Hypotonia Research Articles

Evaluation of Q Angle in Down syndrome

Background: Down Syndrome is a genetic disorder and the most common chromosomal abnormality. It is predominantly characterized by muscle hypotonia and joint hypermobility. Qangle is the angle formed between two imaginary lines one from ASIS to Center of Patella, another from Tibial tuberosity to the Center of Patella. Objectives: Aim of the study is to evaluate the Q-angle in male children with Down syndrome of 7-16 years of age and compare the values between children with internal and external tibial torsion. Methodology: It is an observational study done with convenient sampling carried out in 12 male children with Down syndrome. The tibial torsion was measured. Based on internal and external tibial torsion they were categorized into Group A and B respectively. Group A consisting of 7 children with internal tibial torsion and Group B consisting of 5 children with external tibial torsion. Q-angle was measured using standard goniometer. Results: There is no significant difference in P-value (P>0.05) between the right and left leg of children in Group A and in Group B. On comparison between Group A and Group B, there was a statistical significance in P-Value of 0.005 and 0.050 when compared mean of Q angle for right leg and left leg respectively. Conclusion: The study concluded that assessing Q-angle helps to evaluate the biomechanical changes in knee. In this study done for the male children with Down syndrome, the Q-angle lies within the normal range of 13.1±3.5. However children with internal tibial torsion has comparatively decreased angle and children with external tibial torsion has comparatively increased angle even though there is no deviation from the normal range for the age.

Influence of 2,3-Butanedione-Monoxime on the Interaction of Myosin with Actin in Healthy and in Congenital Myopathy

Congenital myopathies are a heterogeneous group of human skeletal muscle disorders characterized by muscle hypotonia and weakness. Myopathies have a wide range of clinical phenotypes, which makes it extremely difficult to develop approaches to their treatment. There are several pharmacological agents in clinical use or under clinical investigation for the treatment of cardiomyopathies whose mechanism of action can be used to treat congenital myopathies as well. One such agent is 2,3-butanedione-monoxime (BDM), a noncompetitive inhibitor of myosin ATPase activity used to suppress acute myocardial injury. The molecular mechanisms of inhibition of myosin by BDM in skeletal muscle have not been studied, therefore the aim of this work was to estimate the effect of BDM on the interaction of myosin with actin in the modeling of several ATPase stages in skeletal muscle fiber, in order to assess the prospects for the use of BDM for the treatment of congenital myopathies. We found that BDM enhances the rigidity of myosin binding to actin when modeling weak binding forms of these muscle proteins, which can slow down the transition of actomyosin from the AM ∙ ADP ∙ Pi to the AM ∙ ADP state and is one of the reasons for the decrease in myosin ATPase activity in the presence of BDM. When modeling successive stages of the ATPase cycle using ADP, AMPPNP, ATPγS, and ATP, the myosin heads gradually switch to a state of weak interaction with actin. In the presence of the regulatory proteins tropomyosin and troponin in the muscle fiber, BDM does not affect the formation of a weak form of actomyosin binding, but increases the number of myosin heads essential for force generation. BDM can be used to increase the efficiency of myosin conformational rearrangements in the presence of tropomyosin with the R90P mutation associated with congenital myopathy, since this reagent increases the number of myosin heads in the muscle fiber capable of effective conformational rearrangements in the ATPase cycle and partially inhibits the pathological effects of the mutation.

A rare case of type1 proximal spinal muscular atrophy (werdnig - hoffmann disease) – a case report and review of literature

Spinal Muscular Atrophy (SMA) is an autosomal recessive Motor Neuron Disease (MND) with mutation of Survival motor neuron 1 (SMN1) gene located in chromosome 5(5q13.2) characterized by diffuse proximal and distal muscle weakness. Here the authors report a case of SMA in a 3 months old male infant with hypotonia of proximal muscles in both upper limbs and lower limbs with characteristic fasciculations of tongue and confirmed by genetic studies.

Effect of oral stimulation in improving feeding performance of pre-term infants in NICU: A systematic review

Aim: The Aim of this systematic review is to evaluate the effectiveness of oral stimulation techniques in improving feeding performance among pre-term infants in neonatal intensive care units (NICUs). Method: We conducted a comprehensive literature search of electronic databases, including PubMed, CINAHL, and Cochrane Library, from 2010-2021. Studies were included if they investigated the effect of oral stimulation on feeding performance outcomes such as time to full enteral feeding, weight gain, and length of hospital stay. Two reviewers independently assessed the quality of the studies using the Cochrane risk-of-bias tool and extracted data using a standardized data extraction form, and data were synthesized using a narrative approach due to heterogeneity in study design and outcome measures. Result: Our search identified 10 studies that met the inclusion criteria, consisting of randomized controlled trials, quasi-experimental studies, and case series. Eight studies reported significant improvements in feeding performance outcomes with the use of oral stimulation interventions compared to standard care or placebo. The remaining two studies reported mixed findings or no significant differences between groups. Overall, the quality of evidence was low to moderate due to methodological limitations and inconsistency in outcome reporting. Our findings suggest that oral stimulation techniques such as non-nutritive sucking, pacifier-activated device, and oral motor exercises are effective in improving feeding performance among pre-term infants in NICUs. These techniques were associated with reduced time to achieve full oral feeds, shortened hospital stay, and improved weight gain compared to control groups. Conclusion: The results of this systematic review suggest that oral stimulation may be an effective intervention for improving feeding performance in pre-term infants in NICUs. However, further research is needed to establish the optimal timing, frequency, and duration of oral stimulation interventions, as well as their long-term effects on growth and development. Future studies should also address methodological limitations, such as small sample sizes and lack of blinding, to improve the quality of evidence in this field. Significance of the study: Oral feeding is a difficult job for premature infants those who are admitted to NICU. Because of poor muscle tone, underdeveloped oral motor skills and reduced suck-swallow-breathe synchronization, they are unable to commence feeds from the bottle and breast immediately after birth, unlike full-term infants. As long as oral feeding is not developed, a number of non-oral feeding methods are employed which feeding methods can cause severe side effects 1. The primary barrier to oral feeding in infants with gestational age less than 34 weeks is the lack of coordination in sucking, swallowing, and breathing. Oral feeding in these infants can cause apnoea, decreased pulse oximetry, transient bradycardia, and aspiration. Therefore, in neonates those who do not reach the gestational age of 34 weeks for them bottle or breastfeeding are not considered, and developmental transition from gavage to oral feeding in a 28-week-old infant may take 6 weeks or longer. Several studies have shown that oral motor intervention on infants less than 34 weeks results in decreased transition time from gavage to oral feeding 2.

A Novel Homozygous Abnormal Splice Variant in the Myoferlin Gene Leading to Floppy Infant Syndrome in a Saudi Family

Myoferlin (MYOF) (OMIM#604603) is a type II membrane protein that belongs to the ferlin family, which is expressed in cardiac and skeletal muscles. This protein has seven C2 domains that mediate calcium-dependent membrane fusion events and membrane trafficking, while MYOF dysfunction is associated with muscular disorder. We are reporting a case from Saudi Arabia of an 18-month-old male patient with generalized hypotonia, which might be a floppy infant syndrome. In this study, whole exome sequencing (WES) was done, and a novel homozygous abnormal splice variant c.4982+1G>T, p.Val1661fs was identified in the MYOF gene. The results of WES were further validated by using Sanger sequencing; the proband showed homozygous mutation while both parents were heterozygous at this position. Implementing WES improves the screening and detection of novel and causative genetic variants and comprehends patient management. The results of this study, therefore, will add to the literature on the role of MYOF gene and any pathogenic variants that might lead to muscular dysfunction. Furthermore, this will establish a disease database, providing a groundwork for understanding the critical genomic regions.

Terapia miofuncional orofacial associada ao uso da placa palatina de memória em crianças com Trissomia do 21: estudo de casos

ABSTRACT Individuals with trisomy 21 may have muscle hypotonia of the speech articulation organs, an enlarged protruding tongue positioned on the floor of the mouth, and a lack of lip closure. The stimulating palatal plate is an intraoral appliance that, associated with myofunctional therapy, aims to improve these children’s habitual lip and tongue posture. This study aimed to present the cases of four male children with trisomy 21, with a mean age of 6.7 and a standard deviation of 7.8 months, who used the stimulating palatal plate in association with myofunctional therapy. The children used the plate for 6 months and did exercises based on the orofacial regulation therapy, and their parents received instructions on feeding them and removing deleterious oral habits. In the first session and at the end of the treatment, each child’s face was video-recorded for 5 minutes at rest, and two researchers analyzed independently their habitual tongue and lip posture. Participants who began the treatment earlier and had the most severe postural changes had greater tongue and lip posture improvement.

Thiamine-responsive pyruvate dehydrogenase complex deficiency presenting as recurrent muscle weakness: Identification of a novel mutation (p.T111I) in the PDHA1 gene.

Thiamine-responsive pyruvate dehydrogenase complex deficiency presenting as recurrent muscle weakness: Identification of a novel mutation (p.T111I) in the PDHA1 gene.

A rare case of spinomuscular atrophy masquerading neonatal encephalopathy in a newborn

Spinomuscular atrophy is a rare type of inherited neuromuscular disorder of degeneration of alfa cells of the anterior horn. The presentation and prognosis of disease vary depending upon the type, age of presentation and severity of the disease. Here we are presenting a case of a male baby who presented with lethargy, poor feeding, respiratory distress and seizures. On examination the child was sick looking, tachypnoeic, with Downe’s score of 7, with bilateral crypts with hypotonia and having seizures. The laboratory parameters showed thrombocytopenia, leucopenia, hypoglycaemia with normal serum levels of creatine phosphokinase. The septic screening was suggestive of sepsis. The amplitude integrated EEG showed abnormal pattern. The tandem mass spectroscopy for Inborn error of metabolism screening was normal. The neurosonography and MRI brain showed no abnormalities. The baby developed respiratory muscle weakness, hypotonia, bulbar palsy, areflexia and characteristic eyelid and tongue fasciculations subsequently as diseases progressed which required oxygen and respiratory support for prolonged duration. The gene study confirmed the deletion of exons 7 and 8. Sibling and parental screening were advised and the baby was managed with supportive care and referred to a higher centre for further advanced treatment. The knowledge and varying presentations of this illness are important for the treating doctors from the prognostic point of view

THE IMPACT OF ANATOMICAL CHARACTERISTICS ON THE DEVELOPMENT OF ORAL MUCOSAL DISEASES IN CHILDREN WITH DOWN SYNDROME

BACKGROUND: Dental treatment plays a big role in improving the health and quality of life of children with Down syndrome. These children need rationally organized additional dental treatment by different specialists and systematic medical observation. The high incidence and prevalence of periodontal disease in children with Down syndrome are caused by anatomical features of cranial development. OBJECTIVE: pattern identification between anatomical characteristics and development of oral mucosal diseases in children with Down syndrome. METHODS: The study included 24 patients with Down syndrome. They were registered at the Department of Pediatric Dentistry of the Tver Dental Polyclinic (Russia). The age of the patients was from 2 to 13 years old. RESULTS: 59.5% of patients had a missing nasal bone. 58% of children had an arched palate. 65% of children had oral breathing type due to macroglossia and weak temporomandibular joint muscles. It can be the reason for the development of inflammatory oral mucosal diseases. The children with Down syndrome often have stomatitis and gingivitis, which develops into chronic periodontal diseases. 62% of children had the creased tongue at the age of 4 years. Down syndrome has a high prevalence of maxillofacial anomalies of up to 76%. It contributes to the formation of plaque on the teeth and caries. It often leads to damage to the rudiments of permanent teeth. The prevalence of periodontal disease in children with Down syndrome is associated with severe hypotonia of the masticatory muscles up to 87%. CONCLUSION: Pediatric dentists focus on the features of the dental status of children with Down syndrome, taking into account the relationship of pathological processes in the maxillofacial area and somatic pathology. Specialists in pediatric dentistry must understand the importance of early prevention, which can reduce the risk of developing cavities and periodontal disease in children.

Autonomic nervous system dysfunction in Prader-Willi syndrome.

Prader-Willi syndrome is a complex neurodevelopmental genetic disorder due to lack of paternal expression of critical imprinted genes in the 15q11.2-q13.1 chromosomal region, generally from a paternal deletion. Predominant features include infantile hypotonia, a poor suck with failure to thrive, craniofacial features, and developmental and behavioral problems including self-injury and childhood onset of obesity. In addition to severe obesity, patients with PWS present with other symptoms of autonomic nervous system dysfunction. We examined the features seen in Prader-Willi syndrome and searched the literature for evidence of autonomic nervous system involvement in this rare obesity-related disorder and illustrative findings possibly due to autonomic nervous system dysfunction. Additionally, we reviewed the literature in relation to childhood obesity syndromes and compared those syndromes to the syndromic obesity found in Prader-Willi syndrome. We report autonomic nervous system-related symptoms associated with childhood obesity impacting features seen in Prader-Willi syndrome and possibly other obesity-related genetic syndromes. We compiled evidence of both an autonomic route for the obesity seen in PWS and other autonomic nervous system-related dysfunctions. These include decreased salvation, sleep disordered breathing, increased pain and thermal threshold instability, delayed gastric emptying, altered blood pressure readings, and pupillary constriction responses as evidence of autonomic nervous system involvement. We summarized and illustrated findings of autonomic nervous system dysfunction in Prader-Willi syndrome and other obesity-related syndromes and genetic factors that may play a causative role in development.

CRISPR-mediated generation and characterization of a Gaa homozygous c.1935C>A (p.D645E) Pompe disease knock-in mouse model recapitulating human infantile onset-Pompe disease

Pompe disease, an autosomal recessive disorder caused by deficient lysosomal acid α-glucosidase (GAA), is characterized by accumulation of intra-lysosomal glycogen in skeletal and oftentimes cardiac muscle. The c.1935C>A (p.Asp645Glu) variant, the most frequent GAA pathogenic mutation in people of Southern Han Chinese ancestry, causes infantile-onset Pompe disease (IOPD), presenting neonatally with severe hypertrophic cardiomyopathy, profound muscle hypotonia, respiratory failure, and infantile mortality. We applied CRISPR-Cas9 homology-directed repair (HDR) using a novel dual sgRNA approach flanking the target site to generate a Gaaem1935C>A knock-in mouse model and a myoblast cell line carrying the Gaa c.1935C>A mutation. Herein we describe the molecular, biochemical, histological, physiological, and behavioral characterization of 3-month-old homozygous Gaaem1935C>A mice. Homozygous Gaaem1935C>A knock-in mice exhibited normal Gaa mRNA expression levels relative to wild-type mice, had near-abolished GAA enzymatic activity, markedly increased tissue glycogen storage, and concomitantly impaired autophagy. Three-month-old mice demonstrated skeletal muscle weakness and hypertrophic cardiomyopathy but no premature mortality. The Gaaem1935C>A knock-in mouse model recapitulates multiple salient aspects of human IOPD caused by the GAA c.1935C>A pathogenic variant. It is an ideal model to assess innovative therapies to treat IOPD, including personalized therapeutic strategies that correct pathogenic variants, restore GAA activity and produce functional phenotypes.

The Effect of Combination of Core Stability Training and Lower Extremity Strength Training on Static Standing Balance Ability in a Child with Down Syndrome

Balance is the ability to stay in one position with good control. Children with a diagnosis of Down syndrome usually have decreased muscle tone (hypotonia) or muscle weakness, so that their balance is disturbed and they are more prone to falling when standing. Core stability and lower extremity strength exercise are expected to improve the ability of static standing balance in children with a diagnosis of Down syndrome. The aim of the study is to determine the effect of giving a combination of core stability and lower extremity strength exercises on the static standing balance ability in children with Down syndrome. This study uses a single subject research on a child with a diagnosis of Down syndrome who is given core stability and lower extremity strength exercise for 4 weeks to improve the ability of static standing balance. The ability of static standing balance in this study was measured using Gross Motor Function Measure (GMFM). Measurements were taken before exercise was given (A1), follow-up (B) and final evaluation (A2). After being given exercise twice for four weeks, there was no increase in the GMFM score, so it was concluded that there was no increase in the ability of static standing balance in children with Down syndrome in this study. In conclusions, giving core stability exercise and lower extremity strength exercise twice for four weeks is considered not to be able to improve the ability of static standing balance in children with Down syndrome.

Succinic semialdehyde dehydrogenase deficiency – a rare cause of metabolic stroke

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare neurometabolic disorder characterized by defective degradation of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter of the brain. Children with SSADH deficiency present with motor mental delay, intractable seizures, infantile onset hypotonia, speech disturbances, extrapyramidal symptoms and ataxia. This wide spectrum results from increased accumulation of 4hydroxy butyric acid (4HBA) leading to down regulation of GABA receptors, which likely explain epileptogenesis but the pathophysiology of stroke in SSADH deficiency is not much elucidated. Here, we report an infant aged 11 months, product of consanguineous marriage with significant family history of motor delay and intellectual disability, presented with sudden onset focal neurological deficit preceded by diarrheal illness. Examination revealed an infant with age-appropriate milestones having left uncrossed hemiplegia along with neuroradiological evidence of right globus pallidus ischemic infarct. Urinary organic acid profile by chromatography was suggestive of 4 hydroxybutyric aciduria.

A recurrent single-exon deletion in TBCK might be under-recognized in patients with infantile hypotonia and psychomotor delay.

Advanced bioinformatics algorithms allow detection of multiple-exon copy-number variations (CNVs) from exome sequencing (ES) data, while detection of single-exon CNVs remains challenging. A retrospective review of Baylor Genetics' clinical ES patient cohort identified four individuals with homozygous single-exon deletions of TBCK (exon 23, NM_001163435.2), a gene associated with an autosomal recessive neurodevelopmental phenotype. To evaluate the prevalence of this deletion and its contribution to disease, we retrospectively analyzed single nucleotide polymorphism (SNP) array data for 8194 individuals undergoing ES, followed by PCR confirmation and RT-PCR on individuals carrying homozygous or heterozygous exon 23 TBCK deletions. A fifth individual was diagnosed with the TBCK-related disorder due to a heterozygous exon 23 deletion in trans with a c.1860+1G>A (NM_001163435.2) pathogenic variant, and three additional heterozygous carriers were identified. Affected individuals and carriers were from diverse ethnicities including European Caucasian, South Asian, Middle Eastern, Hispanic American and African American, with only one family reporting consanguinity. RT-PCR revealed two out-of-frame transcripts related to the exon 23 deletion. Our results highlight the importance of identifying single-exon deletions in clinical ES, especially for genes carrying recurrent deletions. For patients with early-onset hypotonia and psychomotor delay, this single-exon TBCK deletion might be under-recognized due to technical limitations of ES.

ODP526 Thyrotoxic Periodic Paralysis in Graves’ Disease: A rare presentation in an African American male

Abstract INTRODUCTION: Thyrotoxic Periodic Paralysis is a rare but life-threatening manifestation of hyperthyroidism characterized by hypokalemia, acute flaccid paralysis, and signs of hyperthyroidism. Despite being commonly seen in East Asian males, TPP has been increasingly reported in other parts of the world including western countries. Early recognition and prompt treatment of TPP is essential in preventing its grave and potentially life-threatening consequences. CASE PRESENTATIONA 21-year-old African American male patient with past medical history significant for hypertension and untreated hyperthyroidism presented to the emergency department with sudden onset bilateral lower extremity weakness and difficulty walking for one day. Upon arrival to the emergency department, vitals were unremarkable. On examination, patient had a decreased muscle tone in bilateral lower extremities with depressed deep tendon reflexes. The thyroid gland was diffusely enlarged. The remainder of physical exam was normal. Electrolyte abnormalities were also present with decreased serum potassium level of 1.2 mEq/L (3.6-5.1 mEq/L) and magnesium of 1.7 mg/dL (1.8-2.5 mg/dL). A low TSH level of <0. 010 mIU/mL (0.350-4.940 mIU/mL) with elevated free T4 levels of 4.30 ng/dL (0.70-1.48 ng/dL) were noted. CT Head/ Brain without contrast and Chest X ray were unremarkable. Potassium replacement was initiated with oral and intravenous potassium chloride. He was also started on oral atenolol (25 mg daily) and methimazole (10 mg daily). The patient's symptoms resolved in few hours after the treatment was started. An ultrasound of the thyroid gland showed diffuse heterogeneity of the gland most consistent with thyroiditis or similar abnormality. No definite focal abnormalities were noted. TSH receptor antibodies were also elevated with levels at 10.70 IU/L (≤1.75 IU/L) making Graves’ disease the most likely diagnosis. The patient's condition significantly improved along his hospitalization with complete resolution of symptoms and electrolyte abnormalities. He was subsequently discharged on atenolol and methimazole with outpatient follow up at the endocrinology clinic. DISCUSSION TPP is an underreported yet possibly fatal medical complication of hyperthyroidism. Prevalence is higher in Asia, however, incidence in Western countries has been increasing. While the underlying pathophysiology is poorly understood, h ypokalemia in TPP results from an intracellular shift of potassium induced by an increased adrenergic sensitization of Na + /K + –ATPase pump. Genetic and environmental factors may possibly play a role. Treatment of TPP entails beta-blockade to prevent intracellular shift of potassium, replenishing potassium stores, as well as correcting the underlying hyperthyroid state. Immediate diagnosis and initiation of treatment prevents serious cardiopulmonary complications and increases the probability of full recovery of muscle weakness. Presentation: No date and time listed

Bridging the Gap: Gene Therapy in a Patient With Spinal Muscular Atrophy Type 1.

Molecular therapies exploit the understanding of pathogenic mechanisms to reconstitute impaired gene function or manipulate flawed RNA expression. These therapies include (1) RNA interference by antisense oligonucleotides, (2) mRNA modification using small molecules, and (3) gene replacement therapy, the viral-mediated intracellular delivery of exogenous nucleic acids to reverse a genetic defect. Several molecular therapies are approved for treating spinal muscular atrophy (SMA), a recessive genetic disorder caused by survival motor neuron (SMN)1 gene alterations. SMA involves degeneration of lower motor neurons, which leads to progressive muscle weakness, hypotonia, and hypotrophy. Onasemnogene abeparvovec is a gene replacement therapy for SMA that uses adeno-associated virus delivery of functional SMN1 cDNA to motor neurons. Two other molecular therapies modulate SMN2 transcription: nusinersen, an antisense oligonucleotide, and risdiplam, a small molecule designed to modify faulty mRNA expression. The most suitable individualized treatment for SMA is not established. Here, we describe remarkable clinical improvement in a 4-month-old patient with SMA type 1 who received onasemnogene abeparvovec therapy. This case represents an explanatory bridge from bench to bedside with regard to therapeutic approaches for genetic disorders in neurology. Knowledge of the detailed mechanisms underlying genetic neurologic disorders, particularly monogenic conditions, is paramount for developing tailored therapies. When multiple disease-modifying therapies are available, early genetic diagnosis is crucial for appropriate therapy selection, highlighting the importance of early identification and intervention. A combination of drugs, each targeting unique genetic pathomechanisms, may provide additional clinical benefits.

Clinical manifestations and genetic analysis of a newborn with Arboleda-Tham syndrome.

Arboleda-Tham syndrome (ARTHS) is a rare disorder first characterized in 2015 and is caused by mutations in lysine (K) acetyltransferase 6A (KAT6A, a.k.a. MOZ, MYST3). Its clinical symptoms have rarely been reported in newborns from birth up to the first few months after birth. In this study, a newborn was diagnosed with ARTHS based on the clinical symptoms and a mutation c.3937G>A (p.Asp1313Asn) in KAT6A. The clinical manifestations, diagnosis, and treatment of the newborn with ARTHS were recorded during follow-up observations. The main symptoms of the proband at birth were asphyxia, involuntary breathing, low muscle tone, early feeding, movement difficulties, weak crying, weakened muscle tone of the limbs, and embrace reflex, and facial features were not obvious at birth. There was obvious developmental delay, as well as hypotonic and oro-intestinal problems in the first few months after birth. Mouse growth factor was used to nourish the brain nerves, and touching, kneading the back, passive movements of the limbs, and audio-visual stimulation were used for rehabilitation. We hope that this study expands the phenotypic spectrum of this syndrome to newborns and the library of KAT6A mutations that lead to ARTHS. Consequently, the data can be used as a basis for genetic counseling and in clinical and prenatal diagnosis for ARTHS prevention.

Identification of a novel pathogenic TBCK variant in a Chinese patient with infantile hypotonia with psychomotor retardation and characteristic facies type 3 (IHPRF3): a case report

BackgroundInfantile hypotonia with psychomotor retardation and characteristic facies type 3(IHPRF3) (OMIM #616,900) is an autosomal recessive disorder caused by biallelic pathogenic variants of the TBCK gene, and to date, this disease was reported rather limitedly in number and all described cases were Caucasians.Case presentationThis paper reported the clinical and genetic features of a Chinese patient with IHPRF3. The patient was a 15-month-old male with global developmental delay, profound hypotonia, and typical facial dysmorphic features including mildly coarse facial appearance, hypertelorism, tented upper lip, exaggerated Cupid’s bow, macroglossia and arched eyebrows. Magnetic Resonance Imaging (MRI) analysis of the brain revealed slightly widened bilateral ventricles and subarachnoid space. On genetic analysis, the patient was homozygous for a novel TBCK variant c.247C > T(p.Arg83Ter). The parents were both carriers without any positive symptoms or signs. With an extremely low frequency (0.0000082) in Exome Aggregation Consortium, the variant has not been reported in any other databases or official literatures, and was diagnosed to be pathogenic according to the American College of Medical Genetics and Genomics(ACMG) standards and guidelines. Neurorehabilitation training did not work well and the long-term prognosis remained to be observed.ConclusionsThis study reported the clinical and molecular features of the first non-Caucasian patient with IHPRF3 arising from a novel homozygous TBCK mutation, which provided a novel molecular marker for the definite diagnosis of IHPRF3 patients and for its genetic counseling and prenatal diagnosis in the affected families.

Chronic reduction of store operated Ca2+ entry is viable therapeutically but is associated with cardiovascular complications.

Loss of function mutations in store-operated Ca2+ entry (SOCE) are associated with severe paediatric disorders in humans, including combined immunodeficiency, anaemia, thrombocytopenia, anhidrosis and muscle hypotonia. Given its central role in immune cell activation, SOCE has been a therapeutic target for autoimmune and inflammatory diseases. Treatment for such chronic diseases would require prolonged SOCE inhibition. It is, however, unclear whether chronic SOCE inhibition is viable therapeutically. Here we address this issue using a novel genetic mouse model (SOCE hypomorph) with deficient SOCE, nuclear factor of activated T cells activation, and T cell cytokine production. SOCE hypomorph mice develop and reproduce normally and do not display muscle weakness or overt anhidrosis. They do, however, develop cardiovascular complications, including hypertension and tachycardia, which we show are due to increased sympathetic autonomic nervous system activity and not cardiac or vascular smooth muscle autonomous defects. These results assert that chronic SOCE inhibition is viable therapeutically if the cardiovascular complications can be managed effectively clinically. They further establish the SOCE hypomorph line as a genetic model to define the therapeutic window of SOCE inhibition and dissect toxicities associated with chronic SOCE inhibition in a tissue-specific fashion. KEY POINTS: A floxed stromal interaction molecule 1 (STIM1)hypomorph mouse model was generated with significant reduction in Ca2+ influx through store-operated Ca2+ entry (SOCE), resulting in defective nuclear translocation of nuclear factor of activated T cells, cytokine production and inflammatory response. The hypomorph mice are viable and fertile, with no overt defects. Decreased SOCE in the hypomorph mice is due to poor translocation of the mutant STIM1 to endoplasmic reticulum-plasma membrane contact sites resulting in fewer STIM1 puncta. Hypomorph mice have similar susceptibility to controls to develop diabetes but exhibit tachycardia and hypertension. The hypertension is not due to increased vascular smooth muscle contractility or vascular remodelling. The tachycardia is not due to heart-specific defects but rather seems to be due to increased circulating catecholamines in the hypomorph. Therefore, long term SOCE inhibition is viable if the cardiovascular defects can be managed clinically.

Arthrogryposis multiplex congenita in a child with congenital fractures: a case report

BackgroundBruck syndrome is an exceedingly rare form of osteogenesis imperfecta, inherited autosomal recessively and presenting with the concurrence of bone fragility and congenital contractures of large joints. The disease usually progresses relentlessly to result in recurrent fractures, short stature, severe kyphoscoliosis, and susceptibility to recurrent respiratory tract infections.Case presentationThe index child was a male newborn to healthy, nonconsanguineous, Sinhalese parents. The child had multiple contractures involving all large joints with pterigium formation in addition to congenital fractures involving left humerus and ulna at birth. The phenotypic features in this child were highly suggestive of Bruck syndrome. Genetic counseling was offered to the parents, although specific genetic testing could not be undertaken due to lack of resources. Bone and skin biopsy were not performed since only palliative care was possible. Over the course, he developed recurrent severe chest infections due to poor muscle tone, weak cough reflex, and pooling of secretions. Unfortunately, he succumbed at the age of 7 months following severe pneumonia.ConclusionThe association of arthrogryposis with osteogenesis imperfecta is extremely rare and known as Bruck syndrome. Early diagnosis during the antenatal period is helpful in genetic counseling, assessment of severity, and exploration of therapeutic options