Vicki Fabian

Dominant Mutations in KBTBD13, a Member of the BTB/Kelch Family, Cause Nemaline Myopathy with Cores

We identified a member of the BTB/Kelch protein family that is mutated in nemaline myopathy type 6 (NEM6), an autosomal-dominant neuromuscular disorder characterized by the presence of nemaline rods and core lesions in the skeletal myofibers. Analysis of affected families allowed narrowing of the candidate region on chromosome 15q22.31, and mutation screening led to the identification of a previously uncharacterized gene, KBTBD13, coding for a hypothetical protein and containing missense mutations that perfectly cosegregate with nemaline myopathy in the studied families. KBTBD13 contains a BTB/POZ domain and five Kelch repeats and is expressed primarily in skeletal and cardiac muscle. The identified disease-associated mutations, C.742C>A (p.Arg248Ser), c.1170G>C (p.Lys390Asn), and c.1222C>T (p.Arg408Cys), located in conserved domains of Kelch repeats, are predicted to disrupt the molecules beta-propeller blades. Previously identified BTB/POZ/Kelch-domain-containing proteins have been implicated in a broad variety of biological processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, and myofibril assembly. The functional role of KBTBD13 in skeletal muscle and the pathogenesis of NEM6 are subjects for further studies.

Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis

The prevalence of sporadic inclusion body myositis (sIBM) is variable in different populations and ethnic groups. A previous survey in Western Australia in 2000 found a prevalence of 9.3 per million population. We have now performed a follow-up survey to determine whether there has since been any change in prevalence. The current prevalence was found to be 14.9 per million population, with a prevalence of 51.3 per million population in people over 50 years of age. This is the highest reported prevalence of sIBM and correlates with a high frequency of HLA-DR3 and the 8.1 major histocompatibility complex ancestral haplotype in this population. Review of a combined cohort of 57 sIBM cases from three Australian centres revealed a high rate of initial misdiagnosis and a mean time to diagnosis of 5.2 years, which suggests that even the latest prevalence figure may be an underestimate, and emphasising the need to increase the level of awareness of the condition among the medical community.

Butyrylcholinesterase K variant and Alzheimer’s disease

Abstract This study attempted to corroborate findings on the association between butyrylcholinesterase K variant and Alzheimer’s disease. This was performed on an autopsy-confirmed series of patients with Alzheimer’s disease and controls. The butyrylcholinesterase K variant was found to be of increased allele frequency in patients with sporadic Alzheimer’s disease. When related to APOE ɛ4 typing the association was specific but not sensitive for the diagnosis of Alzheimer’s disease.

Paraspinal and scapular myopathy associated with scleroderma.

Objective: To describe a form of inflammatory myopathy with prominent involvement of the paraspinal and scapular muscles in patients with scleroderma. Methods: Review of clinical records, laboratory investigations, and muscle biopsies. Results: Patients presented with a “dropped head” resulting from weakness of the posterior cervical muscles (three cases) or camptocormia (“bent spine”) resulting from weakness of the paraspinal muscles (two cases) and variable weakness and atrophy of shoulder girdle muscles with mild or absent pelvic girdle involvement. Biopsies from the deltoid or paraspinal muscles showed myositis of variable severity and scleroderma vasculopathy in all cases. The response to prednisolone and cytotoxic agents was poor, but there was a good response to intravenous immunoglobulin therapy in one case. Conclusions: Patients with scleroderma may develop a restricted form of immune-mediated inflammatory myopathy with a predilection for the paraspinal and scapular muscles, which is poorly responsive to treatment with glucocorticoids and immunosuppressive agents and may require consideration of other treatment modalities.

Familial inclusion body myositis in a mother and son with different ancestral MHC haplotypes

An Ashkenazi Jewish family in which the mother and a son both have inclusion body myositis (IBM) is reported. The condition developed at an earlier age and was more rapidly progressive and less responsive to treatment in the son than in the mother or other IBM patients in our clinic. Genetic analysis showed that the mother carried alleles of the 8.1 MHC ancestral haplotype (AH; HLA-B8, DRB1*0301), which is found in 85% of IBM patients in Western Australia. The son did not inherit this haplotype, but carried alleles characteristic of the 52.1AH (HLA-B5, DRB1*1502) of paternal origin. The findings indicate that in this family either the 8.1AH or 52.1AH may carry susceptibility for IBM and that the 52.1AH is associated with a more severe and treatment-resistant form of the disease.

Muscle histopathology in children with spastic cerebral palsy receiving botulinum toxin type A

Introduction: Botulinum toxin A (BoNTA) is routine treatment for hypertonicity in children with cerebral palsy (CP). Methods: This single‐blind, prospective, cross‐sectional study of 10 participants (mean age 11 years 7 months) was done to determine the relationship between muscle histopathology and BoNTA in treated medial gastrocnemius muscle of children with CP. Open muscle biopsies were taken from medial gastrocnemius muscle and vastus lateralis (control) during orthopedic surgery. Results: Neurogenic atrophy in the medial gastrocnemius was seen in 6 participants between 4 months and 3 years post‐BoNTA. Type 1 fiber loss with type 2 fiber predominance was significantly related to the number of BoNTA injections (r = 0.89, P < 0.001). Conclusions: The impact of these changes in muscle morphology on muscle function in CP is not clear. It is important to consider rotating muscle selection or injection sites within the muscle or allowing longer time between injections. Muscle Nerve 53: 407–414, 2016

Classic and desmoplastic medulloblastoma: Complete case reports and characterizations of two new cell lines

Medulloblastoma (MB) is the most common type of brain tumor affecting children. These tumors are a significant cause of childhood mortality and morbidity, and more effective and less invasive treatment options are urgently required. To achieve these aims, it will be critical to develop a more comprehensive understanding of the molecular pathogenesis of MB. At present, there are relatively few well‐characterized MB cell lines available to the research community for the study of MB molecular and cellular biology. Here we present the case reports of two children diagnosed with classic and desmoplastic MB, and describe the characteristics of two new MB cell lines derived from these individuals. A number of genes encoding components of the sonic hedgehog (SHH) and WNT pathways were up‐regulated in the desmoplastic relative to the classic MB cell line consistent with aberrant activation of these pathways in desmoplastic MB. These cell lines represent an additional resource for the analysis of diverse aspects of MB biology.

632: Statins may initiate a persisting immune-mediated myopathy and myositis: a study of 10 cases

Background: Statins may cause a necrotising myopathy and hyperCKaemia which are usually reversible once the drug is discontinued. Aim: To investigate the muscle pathology in a group of 10 patients who developed myopathic symptoms during statin therapy and in whom symptoms persisted or progressed after withdrawal of the drug. Methods: All patients were examined by a neurologist or rheumatologist on more than one occasion and had a muscle biopsy after cessation of statin therapy. Immunohistochemical techniques for MHC Class I and II antigen expression and demonstration of macrophages and lymphocyte subsets were applied in addition to routine biopsy stains. Results: In 4 of the 10 patients the biopsy showed an active necrotizing inflammatory myopathy and in another features of inclusion body myositis. In the remaining cases the biopsy demonstrated a necrotizing myopathy without inflammation but with diffuse upregulation of MHC-I in 5 cases and nonspecific myopathic changes in one. Conclusions: Our findings suggest that statin therapy may initiate an immune-mediated myopathy or myositis with progressive symptoms after withdrawal of the drug, or unmask a pre-existing myopathy. The