Search

Dysfunctional RNA processing caused by genetic defects in RNA processing enzymes has a profound impact on the nervous system, resulting in neurodevelopmental conditions. We characterized a recessive neurological disorder in 18 children and young adults from 10 independent families typified by intellectual disability, motor developmental delay and gait disturbance. In some patients peripheral neuropathy, corpus callosum abnormalities and progressive basal ganglia deposits were present. The disorder is associated with rare variants in NUDT2 , a mRNA decapping and Ap4A hydrolysing enzyme, including novel missense and in-frame deletion variants. We show that these NUDT2 variants lead to a marked loss of enzymatic activity, strongly implicating loss of NUDT2 function as the cause of the disorder. NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, accompanied by changes in mRNA half-life and stability. Amongst the most up-regulated mRNAs in NUDT2-deficient cells, we identified host response and interferon-responsive genes. Importantly, add-back experiments using an Ap4A hydrolase defective in mRNA decapping highlighted loss of NUDT2 decapping as the activity implicated in altered mRNA homeostasis. Our results confirm that reduction or loss of NUDT2 hydrolase activity is associated with a neurological disease, highlighting the importance of a physiologically balanced mRNA processing machinery for neuronal development and homeostasis. [ABSTRACT FROM AUTHOR]

Mutations in the TWNK gene (10q24.31) lead to a variety of clinical characteristics and age-related phenotypes. Most often, diseases associated with mutations in this gene are the main manifestation of neurological symptoms such as ataxia, muscular hypotonia, ophthalmoplegia and extrapyramidal syndrome of varying severity and age - from generalized hypotonia with ophthalmoparesis and chorea, to more discreetly manifested ataxia and/or sensory polyneuropathy with late onset and slow progression. We present a case of a 1-year-old child with motor developmental delay - generalized muscular hypotonia, quadriparetic and extrapyramidal syndrome, ophthalmoparesis, weakened to missing reflexes, increased transaminases and missing tendon reflexes. After conducting a detailed genetic study - whole exome sequencing, a double heterozygous carrier of mutations in the TWNK gene was found. [ABSTRACT FROM AUTHOR]

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms. Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1 -associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies. [ABSTRACT FROM AUTHOR]

Muscular hypotonia is considered as one of the rarest forms of initial onset signs of TBM, in addition to aphasia and hyponatremia, the awareness of those rare onset signs, a well‐conducted diagnostic approach and early treatment can improve the outcome. [ABSTRACT FROM AUTHOR]

Background: Progressive myoclonic epilepsy (PME) is a heterogeneous neurodegenerative disorder, which is commonly manifested with refractory seizures and neurologic deterioration. The prognosis of PME is poor, so early diagnosis of PME is critical. The aim of our study is to identify the novel pathogenic gene in a Chinese family with PME, which may be helpful in future. Subjects and methods: A three-generation consanguineous Chinese Han family with PME was recruited. A novel homozygous variant was identified by the genetic technique of exome sequencing and certificated by Sanger sequencing and functional prediction. Results: A novel homozygous variant, c.6975_6976insCAG, in the CACNA1A was identified in the PME family. The novel variant encoding the alpha-1A subunit of the calcium channel Cav2.1 was found in two siblings in the Chinese family and was absent in 50 normal controls. Our research indicates that the homozygous c.6975_6976insCAG might be the pathogenic mutation for PME. Conclusion: As a molecular diagnostic strategy, our research explores the mutation gene spectrum of PME and has resulted in significant predictions for genetic counseling. [ABSTRACT FROM AUTHOR]

Chromosome 3q syndrome is a well-known genetic condition caused by interstitial deletion in the long arm of chromosome 3. The phenotype of this syndrome is variable and the great variability in the extent of these deletions leads to a wide spectrum of clinical manifestations. Terminal 12p deletion represents one of the rarest subtelomeric imbalances; patients with distal monosomy 12p present different phenotypes ranging from muscular hypotonia to autism spectrum disorders. The present study reported a prenatal diagnosis of a male fetus presenting ultrasound evidence of corpus callosum dysplasia and ventriculomegaly showing a 3q13q21.2 deletion and a 12p13.33 microdeletion paternally inherited. Among several features previously attributed to the terminal deletion of 3q, corpus callosum dysplasia and ventriculomegaly have rarely been reported together. As the 12p13.33 microdeletion in the father was associated only with muscular hypotonia and joint laxity, the involvement of terminal 12p deletions in the clinical features of the fetus was not possible to verify during the prenatal period. The present case report may provide a reference for prenatal diagnosis and genetic counseling in patients who present 3q13q21.2 deletions and 12p13.33 microdeletion. [ABSTRACT FROM AUTHOR]

Ca2+ release-activated Ca2+ (CRAC) channels mediate a specific formof Ca2+ influx called store-operated Ca2+ entry (SOCE) that contributes to the function of many cell types. CRAC channels are composed of ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes. CRAC channelopathy is caused by loss-offunctionmutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in sweat gland function and dental enamel formation. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca2+ levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes. The latter two syndromes are defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from both loss- and gain of- function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca2+ homeostasis in skeletalmuscle function. The cellular dysfunction and clinical disease spectrum observed inmutant patients provide important information about the molecular regulation of ORAI1 and STIM1 proteins and the role of CRAC channels in human physiology. [ABSTRACT FROM AUTHOR]

Abstract: We present two new patients with the recently described mitochondrial m.3242G > A mutation. Although the mutation is situated next to the well known m.3243A > G mutation, the most common alteration associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, the clinical presentation is quite different, but characteristic. All three m.3242G > A patients presented in the neonatal period with hypertrophic and dilated cardiomyopathy, generalized muscle hypotonia and lactic acidosis. Two additionally had creatine kinase elevation, renal tubular acidosis/dysfunction and showed a mild clinical course with a favourable psychomotor development. The third patient had more neurological involvement and died in infancy. The mutation occurred de novo in the two patients where maternal investigations were performed. The combination of hypertrophic cardiomyopathy and renal tubular acidosis/renal tubular dysfunction is clinically distinctive and may represent a separate entity. [Copyright &y& Elsevier]

Abstract: In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia. One child died in infancy, two survived a clinically severe neonatal period. At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development. In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased. This protein is expressed in two tissue-specific isoforms generated by mutually exclusive alternative splicing of the SLC25A3 gene transcript. We identified a homozygous mutation c.158-9A>G located in the 5′-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele. [Copyright &y& Elsevier]

Background: The Ehlers-Danlos syndrome type VI (EDSVI) is an autosomal recessive connective tissue disease which is characterized by severe hypotonia at birth, progressive kyphoscoliosis, skin hyperelasticity and fragility, joint hypermobility and (sub-)luxations, microcornea, rupture of arteries and the eye globe, and osteopenia. The enzyme collagen lysyl hydroxylase (LH1) is deficient in these patients due to mutations in the PLOD1 gene. Case Presentation: We report a 17-year-old boy, born to related parents, with severe dyphoscoliosis, scar formation, joint hypermobility and multiple dislocations, muscular weakness, rupture of an ocular globe, and a history of severe infantile hypotonia. EDS VI was suspected clinically and confirmed by an elevated ratio of urinary total lysyl pyridinoline to hydroxylysyl pyridinoline, abnormal electrophoretic mobility of the α-collagen chains, and mutation analysis. Conclusion: because of the high rate of consanguineous marriages in Iran and, as a consequence thereof, an increased rate of autosomal recessive disorders, we urge physicians to consider EDS VI in the differential diagnosis of severe infantile hypotonia and muscular weakness, a disorder which can easily be confirmed by the analysis of urinary pyridinolines that is highly specific, sensitive, robust, fast, non-invasive, and inexpensive. [ABSTRACT FROM AUTHOR]

Observations: A short lingual frenulum and a lack of tone of the lingual and supra-hyoidal muscles could influence a OSA in a teenager, refractory to conventional treatment. The therapy is based on surgery and rehabilitation with polysomnographic surveillance. Comments: The aggravating factors were to be noted during the treatment. No article in the literature put this relationship into perspective. Conclusion: The results obtained were inconclusive. This line of research could interest the scientific community in order to guide the physiopathological knowledge of the disorder and to optimize the possibilities of therapeutic response in case functions. [ABSTRACT FROM AUTHOR]

Abstract: We describe a 3.5 year old girl presenting with short stature, developmental delay, marked muscular hypotonia with ataxia, premature pubarche, and dysmorphic features. A 1.07–1.12Mb-sized de novo microdeletion of chromosome 19p13.11 is most likely the cause for the clinical phenotype. The patient did not show any abnormalities of the extremities which contrasts with the finding of one previously reported patient with an overlapping deletion presenting with split hand and foot malformation (SHFM). The remarkable difference is that in the previously described patient but not in the patient reported herein the genes EPS15L1 and CALR3 were deleted. As EPS15L1 has been associated with limb development previously, the presented case provides indirect evidence that this may be a new candidate gene for SHFM. A possible genotype–phenotype correlation is provided based on literature review and comparison of our patient to the previously reported patients with overlapping or partly overlapping copy number variations in 19p13.11. [Copyright &y& Elsevier]

Abstract: Interstitial deletions of chromosome 14 have rarely been described. We report on a boy in whom a 2 Mb deletion in 14q13 was discovered by array CGH. The deletion was a de novo event. The boy presented with asymmetrical growth retardation at birth. There was severe developmental delay with muscular hypotonia and focal epilepsy with apneic episodes progressing to serial tonic seizures. At the age of 3 3/12 years he was diagnosed with pneumonia. In the further course he developed symptoms of hemophagocytic lymphohistiocytosis. He died due to organ failure. Herein the clinical findings are compared to patients with cytogenetic visible deletions encompassing the region deleted in the proband and the possible connection with the deleted genes. [Copyright &y& Elsevier]

Abstract: Objective: Intoxication with antidepressants, frequently encountered in pediatric emergency medicine, can often lead to life threatening situations. While hyperthermia, hypertonicity and rigidity are symptoms indicative of a serotonin syndrome triggered by an intoxication with serotonin reuptake inhibitors or monoamine oxidase inhibitors, cardiotoxicity, coma and ECG changes are typical of an intoxication with tricyclic antidepressants. Case report: Hypothermia (instead of the expected hyperthermia) is described for the first time as a persistent symptom during the course of a combined moclobemide–doxepin intoxication in an attempted suicide of a 16-year-old adolescent. Discussion: The administration of serotonin reuptake inhibitors alone or in combination with other medication which increases the level of 5-hydroxytryptamine, i.e. serotonin, in the synaptic cleft mainly leads to hyperthermia. According to a recent study, however, the application of a selective 5-HT1a agonist to transgenic mice with a prominent overexpression of the 5-HT1a receptor lead to immobility and hypothermia. These findings might help to explain the hypothermia observed in the case of the intoxicated 16-year-old. Conclusion: Intoxication with antidepressants should not be excluded a priori in a hypothermic patient who displays other clinical signs of the said intoxication. [Copyright &y& Elsevier]