Merrilee Needham

Background:
Anti–3-hydroxy-3-methylglutaryl-CoA-reductase (HMGCR) antibodies are associated with immune-mediated necrotising myopathy (IMNM), a rare disease typically requiring multi-modal immunosuppression.1,2 PathWest Laboratory Medicine (PathWest) has been the sole provider in Western Australia (WA) of an anti-HMGCR ELISA assay since 2015. Positive predictive value (PPV) of this assay for a WA cohort (2015–2019) was calculated as 88%.3 This was the benchmark for performance set for audit of a WA cohort encompassing 2020–2023.

Methods:
Identified anti-HMGCR requests to PathWest between January 2020–December 2023, and identified positive results (reference: < 11 relative units). Exclusion criteria: aged under 18 years; non-WA resident; requested outside a tertiary public hospital. Electronic records reviewed to confirm HMGCR-IMNM diagnosis by an immunologist, rheumatologist or neurologist. Calculated PPV.

Results:
The number of anti-HMGCR requests from WA between 2020–2023 was 1,120. Twenty-five (2%) were positive. Of these, three were considered false positives resulting in a PPV of 88%. The PPV was previously calculated as 88% from a WA cohort of patients between 2015–2019 with application of the same exclusion criteria. This audit demonstrates the assay remains robust in its performance and meets the benchmark PPV of 88% provided by analysis of our index cohort.

References:
1. Allenbach Y, Benveniste O, Stenzel W, et al. Immune-mediated necrotizing myopathy: clinical features and pathogenesis. Nat Rev Rheumatol 2020; 16: 689–701.
2. Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011; 63: 713–21.
3. Tan E, Knight J, Khonasti S, et al. Clinical associations of patients with anti-3-hydroxy-3-methylglutaryl CoA reductase antibody-associated immune-mediated necrotising myopathy. Intern Med J 2023; 53: 1846–53.

Background
GABA-A encephalitis is rare and presents with seizures and altered cognition. MRI demonstrates multifocal non-enhancing, non-diffusion restricting cortical and subcortical FLAIR signal abnormalities, predominantly in temporal lobes. GABA-A cannot be tested in Australia. Most patients have incomplete responses to immunotherapy.

Case
A 47-year-old man presented with 4-weeks of headache, cognitive change, episodic non-sensical speech and synaesthesia (seeing spoken words written). Examination revealed moderate mixed dysphasia and normal cranial nerve, upper and lower limb examinations.
MRI demonstrated multifocal non-enhancing, non-diffusion restricting T2 hyperintense lesions in temporal and parietal lobes. Lumbar puncture was non-inflammatory with negative oligoclonal bands. Serum and CSF GABA-B, NMDA, AMPA, anti-neuronal, VGKC, and serum MOG and GAD65 were negative. Quantiferon Gold was positive, confirming latent tuberculosis, however additional infective testing resulted negative. EEG showed bilateral epileptiform abnormalities and focal seizures. PET demonstrated FDG activity in the fossa of Rosenmullar, with biopsy negative for malignancy.
Despite anti-seizure medications, intravenous immunoglobulin, and isoniazid he developed intractable hiccups, with progressive imaging changes. He improved following intravenous methylprednisolone and Rituximab, but re-presented with impaired hearing and auditory hallucinations, with further imaging progression. He commenced plasma exchange, methylprednisolone (1g weekly for 6-weeks, then 1g fortnightly for 6-weeks) and cyclophosphamide. Biopsy was considered, however GABA-A resulted positive in CSF and serum. Traditionally these cases are difficult to treat, but he has recovered to almost baseline cognition.

Conclusion
We describe a case of GABA-A encephalitis with typical MRI appearances, which was the clue to the underlying antibody, and an excellent clinical response following immunotherapy.

Valosin-containing protein (VCP) gene mutations are an under recognised autosomal dominant genetic disease presenting with both neurological and non-neurological phenotypes. A missense mutation in VCP can cause a myopathy, Paget’s disease of the bone or frontal temporal dementia. Less commonly seen phenotypes are amyotrophic lateral sclerosis, parkinsonism or axonal CMT. These conditions are not classically recognised as genetically related by clinicians when taking a family history, so the pattern of autosomal dominance is under recognised. This report will describe a case series with varied clinical presentations, gender, and age where VCP missense pathogenic variants were found. It will also describe a case with a variant of uncertain significance in the VCP gene. Valosin-containing protein is involved in regulatory cellular processes such as autophagy, membrane fusion, transcription and cellular degradation. Most pathogenic missense variants alter the N-terminal ubiquitin binding domains. These missense variants result in failure of regulatory cellular processes, which is thought to account for the wide spectrum of body systems affected. This has led to these diseases to be more recently termed VCP Multisystem Proteinopathies (VCP-MSP). It is pertinent that any family history with a combination of these conditions, including varying severity of symptoms, should raise the question of testing for this condition.