Tricuspid mass-curious case of Li-Fraumeni syndrome:A letter to the editor

We focus specifically on the rare occurrence of cardiac thrombi in Li-Fraumeni syndrome(LFS).LFS is a hereditary risk to a diverse range of specific,uncommon,malignancies.Children and young adults have a heightened susceptibility to many malignancies,particularly soft-tissue and bone tumors,breast malignancies,central nervous system malignancies,adrenocortical carcinoma,and blood cancers.Additionally,LFS patients may experience other cancer types such as gastrointestinal,lung,kidney,thyroid,and skin cancers,along with those affecting gonadal organs(ovaries,testicles,and prostate).An accurate diagnosis of LFS is crucial to enable affected families to access appropriate genetic counseling and undergo surveillance for early cancer detection.

Amelioration of cognitive impairment following growth hormone replacement therapy:A case report and review of literature

BACKGROUND Stroke is one of the leading causes of death and disability worldwide.In patients suffering from strokes and other acute brain injuries,the prevalence of pituitary dysfunction is high,and growth hormone deficiency is commonly found.Previous studies have demonstrated that administration of recombinant human growth hormone provides adult growth hormone deficiency(AGHD)patients with beneficial effects such as improving body compositions and quality of life.Nevertheless,other physiological benefits of growth hormone substitution are still controversial and inconclusive.CASE SUMMARY A female with a history of hypertension suffered intracranial hemorrhage,intraventricular hemorrhage,and hydrocephalus at 56 years of age.Her mobility,fluency of speech,and mentality were impaired ever since the event occurred.After five years,the 61-year-old patient was further diagnosed with AGHD and received six-month growth hormone replacement therapy(GHRT).After six months of GHRT,the patient’s body composition was improved.A substantial improvement in Mini-Mental State Examination score was also observed,accompanying with ameliorations in mobility,fluency of speech,and mentality.CONCLUSION In addition to improvements in body composition,GHRT for AGHD may provide further beneficial effects in patients with cognitive or motor impairments due to intracerebral hemorrhage.

Fanconi-Bickel syndrome as an example of marked allelic heterogeneity

Renal tubular acidosis （RTA） encompasses many re-nal tubular disorders characterized by hyperchloremic metabolic acidosis with a normal anion gap. Untreated patients usually complain of growth failure, osteoporo-sis, rickets, nephrolithiasis and eventually renal insuff-ciency. Fanconi-Bickel syndrome （FBS） is an example of proximal RTA due to a single gene disorder; it is caused by defects in the facilitative glucose transporter 2 gene that codes for the glucose transporter protein 2 ex-pressed in hepatocytes, pancreatic β-cells, enterocytes and renal tubular cells. It is a rare inherited disorder of carbohydrate metabolism manifested by huge hepa-tomegaly [hence it is classified as glycogen storage disease （GSD） type XI; GSD XI], severe hypophospha-temic rickets and failure to thrive due to proximal renal tubular dysfunction leading to glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting and hy-pophosphatemia. The disorder has been reported from all parts of Europe, Turkey, Israel, Arabian countries, Ja-pan and North America. Many mutant alleles have been described, its exact frequency is unknown and there is no single mutation found more frequently than the oth-ers. The presence of consanguinity in affected families suggests an autosomal recessive pattern of inheritance. New cases of FBS have been recently reported in the Middle and Far East in collaboration with specialized centers. Two novel mutations have been discovered in two unrelated Egyptian families. The first was two bases deletion, guanine and adenine, （c.253_254delGA） causing a frameshift mutation （p. Glu85fs） and the sec-ond is mutation in exon6 in splicing acceptor site with intron5 （c.776-1G〉C or IVS5-1G〉A）. Moreover, a new different mutation was described in a 3 year old Indian boy.

Place of Ultrasonographic in Screening Brain Lesions in Premature Newborn at Cotonou

Goal: The goal of this study is to define the epidemiological profile and identify the different brain lesions diagnosed in ultrasonography in preterm infants in Benin environment. Patients and methods: It is a prospective cross-sectional study of analytical aiming. It took place over a period of 6 months, from May 1st to October 31st, 2012 at the National Hospital University Centre Koutoukou Hubert Maga in neonatal units and medical scanning unit. It covered 105 premature newborn, classified into the very prematurity and the moderate prematurity. Results: The very premature represented 35.2% and the moderate premature 64.8%, with an average of 33.5% and 1.9 of standard deviation. The average age when implementing ultrasonographic transfontanellar was 7.2 ± 4.6 days old. The lowest birth weight was observed in very premature with p = 0.0025. The nasopharyngeal septum pellucidum was the most found lesions in 46 preterm infants (43.8%) with no statistically significantly difference in two groups, followed by the ventricular haemorrhage found in 21 preterm infants accounting for 20%, and the grade 1 or sub-ependymal haemorrhage prevailed in 14 premature accounting for 66.7%, afterward periventricular leukomalacia in 4 premature infants and hydrocephalus in 2 premature. Conclusion: The nasopharyngeal septum pellucidum and the sub-ependymal ventricular haemorrhage were the predominant anomalies in premature infants followed by leukomalacia.

Compound heterozygous mutations of NTNG2 cause intellectual disability via inhibition of the CaMKII signaling

Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization.In this study,we identify compound heterozygous mutations of c.547delC p.(Arg183Alafs*186)and c.605G>A,p.(Trp202X)in NTNG2 causing a syndrome exhibiting developmenta delay,intellectual disability,hypotonia,and facial dysmorphism.To elucidate the underlying cellular and molecular mechanisms,CRISPR-Cas9 technology is employed to generate a knock-in mouse mode expressing the R183Afs and W202X mutations.We report that the Ntng2^(R183Afs/W202X)mice exhibit hypo tonia and impaired learning and memory.We find that the levels of CaMKII and p-GluA1^(Ser831)are decreased,and excitatory postsynaptic transmission and long-term potentiation are impaired.To increase the activity of CaMKII,the mutant mice receive intraperitoneal injections of DCP-LA,a CaMKII agonist,and show improved cognitive function.Together,our findings reveal molecular mechanisms of how NTNG2deficiency leads to impairments of cognitive ability and synaptic plasticity.

Variable phenotypes and outcomes associated with the MMACHC c.482G>A mutation:follow-up in a large CblC disease cohort

Background The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene(MMACHC)c.482G>A mutation in 195 Chinese cases with CblC disease.Methods We carried out a national,retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G>A variant either in a homozygous or compound heterozygous state.The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G>A mutation.Clinical features,including disease onset,symptoms,biochemical metabolites,gene mutation,and follow-up outcomes were reviewed and analyzed in detail.The median follow-up period spanned 3 years and 8 months,with a range of 1 year and 2 months to 12 years and 10 months.Results Among 195 patients carrying the c.482G>A variant,125(64.1%)cases were diagnosed by newborn screening(NBS),60(30.8%)cases were detected due to disease onset,and 10(5.1%)cases were identified from sibling diagnoses.One hundred and seventeen(93.6%)individuals who were diagnosed by NBS,and nine patients who came from sibling diagnoses remained asymptomatic in this study.From 69 symptomatic patients of the c.482G>A group,more patients presented with later onset,and the top six common clinical symptoms at disease onset were developmental delay(59.4%),lower limb weakness and poor exercise tolerance(50.7%),cognitive decline(37.7%),gait instability and abnormal posture(36.2%),seizures(26.1%),and psychiatric and behavioral disturbances(24.6%).In the 159 symptomatic patients lacking c.482G>A variants,the most frequently observed clinical manifestations at disease onset included developmental delay(81.8%),lethargy and feeding difficulty(62.9%),lower limb weakness and poor exercise tolerance(54.7%),prolonged neonatal jaundice(51.6%),vomiting(47.2%),and seizures(32.7%).Before treatment,the levels of blood propionylcarnitine,propionylcarnitine/acetylcarnitine ratio,and homocysteine in the c.482G>A group were significantly lower(P<0.05)than those in the non-c.482G>A group,while the concentration of urinary methylmalonic acid was slightly lower(P>0.05).The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels(P<0.05).In patients carrying the c.482G>A variant compared with the non-c.428G>A group,there were markedly lower rates of mortality(0.5%vs.2.0%)and developmental delay(20.5%vs.65.5%).When compared with individuals diagnosed due to disease onset,those identified through NBS in either group exhibited a reduced proportion of disease onset(6.7%vs.100%in the c.482G>A group,54.4%vs.100%in the non-c.482G>A group),lower mortality(0.0%vs.1.7%in the c.482G>A group,0.0%vs.3.6%in the non-c.482G>A group),and had a higher percentage of patients exhibiting normal psychomotor and language development(99.3%vs.33.3%in the c.482G>A group,58.9%vs.10.9%in the non-c.482G>A group).Conclusions The c.482G>A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease.Patients with this mutation tend to have a relatively better response to hydroxocobalamin,better metabolic control,and more favorable neurological outcomes.NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis,resulting in favorable clinical outcomes.

HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration

Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes.A nuclear gene HPDL(4-hydroxyphenylpyruvate dioxygenase-like),which encodes an intermembrane mitochondrial protein,has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes.Here,we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity,including developmental delay/intellectual disability,spasm,and hypertonia.Seven different pathogenic variants are identified,of which five are novel.Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function,which is also observed in HPDL-knockdown(KD)He La cells.In these He La cells,overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate.In addition,a decreased activity of the oxidative phosphorylation(OXPHOS)complex II is observed in patient-derived lymphocytes and HPDL-KD He La cells,further supporting an essential role of HPDL in the mitochondrial respiratory chain.Collectively,our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.