Colm Treacy

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

An ITPR1 gene deletion causes spinocerebellar ataxia 15/16: a genetic, clinical and radiological description.

the purpose of this study was to characterise a novel family with very slowly progressive pure spinocerebellar ataxia (SCA) caused by a deletion in the inositol 1,4,5‐triphosphate receptor 1 (ITPR1) gene on chromosome 3. This is a detailed clinical, genetic, and radiological description of the genotype. Deletions in ITPR1 have been shown to cause SCA15/SCA16 in six families to date. A further Japanese family has been identified with an ITPR1 point mutation. The exact prevalence is as yet unknown, but is probably higher than previously thought. The clinical phenotype of the family is described, and videotaped clinical examinations are presented. Serial brain magnetic resonance imaging studies were carried out on one affected individual, and genetic analysis was performed on several family members. Protein analysis confirmed the ITPR1 deletion. Affected subjects display a remarkably slow, almost pure cerebellar syndrome. Serial magnetic resonance imaging shows moderate cerebellar atrophy with mild inferior parietal and temporal cortical volume loss. Genetic analysis shows a deletion of 346,487 bp in ITPR1 (the second largest ITPR1 deletion reported to date), suggesting SCA15 is due to a loss of ITPR1 function. Western blotting of lymphoblastoid cell line protein confirms reduced ITPR1 protein levels. SCA15 is a slowly or nonprogressive pure cerebellar ataxia, which appears to be caused by a loss of ITPR1 function and a reduction in the translated protein. Patients with nonprogressive or slowly progressive ataxia should be screened for ITPR1 defects.

ITPR1 GENE DELETION CAUSES SPINOCEREBELLAR ATAXIA 15/16: A GENETIC, CLINICAL AND RADIOLOGICAL DESCRIPTION OF A NOVEL KINDRED

An ITPR1 gene deletion causes spinocerebellar ataxia 15/16: a genetic, clinical and radiological description of a novel kindred. Spinocerebellar ataxia (SCA) 15/16 is an autosomal dominantly inherited, almost pure cerebellar ataxia, which shows slow or no progression. (It has been designated variably SCA15 and SCA 16; we refer to it here as SCA15/16 to avoid confusion). Deletions in the inositol 1,4,5-triphosphate receptor 1 (ITPR1) on chromosome 3 have been shown to cause SCA15/16 in six families worldwide to date, with one further Japanese family identified as having an ITPR1 point mutation. We present a previously unreported SCA15/16 kindred. We describe the clinical phenotype of the family in detail; affected subjects display a remarkably slow, almost pure cerebellar syndrome. We also present genetic analyses for all subjects and longitudinal MRI data for one affected subject. Genetic analysis shows a deletion of 346 487 bp in ITPR1 (the second largest ITPR1 deletion reported to date), suggesting SCA15 is due to a loss of ITPR1 function, and western blotting of lymphoblastoid cell line protein confirms reduced ITPR1 protein levels. Serial MRIs show midline cerebellar atrophy with mild inferior parietal and temporal cortical volume loss. We believe that genetic testing for SCA15/16 should become a routine DNA screen available in all neurogenetics clinics, which is likely to lead to an increased rate of the diagnosis. Familiarity with the phenotype is therefore important for all neurologists.

Penile rehabilitation for post‐prostatectomy erectile dysfunction

The objectives are as follows: To assess the effects of penile rehabilitation interventions for post-prostatectomy erectile dysfunction.