0216 The benefit of carrier testing in Duchenne and Becker muscular dystrophy families with known deletions

Poster Abstracts Method: Clinical and molecular data on 10 families with changes in

codon 905 of TSC2 were collected and functional studies of the nmtated Rg05Q/W variants were performed. Results: A 2714G > A (R905Q) missense mutation in exon 23 of TSC2 was identified 4 fanfflies. Their phenotype was characterized by the absence of intractable epilepsy, disfiguring skin lesions, mental retardation or major organ involvement. Six patients with a different mutation at the same codon (2713G > T or R905"W) had a more severe phenotype. Both amino acid substitutions affected tuberin function, with Rg05w having a more severe effect than R905Q. Conclusion: We have described ten new fanfflies with codon 905 missense changes in TSC2. In the R905Q families, the TSC phenotype was unusually mild, characterized mainly by seizures that remitted spontaneously or that were easily controlled with anti-epileptic drugs. Functional studies showed both 905 codon mutations to be pathogenic without disrupting tuberin function completely. The finding o f a more severe phenotype associated with the sporadic Rg05w nmtation as compared to the familial R905Q mutation was consistent with the functional studies. Our findings support the observation that familial TSC, even when it is due to a TSC2 mutation, is less severe than sporadic TSC. Genotype-phenotype correlations indicate that mild TSC phenotypes may be associated with specific TSC2 mutations. 0214 A polymorphism in the CYP46 gene may affect Alzheimer's disease risk Koivisqto, A.M 1. 1University Of Kuopio, Kuopio, Finland Background: Cholesterol metabolism seems to be involved in the patho-

genesis of Alzheimer's disease (AD). Cholesterol 24S-hydroxylase (CYP46) in the chromosome [email protected] plays a key role in the hydroxylation of brain cholesterol to 24-hydroxycholesterol. The gene for apolipoprotein E (APOE), a major cholesterol-transporting plasma protein, expresses as three different polymorphic allelic forms (APOE e2, e3 and e4) of which A_POE e4 is associated with an increased risk of AD. Since, depletion of brain cholesterol levels reduces the generation of beta-amyloid protein in the brain and cholesterol-lowering drugs may reduce the risk of dementia, we tested the hypothesis whether single nucleotide polymorphisms (SNP) in the CYP46 gene with or without APOE ~4 allele carriers were associated with AD. Method: We genotyped two single nucleofide polymorphisms (dbSNP:754203 T-to-C, dbSNP:2146238 and G-to-T for CWP46) and apolipoprotein E (APOE) for 422 AD patients and 469 controls in a Finnish case-control study using a SNaPshot multiplex assay. Binary logistic regression analyses were carried out with SPSS version 11.5 and the level of statistical sigtffficance was set p < 0.05. Results: The results showed that a significant association between dbSNP:754203 CC genotype and increased AD risk was observed in all (2.1 fold risk) and APOE4+ subjects (13.6 fold risk) compared to Tcarriers. Genotype frequencies of CYP46 dbSNP:2146238 remained equal between AD and controls. Conclusion: Our results provide an additional support that the polymorphism in the CYP46 dbSNP:754203 may influence susceptibility to AD in a Fimrish population. 0215 Siblings with Xerodenna Pigmentos~un Group A showing mild cutaneous and various neurological ulatdfestatio as Satostd Kuru ~, Midori Yasuma 1, Motoko Sakai ~, Masaaki Konagaya 1,

SlfflliClff Moriwaki 2. 1Departments of Neurology and Dermatology,

Suzuka National Hospital, Japan; 2Photon Medical Research Center, Hamamatsu University School of Medicine, Japan We report siblings with xeroderma pigmentosum group A (XP-A) showing mild cutaneous and late-onset severe neurological mamfestations. The elder brother is 50 years old. He first noticed unstability in walking at age 16 years of age. Sub sequently slowly progressive mental

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deterioration developed with cerebellar atmvia, spastidty, amyotrophy with fasciculation, sensory disturbance and myoclonus-like involuntary movement. In addition, he showed urinary dysfunction and vocal cord paralysis. Cranial MRI revealed marked atrophy of the cerebrum and cerebellmn. Sural nerve biopsy showed axonal degeneration. His younger sister is 45 years old. She presented with dysarthria at age 18 years of age and showed almost similar clinical course and manifestations to her brother's. Both of them suffered from sensitivity to the sun and no malignant skin tumor. They were diagnosed as XP-A by the measurement of unscheduled D N A syuthesis and complementation analysis. Gene analyses revealed compound heterozygote for G-+C substitution at the 3' splicing acceptor site of intron 3 and insertion of 4 bases in exon 6 of XPA gene. The former is a common mutation in Japanese and the latter is a novel mutation. It is suggested that present siblings have a deficit in the nucleotide-exdsion repair, especially in transcription-coupled repair with relative sparing of global genome repair. 0216 The benefit of carrier testing in Duehenne and Becket Muscular Dyslrophy faudlies with known deletions

MaeLennan, S 1, Pedersen, R 1, Mullan, G 3, Taylor, p3, Buckley, M 2"3, Mowat, D Z'z. 1Sydney Children's Hospital, Sydney, Australia,"

2University of New South Wales, Sydney, Australia; 3South Eastern Area Laboratory Service, Prince of Wales Hospital, Sydney, Australia Background: Carrier status determination in Duchenne/Becker muscu-

lar dystrophy has relied on indirect meflmds, such as creatine kinase levels and linkage analysis. The results from these methods are frequently equivocal. Our experience is that many pregnant women with uncertain carrier status opt for invasive prenatal testing. Method: Our laboratory has developed a relative amplification multiplex polymerase chain reaction method (RAMP) that reliably determines carrier status in families where the dystrophin gene deletion is already known. Results: We describe R A M P analysis of 68 women o f uncertain carrier status from 42 families. Fifty of the 68 women tested (174%) were found not to be carriers, which also obviated the need for carrier testing in a further .~ 150 women. Conclusion: Tiffs very accurate, inexpensive technique has the capacity to restore reproductive confidence to female relatives who are proven not to be carriers. This avoids unnecessary invasive prenatal tests with the inherent miscarriage risk and emotional upheaval. Prenatal testing is still recommended for non-carrier mothers o f an isolated male proband due to the residual chance o f gonadal mosaicism. These women do not require cardiological assessment. Confirmed carriers are able to make informed reproductive choices and undergo necessary cardiac assessments. 0217 Novel Mutation in tile Gene SPG3A in Hereditary Spastic Paraplegia

Matsui, M 1, Kawarai, T 2, Hose, yZ, Tomimoto, H 1, lseki, K 3, Rogaeva, E a, Orlacchio, A 4, Bernardi, G 4, George-Hyslop, PS 2, Takahashi, R ~. ZKyoto University School of Medicine, Kyoto, Japan;

2University of Toronto, Toronto, Canada; 3Shizuoka General Hospital, Shizuoka, Japan; 4University of Rome, Rome, Italy" Background" Hereditary spastic paraplegia (HSP) is a clinically and

genetically heterogeneous neurodegenerative disease characterized by progressive spastidty of the lower extremity. Recently, SPG3A mutation was identified in the pure form of autosomal dominant HSP. Genetic analysis identified SPG3A-HSP families in France, Germany, Italy, North America, Tibet, and Portugal. The SPG3A gene encodes the atlastin, which shows homology to guanylate binding protein-l, a member o f the dynanfin fanfily of large GTPase.