GYG1 causing progressive limb girdle myopathy with onset during teenage years (polyglucosan body myopathy 2)

An 84-year-old lady with slowly progressive limb and axial muscle weakness with onset in her teens was referred for genetic investigations. Targeted next generation sequencing (NGS) revealed a homozygous mutation GYG1 in exon5:c.487delG:p.D163fs, confirming the diagnosis of Polyglucosan Body Myopathy 2 (PGBM2). Retrospective review of muscle pathology revealed a florid vacuolar myopathy with histochemical and ultrastructural features consistent with a polyglucosan storage myopathy. No cardiac symptoms were reported. Our case is consistent with the core phenotype of GYG1-related PGBM2 apart from an early onset of weakness without cardiac symptoms. The presence of α-amylase resistant PAS-positive material in skeletal muscle biopsy of patients with slowly progressive limb girdle muscle weakness should prompt the search for GYG1 mutations. This case highlights the combined role of muscle pathology and NGS in the molecular resolution of undiagnosed patients with undiagnosed neuromuscular conditions

RBCK1‐related disease: A rare multisystem disorder with polyglucosan storage, auto‐inflammation, recurrent infections, skeletal, and cardiac myopathy—Four additional patients and a review of the current literature

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto‐inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings

CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies

Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n=6). Symptoms included myalgia (n=7), exercise intolerance (n=6) and episodes of rhabdomyolysis (n=2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other “typical” features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes

A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms

Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle paralysis associated with low serum potassium. Muscle fibre inexcitability during attacks of paralysis is due to an aberrant depolarizing leak current through mutant voltage sensing domains of either the sarcolemmal voltage-gated calcium or sodium channel. We report a child with hypokalaemic periodic paralysis and CNS involvement, including seizures, but without mutations in the known periodic paralysis genes. We identified a novel heterozygous de novo missense mutation in the ATP1A2 gene encoding the α2 subunit of the Na+/K+-ATPase that is abundantly expressed in skeletal muscle and in brain astrocytes. Pump activity is crucial for Na+ and K+ homeostasis following sustained muscle or neuronal activity and its dysfunction is linked to the CNS disorders hemiplegic migraine and alternating hemiplegia of childhood, but muscle dysfunction has not been reported. Electrophysiological measurements of mutant pump activity in Xenopus oocytes revealed lower turnover rates in physiological extracellular K+ and an anomalous inward leak current in hypokalaemic conditions, predicted to lead to muscle depolarization. Our data provide important evidence supporting a leak current as the major pathomechanism underlying hypokalaemic periodic paralysis and indicate ATP1A2 as a new hypokalaemic periodic paralysis gene

Dialysis and pediatric acute kidney injury: choice of renal support modality

Dialytic intervention for infants and children with acute kidney injury (AKI) can take many forms. Whether patients are treated by intermittent hemodialysis, peritoneal dialysis or continuous renal replacement therapy depends on specific patient characteristics. Modality choice is also determined by a variety of factors, including provider preference, available institutional resources, dialytic goals and the specific advantages or disadvantages of each modality. Our approach to AKI has benefited from the derivation and generally accepted defining criteria put forth by the Acute Dialysis Quality Initiative (ADQI) group. These are known as the risk, injury, failure, loss, and end-stage renal disease (RIFLE) criteria. A modified pediatrics RIFLE (pRIFLE) criteria has recently been validated. Common defining criteria will allow comparative investigation into therapeutic benefits of different dialytic interventions. While this is an extremely important development in our approach to AKI, several fundamental questions remain. Of these, arguably, the most important are “When and what type of dialytic modality should be used in the treatment of pediatric AKI?” This review will provide an overview of the limited data with the aim of providing objective guidelines regarding modality choice for pediatric AKI. Comparisons in terms of cost, availability, safety and target group will be reviewed

Studies on the polarographic behaviour of nitrophenols - Part I.o-and m-nitrophenols

Državljanstvo je pravna spona koja veže pojedinca uz određenu državu dajući mu poseban pravni status, tj. krug prava i obaveza. Radi se o svim temeljnim političkim, građanskim, socijalnim i gospodarskim pravima odnosno obvezama koje pojedinac uživa ili snosi, u pravilu, bez obzira na to nalazi li se na teritoriju domaće države ili je u inozemstvu. Ta je veza načelno trajna. Republika Hrvatska donijela je 1991. Zakon o hrvatskom državljanstvu kojim je regulirano da maloljetnici stječu državljanstvo: podrijetlom, rođenjem na teritoriju Republike Hrvatske, prirođenjem i međunarodnim ugovorima. U radu se polazi od određenja pojma hrvatskog državljanstva. Nadalje, navode se načini stjecanja hrvatskog državljanstva te pretpostavke potrebne za provođenje postupka dobivanja hrvatskog državljanstva. Govoreći o načinima stjecanja hrvatskog državljanstva, kao i dalje tijekom rada, više se pažnje posvećuje pravnom položaju djece, budući da su ona glavna tema istraživanja. Velika pozornost daje se zakonodavnim promjenama u stjecanju hrvatskog državljanstva koje su se zbile od 1991. godine do danas i njihovoj opravdanosti. U zadnjem dijelu rada usredotočit ću se na Prijedlog Zakona o izmjenama i dopunama Zakona o hrvatskom državljanstvu budući da je u tijeku postupak njegova donošenja te ću iznijeti svoje zaključke