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Journal of Neurology 07/2012; 259(8):1761-3. · 3.47 Impact Factor
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M Cossburn,
A A Pace,
J Jones,
R Ali,
G Ingram,
K Baker,
C Hirst,
J Zajicek,
N Scolding,
M Boggild,
T Pickersgill,
Y Ben-Shlomo,
A Coles, N P Robertson
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ABSTRACT: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS).
We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7-107.3).
Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12-18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02-17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50-6.19) were predictive of AID expression.
Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment.
This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.
Neurology 08/2011; 77(6):573-9. · 8.31 Impact Factor
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M Ban,
J L McCauley,
R Zuvich,
A Baker,
L Bergamaschi,
M Cox,
A Kemppinen,
S D'Alfonso,
F R Guerini,
J Lechner-Scott, [......],
D A Hafler,
L F Barcellos,
A J Ivinson,
D Sexton,
J R Oksenberg,
S L Hauser,
M A Pericak-Vance,
J Haines,
A Compston,
S Sawcer
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ABSTRACT: Several single-nucleotide polymorphism (SNP) genome-wide association studies (GWASs) have been completed in multiple sclerosis (MS). Follow-up studies of the variants with the most promising rankings, especially when supplemented by informed candidate gene selection, have proven to be extremely successful. In this study we report the results of a multi-stage replication analysis of the putatively associated SNPs identified in the Wellcome Trust Case Control Consortium non-synonymous SNP (nsSNP) screen. In total, the replication sample consisted of 3444 patients and 2595 controls. A combined analysis of the nsSNP screen and replication data provides evidence implicating a novel additional locus, rs3748816 in membrane metalloendopeptidase-like 1 (MMEL1; odds ratio=1.16, P=3.54 × 10⁻⁶) in MS susceptibility.
Genes and immunity 12/2010; 11(8):660-4. · 4.22 Impact Factor
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ABSTRACT: Neuromyelitis Optica (NMO) is a rare neuroinflammatory disorder with limited epidemiological data. Antibodies against aquaporin-4 (Aq4ab) are reported to be highly specific for NMO and NMO spectrum disorders (NMO-SD). In this study we determine the prevalence of these disorders and spectrum of clinical phenotype in a population-based sample and analyse clinical features that predict Aq4ab positivity. Cases were identified from the SE Wales neuroinflammatory database and regional requests for Aquaporin-4 testing. 10 patients (M2:8, age range 7-70) with NMO were identified of which 7 had positive Aq4ab, as well as two female patients with Aq4ab positive NMO-SD; a combined prevalence of 16/million (95% CI 10 to 25). Median disease duration was 4 years (range 1-34) and median relapse frequency 0.63/year (0.14-1.60). Median MS severity score (MSSS) was 8.10 (4.35-9.59) One third of cases had severe visual impairment. MSSS did not differ between those treated with immunosuppressants (5/12) and those not. Both NMO-SD cases had isolated longitudinally extensive transverse myelitis (LETM). Aq-4ab were positive in 9/79 (11.4%) sample requests. Test requests were most commonly associated with poorly recovered optic neuritis (56.6%). Logistic regression identified the presence of LETM on MR as the most predictive feature for NMO (Likelihood ratio=5.43). In this study we have established disease prevalence for NMO in a UK population-based sample and identified LETM as the main indication for Aq4ab testing.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e26-7. · 4.87 Impact Factor
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M D Cossburn,
A A Pace,
J Jones,
R Ali,
G Ingram,
K Baker,
C Hirst,
J Zajicek,
N Scolding,
M Boggild,
T Pickersgill,
A Coles,
Y Ben-Shlomo, N P Robertson
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ABSTRACT: Alemtuzumab is a anti-CD52 humanised monoclonal antibody shown to be an effective treatment for relapsing multiple sclerosis (MS) in phase II studies but exhibits a unique adverse event profile. In limited follow-up studies development of autoimmune disease has been observed 20-30% of patients. Currently, the exact range and temporal evolution of autoimmune disease following treatment remains unclear but will have important implications for screening and safety monitoring. In this study we analyse prospective clinical and serological data from 225 patients treated with Alemtuzumab for a mean of 40.5 months (range 0.2-93.8). Novel autoimmune disease developed in 22.7%. Thyroid autoimmune disease was most common (17.8%) but a range of other autoimmune diseases including immune thrombocytopenic purpura, anti-GBM disease, neutropoenia, skin disorders and asymptomatic development of novel auto-antibodies was also observed. Risk of autoimmune disease was constant up to 55 months, following which there was a rapid decline, and independent of the number of treatments received or interval of dosage. Whilst established risk factors for autoimmune disease such as sex and age had no impact on autoimmune disease frequency, smoking was identified as a major risk factor with a relative risk of 4.95 for ever smokers. Risk of autoimmune disease in MS following alemtuzumab appears to be time limited and screening will need to continue for at least 5 years posttreatment. Individual risk for autoimmune disease is modified by external factors which should be incorporated within the counselling process prior to treatment.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e26. · 4.87 Impact Factor
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ABSTRACT: Clinical details of disease onset in multiple sclerosis (MS) are valuable, providing insight into disease outcome. Age is recognised as an important modifying factor for prognosis and may also exert an effect on characteristics of disease ignition. Understanding age-specific presentations improves interpretation of early disease, informing future management and may identify groups of patients with distinct clinical features. Using prospective data gathered over more than 20 years we have examined associations between age and clinical features at onset in 1207 patients from the UK, making specific comparisons between childhood and late-onset multiple sclerosis (LOMS). Age at onset varied significantly between sexes (M:32.2, F:29.8), 0.6% had paediatric, 2.9% adolescent and 4.0% LOMS. Only 6% had a progressive disease from onset (PPMS). F:M ratios were highest <16 years of age and reversed over the age of 50 (1:1.3). Ataxia at onset was common in the young but fell rapidly after age 30. Sphincteric, lower limb and facial motor symptoms rose with age independent of disease course. Probability of complete recovery from first event declined with age from 84% to 39.6% (p>0.001). Age at disease onset in MS exerts a significant effect on sex ratios, degree of recovery and symptoms. The rate of PPMS is only 6% when recall bias is eliminated. This, together with reducing odds of recovery with age provides little support for the aetiological separation of relapsing and progressive disease.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e31. · 4.87 Impact Factor
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ABSTRACT: Complement is known to play a key role in MS and recent work utilising proteomic analysis identified raised serum levels of C4a in patients compared to controls which decreased following relapse. In order to replicate and validate this finding which has significant implications for the pathogenesis of MS, we have measured serum C4 and C4a in 107 patients with representation from all disease subgroups and 40 controls. We also examined serial samples on 43 patients following relapse to assess dynamic changes. C4 levels showed good correlation with C4a (r=0.27, p=0.001). C4 levels were raised in MS patients (mean 267 mg/l, SD 116) compared to controls (mean 248 mg/l, SD 79; p<0.001) with no discrimination between disease subgroups. C4a levels were not significantly raised in primary (mean 1.40 mg/l, SD 0.67; p=0.89) or secondary (mean 1.69 mg/l, SD 0.70; p=0.18) progressive patients or relapsing remitting patients in remission (mean 1.39 mg/l, SD 0.79; p=0.91) compared to controls; but were significantly increased in patients in acute relapse (mean 2.07 mg/l, SD 1.07; p<0.001) and decreased significantly after 2 months (mean 1.85 mg/l, SD 0.91; p=0.028). In summary, we were able to confirm dynamic changes in C4a levels in patients in acute relapse implying a systemic humoural inflammatory component at relapse ignition; however, because of low sensitivity/specificity between patient groups it is unlikely that C4 or C4a could be employed as reliable clinical diagnostic or disease state biomarkers.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e54. · 4.87 Impact Factor
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ABSTRACT: Sero-epidemiological studies have demonstrated association between multiple sclerosis (MS) and prior Epstein-Barr virus (EBV) infection and it has been hypothesised that peripheral EBV reactivation may drive inflammation. Recent investigation has shown significant differences in median serum levels of EBV nuclear antigen-1 (EBNA-1) IgG between disease subgroups and correlation with disease activity reflected by number of Gd-enhancing lesions and T2 lesion volume. These data have led to hopes that EBNA-1 may be an accessible and effective marker of disease activity. We examined the applicability of these findings in clinical practice, assessing 100 subjects (25 PPMS, 25 RRMS, 25 RRMS in relapse, 25 controls) for serum EBNA-1 using both the Liaison quantitative chemiluminescent assay and Biotest ELISA. We showed no difference in levels between disease subgroups and no correlation with phenotypic characteristics including age at onset (r=-0.17, p=0.16), disease duration (r=0.03, p=0.78), EDSS (r=0.03, p=0.78) or MSSS (r=0.02, p=0.9). There was a poor correlation between the two test methods used (intraclass correlation coefficient 0.67; 0.56-0.78) suggesting potential problems with test interpretation. We have been unable to determine a clinical value for serum EBNA-1 levels in MS or to confirm reported association with disease course and clinical disease activity, although further investigation with larger sample sizes and parallel MR data may be of value to clarify this issue further.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e57. · 4.87 Impact Factor
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ABSTRACT: Sero-epidemiological studies have demonstrated the association between multiple sclerosis (MS) and prior Epstein-Barr virus (EBV) infection. It has been hypothesized that intermittent peripheral EBV reactivation may drive continuing central inflammation. Recent investigation has shown significant differences in median serum levels of anti-EBV nuclear antigen-1 (EBNA-1) IgG between disease subgroups and positive correlation with disease activity reflected by number of Gd-enhancing lesions and T2 lesion volume. These important data have led to hopes that anti-EBNA-1 IgG may be useful as an easily accessible and effective biomarker of disease activity.
We examined the applicability of these findings in routine clinical practice, assessing a well-characterized cohort of 100 subjects (25 primary progressive, 25 stable relapsing remitting, 25 active relapsing remitting seen in acute relapse and 25 controls) for serum anti-EBNA-1 IgG using both the Liaison quantitative chemiluminescent assay and Biotest ELISA.
We were unable to show a difference in quantitative analysis of serum anti-EBNA-1 IgG levels between disease subgroups and no correlation with phenotypic characteristics including age at onset (r = -0.17, P = 0.16), disease duration (r = 0.03, P = 0.78), EDSS (r = 0.03, P = 0.78) or MSSS (r = 0.02, P = 0.9). In addition, there was only moderate correlation between the two test methods used (intraclass correlation coefficient 0.67; 0.56-0.78) suggesting potential problems with test interpretation.
We have been unable to determine a clinical value for serum anti-EBNA-1 IgG levels in MS or to confirm reported association with disease course and clinical disease activity.
European Journal of Neurology 11/2010; 17(11):1386-9. · 3.69 Impact Factor
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European Journal of Neurology 07/2010; · 3.69 Impact Factor
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E A Marsh,
C L Hirst,
J G Llewelyn,
M D Cossburn,
M M Reilly,
A Krishnan,
M Doran,
A M Ryan,
A J Coles,
J L Jones, N P Robertson
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ABSTRACT: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an idiopathic immune mediated neuropathy causing demyelination and conduction block thought to occur as the result of an aberrant autoimmune response resulting in peripheral nerve inflammation mediated by T cells and humoral factors. Diagnosis commonly prompts initial treatment with steroids or intravenous immunoglobulin (IVIG) on which 5-35% subsequently become dependent to maintain function. Despite a number of small scale trials, the role for alternative long-term immunosuppression remains unclear. Alemtuzumab is a humanised monoclonal antibody targeting the CD52 antigen present on the surface of lymphocytes and monocytes. A single intravenous infusion results in rapid and profound lymphopoenia lasting >12 months. We report its use and clinical outcome in a small series of patients with severe IVIG-dependent CIDP. Seven patients (4 Males; 3 Females) who had failed to respond to conventional immunosuppression were treated in 5 centres receiving 9 courses of alemtuzumab (dose range 60-150 mg). Following treatment, mean monthly IVIG use fell 26% from 202 to 149 g and IVIG administration frequency from 22 to 136 days. Two patients had prolonged remission, two patients had a partial response and no clear benefit was observed in the remaining three patients (2 Males, 1 Females). Responding patients had a younger age at onset (19.5 years) and shorter disease duration than non-responders. Three patients developed autoimmune disease following treatment. Alemtuzumab may offer an alternative treatment for a subset of early onset IVIG dependent CIDP patients failing conventional immunosuppressive agents, but concerns about toxicity may limit its use.
Journal of Neurology 06/2010; 257(6):913-9. · 3.47 Impact Factor
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M M Wickremaratchi,
D Perera,
C O'Loghlen,
D Sastry,
E Morgan,
A Jones,
P Edwards, N P Robertson,
C Butler,
H R Morris,
Y Ben-Shlomo
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ABSTRACT: Previous prevalence studies of Parkinson's disease (PD) in the UK have spanned a 40 year period and have predominantly been in the North of the country. These have presented rates by current age but have not examined this by age at disease onset.
A community based prevalence study was undertaken which attempted to identify all clinically diagnosed cases of PD from primary and secondary care for the city of Cardiff, Wales, UK. A meta-analysis of all past studies in the UK, including our own, was also undertaken.
Overall, 380 cases of PD were identified from a population of 292 637 residents, giving a crude prevalence rate of 130 per 100 000 (95% CI 117 to 144) and an age standardised rate of 142 per 100 000 (95% CI 128 156), standardised to the 1997 England and Wales population. Our prevalence rates were very similar to the weighted average of previous UK studies although there was evidence of between study heterogeneity (p = 0.0006). 5.4% and 31.2% of prevalent PD patients had their disease onset below the age of 50 or 65 years, respectively.
The data suggest that there are no major geographical variations in the prevalence of PD in the UK and that the age adjusted prevalence rate has remained relatively stable over the past 40 years. Although PD risk is far greater in older subjects, patients with young onset are not that uncommon in the community, and health and social care provision should reflect their needs.
Journal of neurology, neurosurgery, and psychiatry 08/2009; 80(7):805-7. · 4.87 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system with a poorly defined and complex immunopathogenesis. Although initiated by reactive T cells, persistent inflammation is evident throughout the disease course. A contribution from complement has long been suspected, based on the results of pathological and functional studies which have demonstrated complement activation products in MS brain and biological fluids. However, the extent and nature of complement activation and its contribution to disease phenotype and long-term outcome remain unclear. Furthermore, functional polymorphisms in components and regulators of the complement system which cause dysregulation, and are known to contribute to other autoimmune inflammatory disorders, have not been investigated to date in MS in any detail. In this paper we review evidence from pathological, animal model and human functional and genetic studies, implicating activation of complement in MS. We also evaluate the potential of complement components and regulators and their polymorphic variants as biomarkers of disease, and suggest appropriate directions for future research.
Clinical & Experimental Immunology 12/2008; 155(2):128-39. · 3.36 Impact Factor
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ABSTRACT: Dentatorubral pallidoluysian atrophy (DRPLA) is a rare, autosomal dominant, clinically heterogeneous neurodegenerative disorder characterised clinically by progressive dementia, ataxia, chorea, myoclonic epilepsy and psychiatric disturbance and pathologically by combined degeneration of the dentatorubral and pallidoluysian systems. DRPLA has a marked ethnic predilection, most commonly reported in Japan and thought to be rare in Caucasian populations.
We describe the clinical and genetic characteristics of 17 patients with DRPLA segregating in four families in South Wales.
There was marked clinical heterogeneity with considerable overlap of symptoms and signs between and within families. The age of onset ranged from 34 to 60 years with an earlier onset associated with myoclonic epilepsy and a later onset associated with a Huntington disease-like presentation. We identified a distinct haplotype within one family not present within the other three families, suggesting that the expansion in at least one family did not arise from an immediate common ancestor. Analysis of repeat length polymorphisms in 306 Welsh control patients identified 14 (4.6%) with repeat lengths in the high-normal range, compared with 0% and 7.4% in previously reported north American Caucasian and Japanese control populations, respectively.
DRPLA may not be as geographically or ethnically restricted as previously thought and the diagnosis should be considered in non-Asian patients presenting with a wide spectrum of neurological disease, especially if there is a dominant family history of dementia or movement disorder. The prevalence of high-normal length alleles may account for the relatively high prevalence of DRPLA in Wales.
Journal of neurology, neurosurgery, and psychiatry 08/2008; 79(7):804-7. · 4.87 Impact Factor
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ABSTRACT: Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the CD52 antigen, a low molecular weight glycoprotein present on the surface of most lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T lymphocyte depletion. Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive relapsing multiple sclerosis in a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years. The mean annualised relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion. Mean change in EDSS was -0.36 overall and -0.15 in those patients completing > or =1 year of follow- up. Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting. Transient worsening of pre-existing neurological deficits during infusion was observed in 3 patients. 12 patients developed biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid disease and 1 patient autoimmune skin disease. We conclude that relapse rates fall following Campath 1-H. Whilst side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active relapsing remitting multiple sclerosis.
Journal of Neurology 02/2008; 255(2):231-8. · 3.47 Impact Factor
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ABSTRACT: Spinocerebellar ataxias (SCAs) are a group of clinically and genetically heterogeneous neurological diseases. The expansion of unstable microsatellite repeats has been identified as the underlying pathogenic cause of 10 subtypes of autosomal dominant SCAs. The aetiology of sporadic SCA is unknown. The aim of this study was to investigate the effect of large normal repeats in patients presenting with sporadic or familial ataxia compared to a control population. The size of the expansion was determined using a fluorescent PCR approach in 10 common SCA genes: SCA-1 (ATXN1), SCA-2 (ATXN2), SCA-3 (ATXN3), SCA-6 (CACNA1A), SCA-7 (ATXN7), SCA-8 (ATXN8OS), SCA-10 (ATXN10), SCA-12 (PPP2R2B), SCA-17 (TBP) and DRPLA (ATN1), in 165 ataxia patients and 307 controls of Welsh origin. There was no difference between cases and controls in the distribution of the large normal alleles, or in the distribution of the combined CAG repeats. The normal allele distribution in the Welsh population was largely similar to that of other Caucasian populations. Our study failed to demonstrate an effect of large normal repeats on the susceptibility to develop ataxia.
Neuroscience Letters 01/2008; 429(1):28-32. · 2.11 Impact Factor
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ABSTRACT: Three to 12 evaluations of clinical performance using the mini-clinical evaluation exercise (Mini-CEX) (n = 124) or direct observation of procedural skills (DOPS) (n = 21) were performed on 27 trainees working in an NHS neurology department. The communications/ counselling skills subdomain was scored in 64 evaluations. For Mini-CEX the focus was on gathering data (22%), diagnosis (31%), management (34%) and counselling (7%) (focus not recorded in 6%). For DOPS, lumbar puncture was the most common evaluated procedure (57%). Mini-CEX evaluations lasted 23.8 minutes (10.6) (mean, sd) and DOPS 25.9 minutes (12.6). Mini-CEX scores for overall competence and communication skills were mean 5.99 (sd 0.95, range 4-8) and 5.98 (sd 1.21, range 3-9) and for DOPS 5.71 (sd 0.90, range 4-8) both on scales of 1 to 9. Overall trainee competence and communication scores increased with year of training (p < 0.001, p < 0.004 univariate analysis). Assessors undertook up to three or four assessments in a session. Assessors and trainees considered that the observation and feedback had been 'very' or 'quite' useful in providing a relevant element of assessment. These assessments were feasible and useful in a neurology department and provided some evidence for increasing performance with trainee seniority. More assessor time (approximately one hour) than trainee time (24-26 min) was needed for each assessment undertaken.
Clinical medicine (London, England) 09/2007; 7(4):365-9. · 1.15 Impact Factor
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ABSTRACT: To determine the prevalence and causation of late onset cerebellar ataxia (LOCA) in south east Wales, United Kingdom.
A population based study of LOCA was conducted in a defined geographical region with a total population of 742,400. Multiple sources of ascertainment were used to identify all cases prevalent on 1 January 2001. The inclusion criteria were: a predominantly progressive cerebellar ataxia with onset of symptoms at age > or = 18 years; and disease duration of > or = 1 year. Cases with known acquired ataxias, ataxic syndromes with associated prominent autonomic dysfunction and/or atypical parkinsonism suggestive of multiple system atrophy and disorders with ataxia as a minor feature were excluded.
We identified 76 index cases of LOCA, of whom 63 were sporadic, idiopathic LOCA (ILOCA) and 13 were familial LOCA, of whom six had either spinocerebellar ataxia type 6, Friedreich's ataxia or dominant episodic ataxia. The mean annual incidence rate for the period 1999-2001 was 0.3/100,000 population/year. The crude prevalence rates were 8.4 per 100,000 (95% CI 7.2 to 11.6) for ILOCA and 1.8 per 100,000 (95% CI 0.8 to 2.7) for inherited LOCA. Of the 54/63 (85.7%) patients with ILOCA who were assessed, mean (SD) age at onset of symptoms was 53.8 (14.1) years (range 19 to 78) with a male:female ratio of 2.1:1. The mean disease duration was 8.7 (6.3) years (range 1 to 31). The most frequent presenting complaint was disturbance in gait (90.7%). One-third had a relatively pure cerebellar syndrome (33.3%) and two-thirds (66.7%) had additional extracerebellar neurological features. The majority (92%) were ambulant but only 9.3% were independently self-caring.
This population based study provides insight into LOCA within a defined region and will inform decisions about the rational use of healthcare resources for patients with LOCA.
Journal of Neurology Neurosurgery & Psychiatry 08/2004; 75(8):1129-34. · 4.76 Impact Factor
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Journal of Neurology Neurosurgery & Psychiatry 10/2003; 74(10):1444-5. · 4.76 Impact Factor
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ABSTRACT: Although the exact etiology of MS remains elusive, there is good evidence that genetic factors play an important role. These factors are likely to be polygenic, exerting both independent and interactive effects on the expression of MS. They may determine susceptibility and/or shape the clinical course.
The authors studied clinical phenotype in 245 concordant parent-child pairs recruited from a national register of familial disease over a 10-year period. Data were examined in order to determine the effect of parental sex on expression of disease in the offspring.
Allowing for the observed sex ratio of 2.6 F:1 M in this group of patients, sex pairings of parents and offspring were close to those expected. When assessed independently there was no evidence that either the sex of the affected offspring or the line of inheritance influenced disability, age at onset, or disease course. However, trends were observed toward greater disability and an increased frequency of primary progressive disease in offspring of affected fathers and an earlier age at onset in offspring of affected mothers. The highest mean Expanded Disability Status Scale score was observed in male offspring of affected fathers (5.64) and this group was also more likely to have primary progressive disease (OR 1.92). Thirty-one percent of families had an additionally affected offspring with no preferential maternal or paternal transmission.
In offspring of concordant parent-child families with MS who are at high risk of inheriting increased numbers of susceptibility genes there is no evidence for a parent of origin effect distorting sex ratios in affected offspring, but parent of origin may influence disability and disease course as well as increasing the risk to additional offspring within the same family. The mechanism of these effects is not clear but may result from interactions between genes encoded at different loci (epistasis), which each independently influence susceptibility and phenotype.
Neurology 08/2001; 57(2):290-5. · 8.31 Impact Factor
