A case report with the peculiar concomitance of 2 different genetic syndromes

Rationale: Down syndrome (DS) is the most common chromosome disorder in live born infants, affecting several body systems, but usually sparing skeletal muscles. We present the case of a child with coexistence of DS and dystrophinopathy. Only 1 similar case has been reported so far. Patient Concerns: An 8-year-old boy with DS had a history of incidental finding of increased serum creatine kinase levels up to 1775U/L (normal values 38-174U/L). He presented no delay in motor development; at the neurological examination, no muscle weakness or fatigability was detected in 2 different evaluations performed over a 6-month period. Diagnoses: Skeletal muscle biopsy revealed marked dystrophic changes with patchy immunostaining for dystrophin. The Duchenne muscular dystrophy gene was screened for deletions by multiplex polymerase chain reaction, but no mutations were found. Sequence analysis of the Duchenne muscular dystrophy gene revealed a splice-site mutation c.1812+1G>A in intron 15 and confirmed a diagnosis of Becker muscular dystrophy. Interventions:The patient has started a specific physiotherapy that avoided any deterioration in motor development and muscular wasting. Outcomes: A multidisciplinary follow-up was initiated. The genetician that followed the patient for DS was supported by the neurologist, the physiotherapist, the pulmonologist, and the cardiologist. Lessons: This peculiar "double trouble" case exemplifies the value of careful clinical evaluation and adequate clinical experience to identify the concomitance of 2 different genetic syndromes in the same patient, and it points out the significance of muscular strength assessment in DS patients to make the most correct prognosis, and, consequently, to organize the best long-term care

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PKA regulatory subunit R2B is required for murine and human adipocyte differentiation

ADIPOGENESIS IS A COMPLEX PROCESS MODULATED BY SEVERAL FACTORS, INCLUDING CAMP SIGNALING. THE MAIN CAMP TARGET IS PROTEIN KINASE A (PKA), A TETRAMERIC ENZYME WITH FOUR REGULATORY SUBUNITS SHOWING TISSUE-SPECIFIC EXPRESSION AND FUNCTION: PRKAR2B is the main regulatory subunit in adipose tissue in mice and in adult humans. This study aimed to evaluate the expression of PKA regulatory subunits in human adipose tissue during fetal development and to investigate their role in the differentiation of 3T3-L1 and primary human preadipocytes. The expression of PKA regulatory subunits was evaluated in fetal adipose tissue (immunohistochemistry) and in cultured 3T3-L1 and primary human preadipocytes (western blot analysis). Cultured cells were transiently transfected with siRNA against PRKAR2B and induced to differentiate. Differentiation was evaluated by intracellular triglyceride staining (Oil Red O) and expression of molecular markers of adipocyte differentiation. In this study, we found that PRKAR2B is the main regulatory subunit in human adipose tissue during fetal development, from 12 weeks of gestation to the end of gestation, as well as in 3T3-L1 and primary human preadipocytes. The expression of PRKAR2B increases progressively during in vitro differentiation. The silencing of PRKAR2B abolishes the increase in the expression of peroxisome proliferator-activated receptor gamma (PPAR\u3b3 (PPARG)), fatty acid synthase, aP2 (FABP4), and lipoprotein lipase, as well as intracellular triglyceride accumulation, resulting in impaired adipocyte differentiation in both mouse and human cell systems. In conclusion, PRKAR2B is the key PKA regulatory subunit involved in mouse and human adipose tissue development. The physiological increase in the expression of PRKAR2B is an essential event in adipogenesis in both mice and humans, and it might represent a possible target for future strategies for obesity treatment

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Objective: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. Results: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020

Pseudohypoparathyroidism and GNAS epigenetic defects : clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients

Context: The two main subtypes of pseudohypoparathyroidism (PHP), PHP-Ia and -Ib, are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward PTH and additional hormones, whereas PHP-Ib patients do not have AHO, and hormone resistance appears to be limited to PTH and TSH. Recently, methylation defects have been detected in few patients with PHP and mild AHO, indicating a molecular overlap between the two forms. Objectives: The aim of the study was to screen patients with clinically diagnosed PHP-Ia for methylation defects and to investigate the presence of correlations between the molecular findings and AHO severity. Patients and Methods: We investigated differential methylation of GNAS regions and STX16 microdeletions in genomicDNAfrom 40 patients with sporadicAHOand multihormone resistance, with no mutations in Gs -coding GNAS exons. Results: Molecular analysis showed GNAS cluster imprinting defects in 24 of the 40 patients analyzed. NoSTX16 deletion was detected. The presence of imprinting defects was not associated with the severity of AHO or with specific AHO signs. Conclusions: We report the largest series of the literature of patients with clinical AHO and multihormone resistance and no mutation in the Gs gene. Our findings of frequent GNAS imprinting defects further confirm the existence of an overlap between molecular and clinical features of PHP-Ia and PHP-Ib and highlight the necessity of a new clinical classification of the disease that takes into account the recent knowledge on the molecular basis underlying these defects

Congenital myopathies: Clinical phenotypes and new diagnostic tools

Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually from birth, and a static or slowly progressive clinical course. Historically, congenital myopathies have been classified on the basis of major morphological features seen on muscle biopsy. However, different genes have now been identified as associated with the various phenotypic and histological expressions of these disorders, and in recent years, because of their unexpectedly wide genetic and clinical heterogeneity, next-generation sequencing has increasingly been used for their diagnosis. We reviewed clinical and genetic forms of congenital myopathy and defined possible strategies to improve cost-effectiveness in histological and imaging diagnosis

Can Intestinal Pseudo-Obstruction Drive Recurrent Stroke-Like Episodes in Late-Onset MELAS Syndrome? A Case Report and Review of the Literature

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder that is most commonly caused by the m. 3243A>G mutation in the MT-TL1 mitochondrial DNA gene, resulting in impairment of mitochondrial energy metabolism. Although childhood is the typical age of onset, a small fraction (1-6%) of individuals manifest the disease after 40 years of age and usually have a less aggressive disease course. The clinicalmanifestations are variable and mainly depend on the degree of heteroplasmy in the patient's tissues and organs. They include muscle weakness, diabetes, lactic acidemia, gastrointestinal disturbances, and stroke-like episodes, which are the most commonly observed symptom. We describe the case of a 50-year-old male patient who presented with relapsing intestinal pseudo-obstruction (IPO) episodes, which led to a late diagnosis of MELAS. After diagnosis, he presented several stroke-like episodes in a short time period and developed a rapidly progressive cognitive decline, which unfortunately resulted in his death. We describe the variable clinical manifestations of MELAS syndrome in this atypical and relatively old patient, with a focus on paralytic ileus and stroke-like episodes; the first symptom may have driven the others, leading to a relentless decline. Moreover, we provide a brief revision of previous reports of IPO occurrence in MELAS patients with the m. 3243A>G mutation, and we investigate its relationship with stroke-like episodes. Our findings underscore the importance of recognizing gastrointestinal disturbance to prevent neurological comorbidities