Lyn Kiers

Mitochondrial DNA variants in inclusion body myositis

Mitochondrial DNA variants have been shown to be associated with many diseases. Mutations at mitochondrial DNA nucleotide positions 3192, 3196, 3397 and 4336 have been described in association with late-onset Alzheimers disease. The pathological similarities between inclusion body myositis and Alzheimers disease prompted an analysis of the relationship between the reported mutations and sporadic inclusion body myositis. The 4336G variant was not significantly increased in patients with inclusion body myositis or Alzheimers disease when compared to controls. None of the patients with inclusion body myositis carried mutations at nucleotide positions 3192, 3196 and 3397. A transition at nucleotide position 4580 was detected in some patients with inclusion body myositis and Alzheimers disease but was not significantly higher in frequency when compared to controls. Phylogenetic analysis showed that the 4336G and 4580A variants clustered together in their respective group. A group of patients with inclusion body myositis also clustered together on a separate branch of the phylogenetic tree. Closer investigation of this group revealed a common polymorphism at nucleotide position 16311. The frequency of the 16311C variant was higher in inclusion body myositis than in Alzheimers disease and controls, although when only caucasian patients were considered the increased frequency was not statistically significant. Further studies will be required to determine whether this variant plays a role in the pathogenesis of inclusion body myositis.

Association of acute inflammatory demyelinating polyneuropathy with acute lymphoblastic leukaemia and HLA-A11

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) developed in three patients receiving chemotherapy for acute lymphoblastic leukaemia or the closely related entity lymphoblastic lymphoma, a relationship that has not been previously described. The HLA-A11 antigen was expressed by all patients, two of whom were Chinese, raising the possibility of a genetically-based immunological predisposition to GBS in this patient group.

G.P.63 High-resolution analysis of HLA-DRB1 alleles and diplotypes in an Australian inclusion body myositis cohort

In Caucasians, susceptibility to sporadic inclusion body myositis (s-IBM) is associated with the HLA-DR3 serotype and the HLA-DRB1∗0301 allele which encodes it, and with the extended 8.1 MHC ancestral haplotype. Most previous HLA studies in s-IBM have used serological typing or low-resolution (2-digit) genotyping to identify disease-associated alleles, and the contribution of alleles other than HLA-DRB1∗0301 and of the complementary in trans allele at the HLA-DRB1 locus has received little attention. In the present study we performed high-resolution (4-digit) HLA-DRB1 genotyping in an Australian cohort of 105 s-IBM patients and 189 controls from the Busselton Population Study and analysed risk-associated alleles and effects on age-at-onset (AAO) of the disease. Case–control logistic regression analysis showed that, apart from the strongly associated HLA-DRB1∗0301 allele (OR 13.6), HLA-DRB1∗0101 (OR 3.65) and HLA-DRB1∗1301 (OR 3.31) are independent risk alleles. A number of other alleles, HLA-DRB1∗0401, ∗0404, ∗0701, ∗0901, ∗1101 and ∗1501 were reduced in frequency in s-IBM cases and may be protective. We evaluated the influence of allele combinations on disease risk and found that the strongest estimated risk is with the HLA-DRB1∗0301/∗0101 diplotype, while other allele combinations have diminishing risk effects. HLA-DRB1∗0301 was associated with an AAO 4.3 years earlier than other alleles and DRB1∗1301 with an AAO 4.5 years later, despite it being a risk factor. The findings indicate that the influence of HLA-DRB1 in s-IBM is complex, influencing both disease risk and AAO, and that allelic interactions at the HLA-DRB1 locus contribute to disease susceptibility.

9. The optimization of 2-channel EEG for the detection of generalized and temporal seizures: A pilot study for EEG monitoring study in the intensive care unit (CU)

Objective: Nerve conduction studies are commonly requested for children with pes cavus, to exclude possible underlying neuropathy. We aimed to review our experience and identify predictive factors for abnormal neurophysiologic testing in these children. Materials and methods: Retrospective chart review of 51 patients (36 boys) undergoing neurophysiologic testing for pes cavus at the Royal Children’s Hospital, Melbourne, between 2004 and 2009. Results: Subjects were aged 2–19 (mean 11) years at the time of assessment. All had varying degrees of cavo-varus deformities, 13 had associated weakness, sensory symptoms or ataxia, and 13 had family history of feet deformities. Neurophysiologic results were abnormal in 14 patients (axonal neuropathy in 6, demyelinating neuropathy in 7 and non-specific in 1). Factors predictive of abnormal neurophysiologic results include progressive foot deformities, lower limb weakness, areflexia and sensory abnormalities and evidence of upper limb involvement (p < 0.05 for all). The symmetry of clinical findings and family history of foot deformities were not predictive. Conclusions: Nerve conduction studies were abnormal in only 27% of children referred for investigation of pes cavus. The yield of these studies is low in the absence of areflexia, weakness, sensory abnormalities, upper limb involvement and/or progressive foot deformities.

G.P.16.09 Epistatic interactions between DRB1 alleles influence susceptibility and clinical phenotype in sporadic inclusion body myositis (sIBM)

Background: Susceptibility to sIBM is strongly associated with HLA-DRB1*03 and the 8.1 MHC ancestral haplotype but little is known about the effect of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. Objectives: To determine whether DRB1 allele interactions influence susceptibility to sIBM and disease phenotype. Patients & Methods: HLA-DRB1 genotyping was carried out in 80 biopsy-proven cases of sIBM using high-resolution DNA sequencing in 55 cases and serological typing in 25 cases. Allele frequencies were compared with those in a group of 190 healthy population controls. All patients had manual muscle testing using an expanded 10-point MRC scale as well as documentation of historical aspects of their disease. Results: The strong positive association with HLA-DRB1*03 was confirmed (OR 9.6) while negative associations were found with HLA-DRB1∗04 and DRB1∗07. In addition, amongst those carrying the HLA-DRB1∗03 allele DRB1∗03/∗01 heterozygotes were over-represented in the sIBM group (p < 0.003). DRB1∗03/∗04 was the most significantly under-represented combination (p < 0.008) and remained so when those with DRB1∗03/∗01 were excluded (p = 0.03). Age at onset (AAO) was not associated with any individual allele but the mean AAO was earlier in the HLA-DRB1∗03/∗01 heterozygotes (55.8 years vs 62.3 years, p = 0.006) who also had more severe quadriceps weakness than the rest of the cohort (average MRC grade 3.57 vs 5.63, p = 0.003). Conclusions: The findings indicate that the HLA-DRB1*03 allele interacts with other alleles at the DRB1 locus to influence susceptibility to sIBM as well as AAO of the disease and disease severity.

G.P.5.06 HLA alleles and MHC haplotypes in sporadic inclusion body myositis: Frequencies and phenotypic correlations

Background. Sporadic inclusion body myositis (sIBM) is strongly associated with HLA-DR3 and the MHC 8.1 ancestral haplotype (AH) in Caucasians, but less is known about other HLA associations or whether HLA haplotypes modify disease expression. Objective. To determine the frequency of HLA alleles and haplotypes in a cohort of 80 Australian Caucasian cases of biopsy-proven sIBM and correlations with phenotypic features. Methods. Patients were recruited from neuromuscular clinics in Perth, Melbourne and Sydney. All were examined by one or more of the authors and fulfilled the criteria for definite or probable sIBM [1] and [2]. Typing for Class I and II HLA alleles was performed by high resolution sequence-based genotyping, and assignment of ancestral haplotypes (AHs) was predicted from the presence of specific HLA-B and DRB1 alleles. The frequencies of alleles and AHs were compared with a control group of 190 healthy Caucasian West Australians. Results. The strong association with HLA-DR3 (p < 0.001), HLA-B8 (p < 0.001) and the 8.1AH (p < 0.001) was confirmed. Significant positive associations were also found with HLA-DR1 (p < 0.001) and the 7.2AH (p = 0.026), as well as with HLA-B55 (p = 0.018), the 52.1AH (p = 0.052) and 62.3AH (p = 0.023). HLA-DR1 (p = 0.06) and B27 (p = 0.04) were associated with an earlier age-of-onset. HLA-DR3 was associated with a lower quadriceps muscle strength (p = 0.04) and B27 and B49 with higher quadriceps strength even when allowing for treatment as an independent variable. Conclusions. The findings demonstrate novel HLA alleles and MHC haplotypes associated with susceptibility to sIBM in a Caucasian population, and that certain HLA alleles have a disease-modifying effect.