Normative data of muscle fiber diameter of vastus lateralis during childhood: a field test.

INTRODUCTION: Currently, our knowledge of standard data for muscle morphology in children is largely limited to the 1969 article by Brooke and Engel (BE). In 2016, we reported normal muscle morphology from vastus lateralis biopsies in ambulant children with cerebral palsy (CP). This report compares our normal biopsy results against BE standard value criteria. METHODS: Single-blind prospective cross-sectional study design. RESULTS: Results of biopsies taken in ambulant children with CP were normal according to morphometry and light and electron microscopy; however, only 5 of 10 fulfilled the BE standard value criteria. DISCUSSION: This short report highlights the requirement for contemporary age-specific normative data from a larger number of biopsies, including typically developing children. Review of the literature suggests that biopsy material may be available from typically developing children who were control patients in research trials. This morphometric data could contribute to expanding the normative data set. Muscle Nerve 59:590-590, 2019.

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.

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 molecule's 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.

Long-term outcomes of symptomatic optic pathway glioma: 32-year experience at a single Western Australian tertiary pediatric oncology center.

Introduction: Optic pathway gliomas (OPGs) are associated with significant risk of visual and endocrine morbidity, but data on long-term outcomes in symptomatic patients is sparse. This study reviews the clinical course, disease progression, survival outcomes and long-term sequelae in pediatric patients with symptomatic OPGs in our institution over three decades. Methods: Retrospective review of patients with symptomatic OPG treated in a single tertiary pediatric oncology center from 1984 to 2016. Results: A total of 37 patients were diagnosed with symptomatic OPG. Decreased visual acuity was the commonest presenting symptom (75.7%). Surgical intervention was performed in 62.2%; 56.5% underwent biopsy, 26.1% surgical debulking and 17.4% had orbital decompression with cystic fenestration and cosmetic optic nerve excision at different treatment intervals. CSF diversion was performed in 47.8% patients. Histopathologic examination confirmed 86% to be pilocytic astrocytoma and 1 ganglioglioma. 46% received chemotherapy and 48% had radiotherapy, at different intervals. Median follow-up was 13.74 years. In NF1 patients, overall survival (OS) was 100% at 5 years and 55.6 ± 24.8% at 25 years while progression-free-survival (PFS) was 50 ± 15.8% at 5 and 20 years. In non-NF1 patients, OS was 96.2 ± 3.8% at 5 years and 87.4 ± 9% at 25-years. 5-year PFS was 53.8 ± 9.8% and 25-year PFS was 49.0 ± 10%. Cumulative PFS was 53 ± 8.3% at 5 years and 49.7 ± 8.4% at 20 years while cumulative OS was 97.2 ± 2.7% at 5 years and 77.5 ± 10.8% at 25 years. 59.5% patients developed post-operative endocrinopathy. Long-term vision was normal in 8.1%, improved in 13.5%, stabilized in 40.5% but worsened in 37.8% patients. Three patients treated with radiotherapy developed second brain tumors. Conclusion: 25-year OS in this cohort was 77.5% but survivorship carried significant long-term morbidities including radiation-induced second malignant brain tumors.

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.

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.

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.

Compliance with reporting guidelines by Australian pathologists: an audit of the quality of histopathology reporting in high-grade glioma.

BACKGROUND: Diagnostic pathology reports inform management plans for patients with glioma, and there is an increasing clinical need for molecular testing. We assessed the quality of histopathology reports of grade III/IV gliomas. METHODS: Reports were obtained as part of a tumor biobank. From 720 pathology reports, 594 eligible reports were assessed for 28 elements derived from published checklists. A summary quality score incorporated 9 critical parameters for clinical decision making: diagnosis using World Health Organization 2007 criteria; cell type; grade; narrative supporting cell type and grade; absence of equivocal language; conclusion reporting cell type and grade; and conclusion aligned with report narrative. RESULTS: Of 594 eligible reports, the final conclusion was not supported by the report narrative in 122 (21%). Tumor classification and grade were not supported by the narrative in 105 (18%) and 36 (6%) reports, respectively. Only 145 (24%) reports fulfilled all 9 quality criteria, while 25% contained 6 or fewer key quality indices. Report quality was higher when pathologists had neuropathology subspecialization, when a grade IV tumor was reported, and when the specimen was from an initial resection or grade-progressed tumor rather than recurrent high-grade glioma. Use of molecular testing increased over time, from 29% to 48% over four quartiles of the study. Molecular testing was more frequently done where oligodendroglial elements were reported. CONCLUSION: A significant proportion of reports failed to meet key indicators of report quality. Pathology reporting is critical in communicating between pathologists and treating clinicians. Clinicians should be aware of reporting quality and seek clarification when required.

Investigation of splicing changes and post-translational processing of LMNA in sporadic inclusion body myositis.

Some features of sporadic inclusion body myositis (s-IBM) suggest that there is acceleration of the normal ageing process in muscle tissue. LMNA encodes the nuclear lamina proteins lamin A/C through alternative splicing, and aberrant splicing of exon 11 leads to the premature ageing disease, Hutchinson-Gilford progeria syndrome. Progerin, the pathogenic isoform expressed in HGPS tissues, has also been detected at low levels in tissues of normal individuals with aging. We therefore investigated the alternative splicing of LMNA gene transcripts, and the post-translational processing of prelamin A, in s-IBM and control muscle samples. Age-related low level expression of the progerin transcript was detected in both s-IBM and control muscles, but was not increased in s-IBM and there was no increase in progerin protein or demonstrable accumulation of intermediate prelamin isoforms in the s-IBM muscles. However, an age-related shift in the balance of splicing towards lamin A-related transcripts, which was present in normal muscles, was not found in s-IBM. Our findings indicate that while there are changes in the patterns of LMNA splicing in s-IBM muscle which are probably secondary to the underlying pathological process, it is unlikely that aberrant splicing of exon 11 or defective post-translational processing of prelamin A are involved in the pathogenesis of the 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.

Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1).

We previously linked Laing-type early-onset autosomal dominant distal myopathy (MPD1) to a 22-cM region of chromosome 14. One candidate gene in the region, MYH7, which is mutated in cardiomyopathy and myosin storage myopathy, codes for the myosin heavy chain of type I skeletal muscle fibers and cardiac ventricles. We have identified five novel heterozygous mutations--Arg1500Pro, Lys1617del, Ala1663Pro, Leu1706Pro, and Lys1729del in exons 32, 34, 35, and 36 of MYH7--in six families with early-onset distal myopathy. All five mutations are predicted, by in silico analysis, to locally disrupt the ability of the myosin tail to form the coiled coil, which is its normal structure. These findings demonstrate that heterozygous mutations toward the 3' end of MYH7 cause Laing-type early-onset distal myopathy. MYH7 is the fourth distal-myopathy gene to have been identified.