Susan Brammah

Transurethral Prostate Resection in Patients with Hypocontractile Detrusor—What is the Predictive Value of Ultrastructural Detrusor Changes?

PURPOSE Men with detrusor failure and chronic urinary retention have a lower voiding success rate and higher postoperative morbidity following transurethral prostatectomy than those with bladder outlet obstruction. Current investigations, including urodynamics, may be unable to predict the response to surgical treatment. We identified ultrastructural features on detrusor biopsy that correlated with the postoperative voiding outcome in patients with a hypocontractile detrusor undergoing transurethral prostatectomy. MATERIALS AND METHODS Detrusor biopsies were obtained from 17 patients with urodynamic evidence of bladder outlet obstruction or a hypocontractile detrusor undergoing transurethral prostatectomy and from 5 controls. Specimens were examined by transmission electron microscopy. Ten individual detrusor ultrastructural features were analyzed. Findings were compared with preoperative and postoperative clinical parameters. RESULTS Failure to void after transurethral prostatectomy was significantly associated with the ultrastructural features of variation in muscle cell size, muscle cell shape, collagenosis and abnormal fascicles. These 4 features were significantly associated with each other, defining a distinctive pattern of detrusor failure. For transurethral prostatectomy failure the sensitivity, specificity, and positive and negative predictive values of all 4 features together were 60%, 91%, 75% and 84%, respectively. Three or 4 features on detrusor biopsy predicted voiding failure. CONCLUSIONS Detrusor ultrastructural analysis is highly predictive of voiding outcome following transurethral prostatectomy in patients with detrusor failure. Patients with ultrastructural features previously described as part of the myohypertrophy pattern do not have a primary diagnosis of bladder outlet obstruction but rather detrusor failure secondary to bladder outlet obstruction.

Anncaliia algerae Microsporidial Myositis

Immunosuppression is a risk factor for serious infection in humans.

Tactile Corpuscle-Like Bodies in Colonic Mucosa

During the routine examination of a segment of colon resected for adenocarcinoma, a diffuse proliferation of mucosal tactile corpuscle-like bodies was identified. The bodies showed a lamellar structure by light microscopy and were S-100 positive. Electron microscopy demonstrated parallel slender processes with prominent surface caveolae, arising from peripheral cell bodies. Similar structures sometimes occur in neurofibromas but they have not previously been reported in the gastrointestinal tract.

Variants in the oxidoreductase PYROXD1 cause early-onset myopathy with internalized nuclei and myofibrillar disorganization

This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase. Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands. PYROXD1 is a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins (FAD-binding) and catalyze pyridine-nucleotide-dependent (NAD/NADH) reduction of thiol residues in other proteins. Complementation experiments in yeast lacking glutathione reductase glr1 show that human PYROXD1 has reductase activity that is strongly impaired by the disease-associated missense mutations. Immunolocalization studies in human muscle and zebrafish myofibers demonstrate that PYROXD1 localizes to the nucleus and to striated sarcomeric compartments. Zebrafish with ryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease.

Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine

Variants in ACTA1, which encodes α-skeletal actin, cause several congenital myopathies, most commonly nemaline myopathy. Autosomal recessive variants comprise approximately 10% of ACTA1 myopathy. All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth. Targeted next-generation sequencing in two brothers with congenital muscular dystrophy with rigid spine revealed homozygous missense variants in ACTA1. Skeletal α-actin expression was preserved in these patients. This report expands the clinical and histological phenotype of ACTA1 disease to include congenital muscular dystrophy with rigid spine and dystrophic features on muscle biopsy. This represents a new class of recessive ACTA1 variants, which do not abolish protein expression.

Congenital Titinopathy: Comprehensive characterization and pathogenic insights: Congenital Titinopathy

Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.

A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

G.P.35

TTN encodes titin, the largest human protein. In striated muscle two titin molecules align “head to head” to span the full length of the sarcomere, providing a scaffold for sarcomere organisation, a sensing and signalling hub, and both passive and active modulation of muscle contraction. Dominant mutations in TTN are established causes of cardiomyopathy, tibial muscular dystrophy, and hereditary myopathy with early respiratory failure. More recently, several individuals with two truncating mutations have been described with increased internalised nuclei (CNM) with or without multi-minicores (MMC). Using next generation sequencing, we identified 14 individuals from 11 families with compound heterozygous or homozygous truncating TTN mutations. Presentation was in utero or during infancy in all cases. Weakness of truncal and respiratory muscles was often prominent, and early-onset scoliosis and respiratory failure were common complications. Three affected individuals had dilated cardiomyopathy (DCM) or left ventricular dysfunction, and one carrier parent developed DCM in later life. Two individuals had congenital aortic abnormalities (coarctation and stenosis). Many affected individuals had distinctive clinical features which are unusual for congenital myopathies, including congenital or early-onset hand and foot deformities, congenital scoliosis, spinal rigidity, cleft palate, distal hypermobility and short stature. The most common histological abnormality was a mixed CNM-MMC pattern. Novel histological patterns included typical congenital fibre-type disproportion (CFTD) and CNM-MMC with caps and nemaline rods. The presence of palatal clefts, facial dysmorphology, and cardiac malformations in several individuals with TTN mutations suggests that titin plays a role in foetal development. Mutations in TTN should be considered in any individual with predominant truncal and respiratory weakness, and CNM, MMC, CFTD, caps, rods, or any combination of these, on muscle biopsy.

Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant

A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G > A, NM_006757.3:c.681+1G > A). TNNT3 encodes skeletal troponin‐Tfast and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon‐skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin‐Tfast protein with secondary loss of troponin‐Ifast. We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type‐2 fibers and deficiency of troponin‐Tfast.

Anncaliia algerae Microsporidial Myositis, New South Wales, Australia

We describe the successful management of Anncaliia algerae microsporidial myositis in a man with graft versus host disease after hemopoietic stem cell transplantation. We also summarize clinical presentation and management approaches and discuss the importance of research into the acquisition of this infection and strategies for prevention.