Positronium imaging with the novel multiphoton PET scanner.

In vivo assessment of cancer and precise location of altered tissues at initial stages of molecular disorders are important diagnostic challenges. Positronium is copiously formed in the free molecular spaces in the patient's body during positron emission tomography (PET). The positronium properties vary according to the size of inter- and intramolecular voids and the concentration of molecules in them such as, e.g., molecular oxygen, O2; therefore, positronium imaging may provide information about disease progression during the initial stages of molecular alterations. Current PET systems do not allow acquisition of positronium images. This study presents a new method that enables positronium imaging by simultaneous registration of annihilation photons and deexcitation photons from pharmaceuticals labeled with radionuclides. The first positronium imaging of a phantom built from cardiac myxoma and adipose tissue is demonstrated. It is anticipated that positronium imaging will substantially enhance the specificity of PET diagnostics.

Pathology of skeletal muscle fibers and small blood vessels in MERRF syndrome: an ultrastructural study.

Our studies concerned skeletal muscle biopsy specimens from a patient with clinically suspected MERRF syndrome, confirmed by genetic tests showing the presence of point mutation in the m.8344A> G in the tRNALys gene. Ultrastructurally, extensive damage of mitochondria in skeletal muscle fibres was observed, including the presence of two types of mitochondrial inclusions. Mild damage of mitochondria was revealed in small blood vessels and the presence of calcium deposits in the vascular walls were observed. The differences in mitochondrial damage may be related to different origin and expenditure of biologically useful energy in these cells.

Coexistence of mutations in keratin 10 (KRT10) and the mitochondrial genome in a patient with ichthyosis with confetti and Leber's hereditary optic neuropathy.

Ichthyosis with confetti (IWC) is a severe congenital genodermatosis characterized by ichthyosiform erythroderma since birth and confetti-like spots of normal skin appearing in childhood as a results of revertant mosaicism. This disorder is caused by mutations in KRT10 or KRT1 genes. We report a 16-year-old boy who presented ichthyosiform erythroderma with severe desquamation since birth and gradually worsening psycho-neurological symptoms (mental retardation, ataxia, dystonia, hypoacusis). The patient conspicuously lacked typical confetti-like spots at the age of 16. The molecular diagnostics by the whole exome sequencing showed a novel de novo (c.1374-2A>C) mutation in the KRT10 gene responsible for the development of IWC (KRT10 defect was confirmed by immunofluorescent study). Concurrently, the m.14484T>C mutation in mitochondrial MTND6 gene (characteristic for Leber's hereditary optic neuropathy or LHON) was detected in patient, his mother and brother. LHON causes frequent inherited blindness typically appearing during young adult life whose expression can be triggered by additional factors such as smoking or alcohol exposure. We speculate the effects of KRT10 and LHON mutations influence each other-skin inflammatory reaction due to severe ichthyosis might trigger the development of psychoneurological abnormalities whereas the mitochondrial mutation may reduce revertant mosaicism phenomenon resulting in the lack of confetti-like spots characteristic for IWC. However, based on a single case we should be cautious about attributing phenotypes to digenic mechanisms without functional data.

Screening for scoliosis: different countries' perspectives and evidence-based health care.

Idiopathic scoliosis affects 2-3% of adolescents. Large, progressing deformities, mostly present in girls, may lead to pulmonary complications, pain symptoms, the feeling of social isolation, and even mental disorders. The correlation of screening programs with surgery rate reduction and the clinical effectiveness of bracing remain a matter of debate. Critics indicate overdetection, qualification for therapy of insignificant curves, unjustified treatment, and risks of psychological side effects, whereas supporters underline the need for screening, and suggest improvements. It remains unclear whether such opposite opinions are based on sound evidence. To identify relevant studies, guidelines, and recommendations, MEDLINE, Google Scholar, and Cochrane Library databases were searched. The levels of evidence presented in selected studies and grading of recommendations reported in available guidelines and recommendation statements were assessed using the SIGN scoring system. Screening programs are legislated, recommended, or not recommended in different American states. British and Canadian screening recommendations do not mention scoliosis; Australian boards recommend against scoliosis screening programs. Other publications such as Singapore, Turkish, and Malaysian publications underline the cost-effectiveness and clinical importance of the procedures. Different Greek authors postulate the benefits and harms caused by the programs to many schoolchildren. Such a polarity illustrates the topicality of the quality of scientific evidence analyses and the significance of the grading of the recommendations process. It appears that critical opinions often result from implementing such analyses, whereas those supporting the programs tend to value the importance of expert opinions.

Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure.

Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogenicity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates.

A homozygous mutation in the SCO2 gene causes a spinal muscular atrophy like presentation with stridor and respiratory insufficiency.

UNLABELLED: Infants with deficiency of cytochrome c oxidase (COX) due to SCO2 mutations observed so far usually demonstrated early cardiomyopathy, encephalopathy and lactic acidosis. Milder spinal muscular atrophy-like (SMA-like) phenotype was also rarely reported. The aim is to present 18 Polish patients with SCO2 mutations. Molecular study revealed p.E140K mutation in all cases (on 32 alleles); p.Q53X mutation and novel p.M177T change were identified in single patients. In three families no second mutation was found. Thirteen p.E140K homozygotes presented in infancy with floppiness and remarkable stridor. Survival motor neuron (SMN) gene deletion was excluded. Mild to moderate lactic academia was found. Neurological involvement manifested as spasticity and psychomotor retardation. In some patients strabismus, ptosis and episodes of seizures were seen. During second half of the year chronic respiratory failure with artificial respiration dependency appeared in all homozygotes. Heart involvement was never present at the beginning. Rapidly progressive hypertrophic cardiomyopathy developed in several patients at the terminal stage. The stridor was constant and striking feature. Skeletal muscle biopsy was performed in 16 patients including 11 homozygotes. Four pathological patterns were discerned - from neurogenic muscle changes, including spinal muscular atrophy (SMA) to unspecific findings. Histochemical cytochrome c oxidase (COX) deficit was not a constant feature. Significant decrease in respiratory chain complex IV activity was detected in muscle homogenate by spectrophotometric method only in 7 out of 12 examined cases. CONCLUSIONS: 1/Mutations of SCO2 gene should be considered as a possible cause of neurogenic skeletal muscle features (including SMA-like) in infants with encephalomyopathy even in the absence of heart involvement and COX deficit; 2/Inspiratory stridor may be symptomatic of SCO2 gene mutation(s).

G8363A mitochondrial DNA mutation is not a rare cause of Leigh syndrome - clinical, biochemical and pathological study of an affected child.

UNLABELLED: Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, having relatively homogeneous clinical symptomatology and pattern of neuropathological changes, shows remarkable heterogeneity in biochemical and molecular background. G8363A mitochondrial DNA mutation typical for MERRF syndrome and progressive cardiomyopathy may also be associated with LS. Clinical, biochemical and pathological findings in a boy aged 28 months who died with classical COX-deficientLSassociatedwithmtG8363Aisdescribedindetail.Hyperlactataemia,LCHAD-like organic acids profile and respiratory alkalosis(pH7.47,pCO2 4.9 mmHg, HCO3 3.0 mmol/l) were observed. Spectrophotometric assay showed deficit of respiratory chain complexes IVand I. Skeletal muscle biopsy revealed mosaic cytochrome oxidase deficit,lipid accumulation and ultrastructural abnormalities of mitochondria. Postmortem examination confirmed the presence of typical LS central nervous system lesions as well as hypertrophy of the left ventricle of the heart. CONCLUSION: mtG8363A "MERRF-like" mutation should be included in the differential diagnosis of classical LS in infants. This case is in agreement with our hypothesis that hyperventilation plays a substantial role in progression of central nervous system damage.