12 was expanded to 59 (normal allele 10). In addition to atrophy of the cerebral cortex, cerebellum, and pontomesencephalic tegmentum, the cerebral white matter and a part of the white matter tracts within the brainstem showed prominent high signal intensities on FLAIR images. These MR findings suggest that, in addition to the degeneration of the dentatorubral and pallidoluysian systems, the pathological process extends to the white matter in DRPLA. This could be important for differentiating DRPLA from other clinically similar diseases such as Machado-Joseph disease or Huntington's disease.

Arq Neuropsiquiatr. 1997 Sep; 55(3B): 519-29
Lopes-Cendes I, Teive HG, Calcagnotto ME, Da Costa JC, Cardoso F, Viana E, Maciel JA, Radvany J, Arruda WO, Trevisol-Bittencourt PC, Rosa Neto P, Silveira I, Steiner CE, Pinto Júnior W, Santos AS, Correa Neto Y, Werneck LC, Araújo AQ, Carakushansky G, Mello LR, Jardim LB, Rouleau GA

Spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2) and Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) are three distinctive forms of autosomal dominant spinocerebellar ataxia (SCA) caused by expansions of an unstable CAG repeat localized in the coding region of the causative genes. Another related disease, Dentatorubropallidoluysian atrophy (DRPLA) is also caused by an unstable triplet repeat and can present as SCA in late onset patients. We investigated the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations in 328 Brazilian patients with SCA, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of Brazil. We found mutations in 35 families (39%), 32 of them with a clear autosomal dominant inheritance. The frequency of the SCA1 mutation was 3% of all patients; and 6% in the dominantly inherited SCAs. We identified the SCA2 mutation in 6% of all families and in 9% of the families with autosomal dominant inheritance. The MJD/SCA3 mutation was detected in 30% of all patients; and in the 44% of the dominantly inherited cases. We found no DRPLA mutation. In addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of Brazil. These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil.

Am J Med Genet. 1998 Mar 28; 81(2): 134-8
Silveira I, Coutinho P, Maciel P, Gaspar C, Hayes S, Dias A, Guimarães J, Loureiro L, Sequeiros J, Rouleau GA

The spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. To date, eight different loci causing SCA have been identified: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA6, SCA7, and Dentatorubropallidoluysian atrophy (DRPLA). Expansion of a CAG repeat in the disease genes has been found in five of these disorders. To estimate the relative frequencies of the SCA1, DRPLA, MJD, SCA2, and SCA6 mutations among Portuguese ataxia patients, we collected DNA samples from 48 ataxia families and performed polymerase chain reaction (PCR) amplification of the CAG repeat mutations on chromosomes 6p, 12p, 14q, 12q, and 19p, respectively. Fifty-five individuals belonging to 34 dominant families (74%) had an expanded CAG repeat at the MJD gene. In five individuals from two kindreds with a dominant pattern of inheritance (4%), an expanded CAG repeat at the SCA2 gene was found. In MJD patients, the normal allele size ranged from 13 to 41, whereas the mutant alleles contained 65 to 80 repeats. For the SCA2 patients, normal alleles had 22 or 23, while expanded alleles had between 36 and 47 CAG units. We did not find the SCA1, DRPLA, or SCA6 mutations in our group of families. The MJD mutation remains the most common cause of SCA in Portugal, while a small number of cases are caused by mutations at the SCA2 gene, and 22% are due to still unidentified genes.

Eur Neurol. 1998; 39(2): 97-102
Hanihara T, Amano N, Takahashi T, Itoh Y, Yagishita S

Hypertrophic changes in the inferior olivary nuclei have been occasionally described in patients with progressive supranuclear palsy (PSP). To elucidate the incidence of olivary hypertrophy, we investigated morphologically the olives and their associated pathways in 20 autopsied cases: 11 cases of PSP, 3 cases of Machado-Joseph disease and 6 cases of Dentatorubropallidoluysian atrophy (DRPLA) as control diseases that usually exhibited lesions of the cerebellofugal pathway. Olivary hypertrophy was observed in 5 of 11 PSP cases, but not in the other diseases, except for 1 case of DRPLA with an old infarct in the dentate nucleus. In the olivopetal pathway, grumose degeneration of the dentate nucleus and mild neuronal loss in the red nucleus were observed in all patients with PSP and in the control subjects. atrophy and fibrillary gliosis of the tegmentum of the pons, including that of the bilateral central tegmental tracts, were observed in all patients with PSP, more severe in the cases with hypertrophic neurons in the olives. We speculate that a lesion that involves the central tegmental tracts may play a major role in inducing hypertrophy of the olives in patients with PSP.

Am J Hum Genet. 1997 Apr; 60(4): 842-50
Geschwind DH, Perlman S, Figueroa CP, Treiman LJ, Pulst SM

The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and Dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.