SPG4 founder effect in French Canadians with hereditary spastic paraplegia

BACKGROUND: The most common cause of autosomal dominant Hereditary Spastic Paraplegia (HSP) is mutations in the SPG4 gene. We have previously identified novel SPG4 mutations in a collection of North American families including the c.G1801A mutation present in two families from Quebec. The aim of this study is to estimate the frequency of the c.G1801A mutation in the French Canadian (FC) population and to determine whether this mutation originates from a common ancestor. METHODS: We collected and sequenced exon 15 in probands of 37 families. Genotypes of markers flanking the SPG4 gene were used to construct haplotypes in five families. Clinical information was reviewed by a neurologist with expertise in HSP. RESULTS: We have identified three additional unrelated families with the c.G1801A mutation and haplotype analysis revealed that all five families share a common ancestor. The mutation is present in 7% of all our FC families and explains half of our spastin linked FC families. The phenotype associated with the c.G1801A genotype is pure HSP with bladder involvement. CONCLUSION: In this study we have determined that the relative frequency of the c.G1801A mutation in our FC collection is 7%, and approximately 50% in the spastin positive FC group. This mutation is the most common HSP mutation identified in this population to date and is suggestive of a founder effect in Quebec.     

The role of the α-synuclein gene mutation in patients with sporadic Parkinson's disease in the United Kingdom

Parkinson's disease is a common neurodegenerative disorder ofunknown aetiology. A pathogenic point mutation within the α-synuclein gene has recently been identified in one Italian-American kindred andthree families of Greek origin with parkinsonism. DNA from 70 patientswith Parkinson's disease was screened for this G209A mutation. Nosamples were positive for the mutation, suggesting that it is notrelevant for most patients with sporadic idiopathic Parkinson's disease.

     

Epidemiology of Parkinson's disease

The incidence of Parkinson syndrome in North America is 20.5/10⁵, adjusted to 1970 US population, and there has been no significant change between 1935 and 1979. The composition of different Parkinson variants in the general population, however, has altered remarkably during recent decades. Arteriosclerotic Parkinsonism is very rarely diagnosed now, post-encephalitic Parkinsonism is extinct and drug induced Parkinsonism, first identified in the 1950s, is now the second most common variant in the combined community and institutionalised population survey. There has been a trend to higher incidence of Parkinson's disease in recent decades and it is predicted that the incidence would rise further if the current population survival trends continue. There is no race or gender difference for the risk of Parkinson's disease. Survival in Parkinson's disease has increased since the widespread use of levodopa. The prevalence rate of Parkinson syndrome in North America is estimated at 300/105. Increased risk of Parkinson's disease in essential tremor patients and the reported protective effect of smoking are artifactual. Twin studies show a concordance rate of 10.5% in monozygotic and 10.8% in dizygotic twins, indicating against a major genetic basis for Parkinson's disease. Several large Parkinson's disease families with autosomal dominant inheritance are well documented. In one such family, linkage to chromosome 4 is reported and mutation in the a-synuclein gene has been identified. In several other families, linkage to that region was not detected. These families are believed to inherit a Parkinson's disease susceptibility trait.     

Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families.

Mutations in the leucine-rich repeat kinase-2 gene (LRRK2) are responsible for some forms of familial as well as sporadic Parkinson's disease (PD). The purpose of this study was to examine the frequency of a single pathogenic mutation (6055G > A) in the kinase domain of this gene in United States and Tunisian familial PD and to compare clinical characteristics between patients with and without the mutation. Standardized case report forms were used for clinical and demographic data collection. We investigated the frequency of the most common substitution of LRRK2 (G2019S, 6055G>A) and its impact on epidemiological and phenotypic features. The frequency of mutations in Tunisian families was 42% (38/91) and in U.S. families 2.6% (1/39), with the unique opportunity to compare homozygous (n = 23) and heterozygous (n = 109) Tunisian carriers of G2019S substitutions. Individuals with G2019S substitutions had an older age at onset but few other differences compared with families negative for the substitution. Patients with LRRK2 mutations had typical clinical features of PD. Comparisons between individuals with heterozygous and homozygous LRRK2 mutations suggested that gene dosage was not correlated with phenotypic differences; however, the estimated penetrance was greater in homozygotes across all age groups.     

Parkinson's disease due to the R1441G mutation in Dardarin: a founder effect in the Basques.

The recent discovery of mutations in Dardarin (LRRK2) have been related to the appearance of Parkinson's disease in several families. Notably, one single mutation in this gene (R1441G) not only appeared in familial, but also in apparently sporadic Parkinson disease (PD) patients of Basque descent. A clinical population was ascertained, and subjects were classified into Basque and non-Basque descent according to their known ancestry. The R1441G mutation was assayed using an allele-specific polymerase chain reaction, and several single nucleotide polymorphisms surrounding this mutation were analyzed by direct sequencing. In addition to 22 members of the original Basque families where R1441G was identified, we observed 17 carriers of the mutation who were apparently related through a common ancestor. From a clinical perspective, the disease observed in mutation carriers is indistinguishable from that in noncarriers. The R1441G mutation causes a form of Parkinson's disease that is equivalent to that observed in idiopathic Parkinson's disease. This mutation appears in 16.4% and 4.0% of familial and sporadic PD in this Basque population, respectively.     

SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia

Mutations in the SPG3A gene encoding the novel GTPase atlastin have recently been implicated in causing autosomal dominant hereditary spastic paraplegia (ADHSP) in six unrelated families. The phenotype of affected individuals in all cases has been of an early onset uncomplicated form of the disease. One particular missense mutation, R239C, in exon 7 of SPG3A has been identified in three of these families. We performed mutation screening by direct sequencing of all 14 exons and flanking sequences of the SPG3A gene in affected individuals from 12 unrelated English families, all with an early onset uncomplicated ADHSP in whom spastin mutations had previously been excluded. The R239C mutation was found to co-segregate with the disease in one English ADHSP family confirming a widespread prevalence for this commonly occurring mutation. No additional SPG3A mutations were identified in the remaining 11 families suggesting that even within this specific sub-set of early onset uncomplicated ADHSP patients atlastin mutations are relatively rare.     

Mutation analysis of the small heat shock protein 27 gene in chinese patients with Charcot-Marie-Tooth disease

BACKGROUND: Charcot-Marie-Tooth (CMT) disease, the most common hereditary peripheral neuropathy, is highly clinically and genetically heterogeneous, and mutations in at least 18 genes have been identified. Recently, mutations in small heat shock protein 27 (Hsp27) were reported to cause CMT disease type 2F and distal hereditary motor neuropathy. OBJECTIVE: To investigate the frequency and phenotypic features of an Hsp27 mutation in Chinese patients with CMT disease. DESIGN: DNA samples from 114 unrelated patients with CMT disease were screened for mutations in Hsp27 by polymerase chain reaction and direct sequencing. A cosegregated study was performed using the MbiI restriction endonuclease, and 50 healthy control subjects were analyzed. Haplotype analysis was performed using 5 short tandem repeat markers to analyze whether the families with the same mutation probably had a common ancestor. RESULTS: One missense mutation, C379T, was detected in 4 autosomal dominant families with CMT disease type 2, and haplotype analysis indicated that the 4 families probably had a common founder. The frequency of the Hsp27 mutation is 0.9% (1/111) in Chinese patients with CMT disease in our study, and the phenotypes were characterized by later onset (age, 35-60 years) and mild sensory impairments. Electrophysiological findings showed moderately to severely slowed nerve conduction velocities in lower limb nerves but normal or mildly reduced velocities in upper limb nerves. CONCLUSIONS: To our knowledge, this is the first report of an Hsp27 mutation in the People's Republic of China. The C379T mutation in Hsp27 also causes CMT disease type 2, except for distal hereditary motor neuropathy, and the phenotypes are distinct from the family with CMT disease type 2F described previously. A mutation of Hsp27 may be uncommon in Chinese patients with CMT disease.     

Founder effect and ancestral origin of the spinocerebellar ataxia type 7 (SCA7) mutation in Mexican families

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disease characterized by progressive cerebellar ataxia and macular degeneration causing progressive blindness. It accounts for 1 to 11.6 % of spinocerebellar ataxias (SCAs) cases worldwide and for 7.4 % of SCA7 cases in Mexico. We identified a cluster of SCA7 families who resided in a circumscribed area of Veracruz and investigated whether the high incidence of the disease in this region was due to a founder effect. A total of 181 individuals from 20 families were studied. Four microsatellite markers and one SNP flanking the ATNX7 gene were genotyped and the ancestral origin and local ancestry analysis of the SCA7 mutation were evaluated. Ninety individuals from 19 families had the SCA7 mutation; all were found to share a common haplotype, suggesting that the mutation in these families originated from a common ancestor. Ancestral origin and local ancestry analysis of SCA7 showed that the chromosomal segment containing the mutation was of European origin. We here present evidence strongly suggesting that the high frequency of SCA7 in Veracruz is due to a founder effect and that the mutation is most likely of European origin with greatest resemblance to the Finnish population.     

Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer’s disease in Mexican families

The etiology of Alzheimer’s disease (AD) is complex. To date, molecular genetic studies in several families affected with AD have identified three genes associated with highly penetrant early-onset AD: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and β-amyloid precursor protein (APP); and one gene (apolipoprotein E) associated with late-onset AD. Molecular analysis of the PSEN1 gene was performed by direct sequencing of genomic DNA. The possible founder effect was investigated analyzing two highly polymorphic microsatellite markers flanking the PSEN1 gene. Twelve unrelated Mexican families with early-onset AD were analyzed. The Ala431Glu mutation in exon 12 of PSEN1 was found in nine (75%) of these families, which segregated showing autosomal dominant inheritance. Because all families bearing the mutation are from the State of Jalisco (located in Western Mexico), a founder effect was hypothesized. Microsatellite haplotype analysis suggested a common ancestor in these nine kindreds. In conclusion, the Ala431Glu mutation is a prevalent cause of early-onset familial Alzheimer’s disease in families from the State of Jalisco, Mexico. Genetic evidence supports that it is a founder mutation descending from a single common ancestor. These findings have important implications for prompt diagnosis and genetic counseling for Mexican patients with familial AD from Jalisco.A summary of the results of this study was presented at the Congress of the Human Genome Organization (HUGO, April, 2003). Workshop Abstract No 11: pp 14.     

SCA2 trinucleotide expansion in German SCA patients

Autosomal dominant spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders which lead to progressive cerebellar ataxia. A gene responsible for SCA type 2 has been mapped to human chromosome 12 and the disease causing mutation has been identified as an unstable and expanded (CAG)_n trinucleotide repeat. We investigated the (CAG)_n repeat length of the SCA2 gene in 842 patients with sporadic ataxia and in 96 German families with dominantly inherited SCA which do not harbor the SCA1 or MJD1/SCA3 mutation, respectively. The SCA2 (CAG)_n expansion was identified in 71 patients from 54 families. The (CAG)_n stretch of the affected allele varied between 36 and 64 trinucleotide units. Significant repeat expansions occurred most commonly during paternal transmission. Analysis of the (CAG)_n repeat lengths with the age of onset in 41 patients revealed an inverse correlation. Two hundred and forty-one apparently healthy octogenerians carried alleles between 16 and 31 repeats. One 50-year old, healthy individual had 34 repeats; she had transmitted an expanded allele to her child. The small difference between ‘normal’ and disease alleles makes it necessary to define the extreme values of their ranges. With one exception, the trinucleotide expansion was not observed in 842 ataxia patients without a family history of the disease. The SCA2 mutation causes the disease in nearly 14% of autosomal dominant SCA in Germany. Received December 30, 1996; Revised and Accepted January 31, 1997     

Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma

BACKGROUND: We previously discovered spinocerebellar ataxia type 14 (SCA14) in a single Japanese family with an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia and intermittent axial myoclonus. The latter manifestation is selectively observed in patients with early onset. We mapped the locus to chromosome 19q13.4-qter, but the etiologic gene was not known. Recently, a mutation in the protein kinase C gamma gene (PRKCG) was identified in a US family of English and Dutch ancestry with autosomal dominant SCA whose disease mapped to a region overlapping that of the SCA14 locus. Different PRKCG mutations were found in another family with SCA and in a sporadic case from the United States. Axial myoclonus was not observed in any of these US families. OBJECTIVES: To determine whether a mutation in the PRKCG gene is responsible for SCA14 and to investigate the prevalence of PRKCG mutations in Japanese patients with autosomal dominant SCA.Patients and METHODS: Direct nucleotide sequencing analysis of the 18 coding exons of the PRKCG gene was performed in the 19 members of the original Japanese family with SCA14 and in 24 Japanese probands with SCA. After identifying a PRKCG mutation, DNA samples from 72 patients with multiple system atrophy and 50 healthy individuals were examined for the mutation as controls. RESULTS: Sequence analysis revealed a novel missense mutation, Gln127Arg, in all affected members of the family with SCA14. This mutation was not found in 122 control individuals. No mutations in the PRKCG gene were detected in the group of 24 probands with SCA of unknown type. CONCLUSIONS: These findings document that SCA14 is caused by mutations in the PRKCG gene. The observation that all 4 PRKCG mutations identified in patients with SCA to date are located in exon 4 suggests a critical role for this region of the gene in cerebellar function. Mutations in the same region of the gene can result in myoclonus in some families but not in others.     

Identification of a high frequency of mutation at exon 8 of the ATP7B gene in a Chinese population with Wilson disease by fluorescent PCR.

BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder of copper transport. Mutation analysis has led to the discovery of more than 100 mutations at ATP7B, and most of them are population specific. OBJECTIVES: To verify the high frequency of mutation at exon 8 of ATP7B in Chinese patients with WD and to establish a DNA diagnostic method for WD. SETTING: University medical centers. PATIENTS AND METHODS: Screening for mutations at exon 8 of ATP7B by fluorescent polymerase chain reaction analysis and restriction analysis was conducted in 106 unrelated Chinese patients with WD and in 55 individuals from 10 Chinese families with WD. RESULTS: Five homozygotes and 32 heterozygotes were identified. Sequence analysis showed a missense mutation (2273G-->T) and a nonsense mutation (2250C-->G) together at exon 8. The rate of gene mutation in 106 patients was 35% (5% homozygous and 30% heterozygous). Samples of DNA from 55 individuals from 10 Chinese families with WD were examined by fluorescent polymerase chain reaction. We found that 13 siblings were carriers (24%). CONCLUSIONS: A high frequency of mutation at exon 8 of the ATP7B gene exists in the Chinese population, and fluorescent polymerase chain reaction analysis may be an effective and accurate assay in detection of the WD gene.     

Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2

OBJECTIVE: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive. METHODS: Here, we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients. Detailed clinical and genetic studies were performed. RESULTS: In each pedigree, we identified a unique mutation in the gene mitofusin 2 (MFN2). In three families, the MFN2 mutation occurred de novo; in two families the mutation was subsequently transmitted from father to son indicating autosomal dominant inheritance. INTERPRETATION: MFN2 is a mitochondrial membrane protein that was recently reported to cause axonal CMT type 2A. It is intriguing that MFN2 shows functional overlap with optic atrophy 1 (OPA1), the protein underlying the most common form of autosomal dominant optic atrophy, and mitochondrial encoded oxidative phosphorylation components as seen in Leber's hereditary optic atrophy. We conclude that autosomal dominant HMSN VI is caused by mutations in MFN2, emphasizing the important role of mitochondrial function for both optic atrophies and peripheral neuropathies.     

The epidemiology of CuZn-SOD mutations in Germany: a study of 217 families

We screened 217 patients from Germany (n = 213), Austria (n = 2) and Switzerland (n = 2) with a positive family history for amyotrophic lateral sclerosis (ALS) for mutations in the copper/zinc superoxide dismutase (SOD1) gene. We found that 13% of the families tested carried mutations. By analyzing inheritance, we detected a clear-cut co-segregation in 5 of the 28 families; however, in two families with an established mutation, co-segregation was absent. In Germany, the R115G mutation is comparatively frequent and exhibits a specific aggressive phenotype. The L144F mutation, which is the most prevalent mutation in the Balkan countries, and the D90A mutation which is the most frequent SOD1 mutation globally, seem to be the second most common disease-causing mutations in Germany.     

X连锁腓骨肌萎缩症Cx32基因的突变、临床和电生理特点

目的 分析X连锁腓骨肌萎缩症（CMTX）患者Cx32基凶的突变及其临床表现和电生理特点、方法应用多聚酶链反应一单链构象多态性分析结合DNA直接测序的方法,对24例无周围髓鞘蛋白（PMP）22基因大片段重复突变,家系中无男传男的腓骨肌萎缩症（CMT）先证者进行Cx32基因的突变分析;对先证者及其家系内患者进行临床和电生理检查。结果 在6个X连锁遗传家系和1例散发患者中发现了7个不同的Cx32基因突变,其中4个家系临床分型为CMTI型,2个家系为CMT中间型,散发病例为CMT1型检测到有Cx32基因突变的家系成员共38例,其巾男性20例,全部为CMTX患者;女性18例,其中6例为CMTX患者,12例为无临床症状的携带者;26例患者均为周围神经轻、中度受累。结论 CMTX的遗传方式可为X连锁显性、X连锁隐性遗传,也可为散发。根据临床和电生理特点分为CMTI型或CMT中间型,多为周围神经轻、中度受累,男性患者的症状通常较女性重。在没有检测到PMP22基因大片段重复突变和无男传男的CMT家系中应首先进行Cx32基因突变分析。     

Adult onset spinocerebellar ataxia in a Canadian movement disorders clinic

BACKGROUND: The spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of neurodegenerative disorders. Relative frequencies vary within different ethnic groups and geographical locations. OBJECTIVES: 1) To determine the frequencies of hereditary and sporadic adult onset SCAs in the Movement Disorders population; 2) to assess if the fragile X mental retardation gene 1 (FMR1) premutation is found in this population. METHODS: A retrospective chart review of individuals with a diagnosis of adult onset SCA was carried out. Testing for SCA types 1, 2, 3, 6, 7, and 8, Dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich ataxia and the FMR1 expansion was performed. RESULTS: A total of 69 patients in 60 families were identified. Twenty-one (35%) of the families displayed autosomal dominant and two (3.3%) showed autosomal recessive (AR) pattern of inheritance. A positive but undefined family history was noted in nine (15%). The disorder appeared sporadic in 26 patients (43.3%). In the AD families, the most common mutation was SCA3 (23.8%) followed by SCA2 (14.3%) and SCA6 (14.3%). The SCA1 and SCA8 were each identified in 4.8%. FA was found in a pseudodominant pedigree, and one autosomal recessive pedigree. One sporadic patient had a positive test (SCA3).Dentatorubral-pallidoluysian atrophy and FMR1 testing was negative. CONCLUSION: A positive family history was present in 53.3% of our adult onset SCA patients. A specific genetic diagnosis could be given in 61.9% of dominant pedigrees with SCA3 being the most common mutation, followed by SCA2 and SCA6. The yield in sporadic cases was low. The fragile X premutation was not found to be responsible for SCA.     

Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism

BACKGROUND: Autosomal recessive juvenile parkinsonism is a neurodegenerative disorder associated with mutations in the parkin gene. OBJECTIVES: To search for the presence of parkin gene mutations in Spanish patients with Parkinson's disease (PD) and characterise the phenotype associated with these mutations. METHODS: Thirty seven PD patients with either early onset or autosomal recessive pattern of inheritance were selected for genetic study. RESULTS: Mutations were identified in seven index patients (19%). Homozygous mutations were detected in six patients and a heterozygous mutation in one. The age at onset was lower in patients with mutations than in patients without mutations. Dystonia at onset was present in two patients with parkin gene mutations. The disease began in two patients with postural tremor in the upper limbs mimicking essential tremor. Four patients exhibited a long term response to dopamine agonists. The c.255delA mutation was identified in four unrelated families. This is a frameshift mutation leading to protein truncation. CONCLUSIONS: Parkin gene mutations are present in Spanish patients with early onset and/or an autosomal recessive parkinsonism. The c.255delA is the most frequent mutation found, suggesting a relative high prevalence in the Spanish population.     

Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families

Autosomal dominant cerebellar ataxia type I is the most common form of dominant ataxia. A genetic heterogeneity has been identified with five different loci (SCA1, 2, 3, 4, and 6). A pathological expansion of a CAG sequence has been identified in SCA1, 2, 3, and 6. We performed molecular analysis in 51 families with autosomal dominant cerebellar ataxia type I, mainly originating from southern Italy and Sicily. Thirty families carry an expanded CAG sequence within SCA2 gene. The mean number of repeats was 39.9 ± 3.3 in 85 expanded alleles, with a range of 34–52. The number of triplets was inversely correlated with age at onset and explained 76% of the variance. The best fit was obtained with an exponential relationship between variables. Expanded alleles were unstable when transmitted from parents to offspring. Expansions were more common than contractions, accounting for 59% of the total meioses and for 80% of the father-child transmissions. The mean intergenerational variation was 1.9 repeats (range –3 to +15) with higher values for male transmissions. Bulbar and autonomic signs were related to disease duration, pyramidal signs to CAG size, cerebellar features and peripheral neuropathy to both. Among the remaining 21 families, three carried the SCA1 and one the SCA6 mutation. This study suggests that SCA2 is the prevalent mutation in southern Italy. Received: 24 November 1997 Received in revised form: 26 October 1998 Accepted: 8 November 1998     

Novel mutations in the arylsulfatase A gene in eight Italian families with metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. We analysed the ARSA gene in eight unrelated Italian families with different clinical variants of MLD and identified three novel mutations: two Ser406Gly, (Glu329Ter) associated with late infantile MLD and one (Leu52Pro) with juvenile MLD. Only one family carried a pseudodeficiency allele (Asn350Ser). The IVS2+1G>A mutation occurred in four families. We also identified three polymorphisms, all in heterozygosis: Thr391Ser was present in five families, Trp193Cys in four families, and Ala210Ala in one family. We could identify 100% of the alleles causing MLD in the families, involving 12 different mutations, resulting in improved prognosis and genetic counselling.