scholarly journals Novel CLCN4 variant associated with syndromic X-linked intellectual disability in a Chinese girl: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xin Xu ◽  
Fen Lu ◽  
Li Zhang ◽  
Hongying Li ◽  
Senjie Du ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Language Impairment ◽  
Brain Magnetic Resonance Imaging ◽  
Rare Condition ◽  
Missense Variant ◽  
Brain Abnormalities ◽  
Case Presentation ◽  
Whole Exome ◽  
Chinese Girl ◽  
Magnetic Resonance Imaging Mri

Abstract Background The Raynaud-Claes type of X-linked syndromic mental retardation (MRXSRC) is a very rare condition, by intellectual disability ranged from borderline to profound, impaired language development, brain abnormalities, facial dysmorphisms and seizures. MRXSRC is caused by variants in CLCN4 which encodes the 2Cl−/H+ exchanger ClC-4 prominently expressed in brain. Case presentation We present a 3-year-old Chinese girl with intellectual disability, dysmorphic features, brain abnormalities, significant language impairment and autistic features. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, a mega cisterna magna and ventriculomegaly. Whole exome sequencing (WES) was performed to detect the molecular basis of the disease. It was confirmed that this girl carried a novel heterozygous missense variant (c.1343C > T, p.Ala448Val) of CLCN4 gene, inherited from her mother. This variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. Conclusion Our investigation expands the phenotype spectrum for CLCN4 variants with syndromic X-linked intellectual disability, which help to improve the understanding of CLCN4-related intellectual disability and will help in genetic counselling for this family.

scholarly journals Novel Imaging and Clinical Manifestations of Ndmsba Disorder Caused by a Homozygous Missense Variant of Plaa

2021 ◽  
Author(s):  
Ali Dehghani ◽  
Ehsan Razmara ◽  
Maryam Rasoulinezhad ◽  
Fatemeh Bitarafan ◽  
Ali Reza Tavasoli ◽  
...  
Keyword(s):  
White Matter ◽  
Neurodevelopmental Disorder ◽  
Clinical Manifestations ◽  
Brain Magnetic Resonance Imaging ◽  
Missense Variant ◽  
The Novel ◽  
Neurodevelopmental Disease ◽  
Brain Anomalies ◽  
Whole Exome ◽  
Magnetic Resonance Imaging Mri

Abstract BackgroundPhospholipase A-2-activating protein (PLAP) has essential roles in biological pathways. Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA) is a complex neurodevelopmental disease caused by defects in the PLAA gene (MIM: 603873). Herein, we aimed to detect the potential genetic factors contributing to the NDMSBA phenotype in a 2.5-year-old affected male in an Iranian consanguineous family.ResultsAfter meticulously performing neuroimaging and clinical examinations, due to heterogeneity of neurodevelopmental diseases, the proband was subjected to paired-end whole-exome sequencing (WES). The brain magnetic resonance imaging (MRI) revealed lissencephaly, polymicrogyria, severe subcortical, deep and deep white matter signal abnormalities, thinning of the corpus callosum, and severe vermis atrophy. Interestingly, we detected a novel homozygous missense variant, NM_001031689.3:c.2264A>G;p.(Asp755Gly) in the PLAA gene. To the best of our knowledge, this variant is the second one identified within the PUL domain (PLAP, Ufd3p, and Lub1p) of PLAP and also the sixth reported variant throughout the PLAA gene. In silico analyses underscored the pathogenicity of the variant. ConclusionsThe present study demonstrated severe cerebral and cerebellar white matter signal abnormalities, hypertelorism, strabismus, and drooling in the proband as the novel manifestation of NDMSBA that in turn caused by a novel likely pathogenic missense variant. Further studies are required to confirm how this variant contributes to NDMSBA.

Unusual presentation of acute encephalopathy with biphasic seizures and late reduced diffusion in Miller–Dieker syndrome

2019 ◽  
Author(s):  
Satoru Kobayashi ◽  
Mai Kamishima ◽  
Akari Tago ◽  
Kyoko Yokoi ◽  
Satoshi Suzuki
Keyword(s):  
Brain Magnetic Resonance Imaging ◽  
Subcortical White Matter ◽  
Acute Encephalopathy ◽  
Case Presentation ◽  
Delta Waves ◽  
Diffusion Weighted Images ◽  
Disturbance Of Consciousness ◽  
Intravenous Diazepam ◽  
Severe Motor ◽  
Magnetic Resonance Imaging Mri

Abstract Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a unique subtype of acute encephalopathy that occurs in children. To date, there is no description of a patient with concurrent Miller–Dieker syndrome (MDS) and AESD. Case presentation: We present a case of 2-year-old girl with MDS, who was admitted for status epilepticus with a high fever, was diagnosed with AESD. She exhibited seizure for more than 1 h, which disappeared after administration of intravenous diazepam and phenobarbital. Brain magnetic resonance imaging (MRI), performed on the third day post-admission because she had not regained consciousness after the seizure ceased, showed abnormally high intensities in subcortical white matter, predominantly in the frontal areas on diffusion-weighted images (DWI). Acute encephalitis/encephalopathy was diagnosed based on electroencephalography (EEG) findings of diffuse high-voltage delta waves without seizure activity. Six days post-admission, frequent apneic episodes were observed, with oxygen desaturation due to clustered seizures. Although seizures disappeared with continuous intravenous midazolam, subclinical seizures were present in amplitude-integrated EEG (aEEG); these were suppressed by increasing the midazolam dose. Conclusion: This is the first report of AESD in a patient with MDS. Ther disturbance of consciousness was difficult to recognize because of severe motor and intellectual disabilities due to MDS. EEG aids the evaluation of consciousness in the acute phase, and aEEG can be helpful for monitoring and controlling subclinical seizures in the biphasic phase of AESD, especially patients with underlying neurological disorders.

scholarly journals Hypertrophic olivary degeneration concomitant with bilateral middle cerebellar peduncles Wallerian degeneration following unilateral pontine infarction

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Bing Bao ◽  
Xiangbin Wu ◽  
Zhongbin Xia ◽  
Yaoyao Shen
Keyword(s):  
Wallerian Degeneration ◽  
Corticospinal Tract ◽  
Brain Magnetic Resonance Imaging ◽  
Acute Onset ◽  
Case Presentation ◽  
Hypertrophic Olivary Degeneration ◽  
Pontine Infarction ◽  
Cerebellar Peduncles ◽  
Magnetic Resonance Imaging Mri

Abstract Background Wallerian degeneration (WD) can occur in different projecting systems, such as corticospinal tract, dentate-rubro-olivary pathway, and corticopontocerebellar tract. However, the co-occurrence of hypertrophic olivary degeneration (HOD) and middle cerebellar peduncles (MCPs) degeneration secondary to unilateral pontine infarction in a single patient is extremely rare. Case presentation A 71-year-old man presented with acute onset of dizzness, slurred speech, and right-sided weakness. On the next day, his previous neurologic deficits deteriorated. Brain magnetic resonance imaging (MRI) revealed acute ischemic stroke of the left pons. After treatment with thrombolysis, antiplatelets, and rehabilitation training, his speaking and motor function improved moderately. At the 3-month follow-up, the MRI showed hyperintensity in the left medulla oblongata and bilateral MCPs on T2-weighted and FLAIR images, suggesting HOD as well as MCPs degeneration. Conclusions It is of great importance for us to know the anatomic knowledge of dentate-rubro-olivary and corticopontocerebellar pathways.

scholarly journals Novel homozygous variant in the TPO gene associated with congenital hypothyroidism and mild-intellectual disability

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Amjad Khan ◽  
Muhammad Umair ◽  
Rania Abdulfattah Sharaf ◽  
Muhammad Ismail Khan ◽  
Amir Ullah ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Congenital Hypothyroidism ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Thyroid Peroxidase ◽  
Mild Intellectual Disability ◽  
Complex Disorder ◽  
Whole Exome ◽  
Hereditary Disorders ◽  
Autosomal Recessive Manner

AbstractCongenital hypothyroidism (CH) is one of the most common hereditary disorders affecting neonates worldwide. CH is a multifactorial complex disorder and can be caused by either environmental factors or genetic factors. We studied one Pakistani family with segregating mutations in CH inherited in an autosomal recessive manner. Using whole-exome sequencing (WES), we found a novel homozygous missense variant (c.2315A>G; p.Tyr772Cys) in the thyroid peroxidase (TPO) gene. Different bioinformatics prediction tools and Sanger sequencing were performed to verify the identified variant. Our findings highlight the importance of this gene in causing CH and mild-intellectual disability (ID) in two affected brothers. WES is a convenient and useful tool for the clinical diagnosis of CH and other associated disorders.

A Conjunctival Vascular Malformation as a Rare Presenting Sign of Wyburn–Mason Syndrome

2017 ◽  
Vol 16 (04) ◽  
pp. 239-242
Author(s):  
Gunnar Buyse ◽  
Lieven Lagae ◽  
Philippe Demaerel ◽  
Frank Kesteloot ◽  
Ingele Casteels ◽  
...  
Keyword(s):  
Vascular Malformation ◽  
Arteriovenous Malformations ◽  
Brain Magnetic Resonance Imaging ◽  
Rare Condition ◽  
Vascular Lesion ◽  
Facial Skin ◽  
Sudden Appearance ◽  
Magnetic Resonance Imaging Mri ◽  
The Right ◽  
The Brain

AbstractWyburn–Mason syndrome is a rare condition that is characterized by ipsilateral arteriovenous malformations affecting the eye, brain, and facial skin. A conjunctival vascular dilation can be a rare ocular presenting sign. We report a 6-year-old boy who attended the hospital because of the sudden appearance of a conjunctival vascular lesion in his right eye. Inspection of his facial skin showed a subtle discoloration along the right trigeminal nerve and a vascular structure of the conjunctiva. Fundoscopy showed dilated and tortuous retinal vessels. Brain magnetic resonance imaging (MRI) revealed a large arteriovenous malformation involving the thalamus and perimesencephalic area. Ophthalmologic and neuroradiologic findings were consistent with the diagnosis of Wyburn–Mason syndrome. The sudden emergence of a vascular malformation in the conjunctiva should alert the clinician to perform an ophthalmoscopy, and in our patient, this finding was the clue to diagnosis of Wyburn–Mason syndrome. Because of the association between retinal and intracranial arteriovenous malformations, an MRI of the brain is strongly recommended in all patients with ocular arteriovenous malformations.

scholarly journals OTUD5 Variants Associated With X-Linked Intellectual Disability and Congenital Malformation

2021 ◽  
Vol 9 ◽  
Author(s):  
Ken Saida ◽  
Tokiko Fukuda ◽  
Daryl A. Scott ◽  
Toru Sengoku ◽  
Kazuhiro Ogata ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Ovarian Tumor ◽  
Brain Magnetic Resonance Imaging ◽  
Missense Variant ◽  
The Novel ◽  
Nasal Bridge ◽  
Congenital Cardiac Anomalies ◽  
Novel Variant ◽  
Long Term Prognosis

BackgroundX-linked intellectual disability (XLID), which occurs predominantly in males, is a relatively common and genetically heterogeneous disorder in which over 100 mutated genes have been reported. The OTUD5 gene at Xp11.23 encodes ovarian tumor deubiquitinase 5 protein, which is a deubiquitinating enzyme member of the ovarian tumor family. LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome, arising from pathogenic OTUD5 variants, was recently reported as a new XLID with additional congenital anomalies.MethodsWe investigated three affected males (49- and 47-year-old brothers [Individuals 1 and 2] and a 2-year-old boy [Individual 3]) from two families who showed developmental delay. Their common clinical features included developmental delay, hypotonia, short stature, and distinctive facial features, such as telecanthus and a depressed nasal bridge. Individuals 1 and 2 showed epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly. Individual 3 showed congenital malformations, including tetralogy of Fallot, hypospadias, and bilateral cryptorchidism. To identify the genetic cause of these features, we performed whole-exome sequencing.ResultsA hemizygous OTUD5 missense variant, c.878A>T, p.Asn293Ile [NM_017602.4], was identified in one family with Individuals 1 and 2, and another missense variant, c.1210 C>T, p.Arg404Trp, in the other family with Individual 3, respectively. The former variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. The latter variant p.Arg404Trp was previously reported as a pathogenic OTUD5 variant, and Individual 3 showed a typical LINKED syndrome phenotype. However, Individuals 1 and 2, with the novel variant (p.Asn293Ile), showed no cardiac or genitourinary malformations.ConclusionsUnlike previous reports of LINKED syndrome, which described early lethality with congenital cardiac anomalies, our three cases are still alive. Notably, the adult brothers with the novel missense OTUD5 variant have lived into their forties. This may be indicative of a milder phenotype as a possible genotype-phenotype correlation. These findings imply a possible long-term prognosis for individuals with this new XLID syndrome, and a wider phenotypic variation than initially thought.

scholarly journals Dyke-Davidoff-Masson Syndrome: A case Report in a patient presenting with drug-resistant epilepsy and pseudoseizures

2021 ◽  
Author(s):  
Pedro Schmidt dos Reis Matos Figueiredo ◽  
Thiago Oliveira Chaves
Keyword(s):  
Case Report ◽  
Cognitive Dysfunction ◽  
Brain Magnetic Resonance Imaging ◽  
Rare Condition ◽  
Signs And Symptoms ◽  
Drug Resistant ◽  
Cerebral Hemiatrophy ◽  
History Of ◽  
Magnetic Resonance Imaging Mri ◽  
Drug Resistant Epilepsy

Context: Dyke-Davidoff-Masson (DDM) syndrome is a rare neurological condition, first described in 1933. Characteristics include cerebral hemiatrophy, contralateral hemiparesis, seizures, and cognitive dysfunction, combined into different degrees and patterns. Brain magnetic resonance imaging (MRI) is used to perform diagnosis throughout its specific findings. Case Report: A eighteen-year-old female presented to our service with a history of cognitive dysfunction and seizures since early childhood, which persistence even with adequate use of antiepileptic drugs. During Investigation were found signs and symptoms compatible with DDM syndrome, and evidence of pseudoseizures captured in a video electroencephalography monitoring. Conclusion: DDM syndrome is a rare condition that must be part of differential diagnosis in patients with seizures and cerebral hemiatrophy. Management is based on adequate control of seizures and other comorbidities.

3-M syndrome – a primordial short stature disorder with novel CUL7 mutation in two Indian patients

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Radha Rama Devi Akella
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Whole Exome ◽  
Heterozygous Variant

Abstract Objective To evaluate the cause of short stature in children. Case presentation Two children with suspected skeletal dysplasia and short stature were evaluated. Conclusions The 3-M syndrome is a primordial growth disorder manifesting severe postnatal growth restriction, skeletal anomalies and prominent fleshy heels. The 3-M syndrome is a genetically heterogeneous disorder and the phenotype is similar. This is a rare autosomal recessive disorder with normal intellect. Two affected children have been identified by whole-exome sequencing. One patient harboured a compound heterozygous variant and the other was a homozygous missense variant. The genetic diagnosis helped in counselling the families and facilitated prenatal diagnosis in one (case 1) family.

scholarly journals A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

2018 ◽  
Vol 08 (01) ◽  
pp. 010-014 ◽  
Author(s):  
Wafa Alazaizeh ◽  
Asem Alkhateeb
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Frameshift Mutation ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Magnetic Resonance Imaging ◽  
Comparative Genomic ◽  
Feeding Difficulties ◽  
Whole Exome

AbstractIntellectual disability is a common condition with multiple etiologies. The number of monogenic causes has increased steadily in recent years due to the implementation of next generation sequencing. Here, we describe a 2-year-old boy with global developmental delay and intellectual disability. The child had feeding difficulties since birth. He had delayed motor skills and muscular hypotonia. Brain magnetic resonance imaging revealed diffuse white matter loss and thinning of the corpus callosum. Banded karyotype and comparative genomic hybridization (CGH) array were normal. Whole exome sequencing revealed a novel de novo frameshift mutation c.3390delA (p.Lys1130Asnfs*4) in KAT6A gene (NM_006766.4). The heterozygous mutation was confirmed by Sanger sequencing in the patient and its absence in his parents. KAT6A that encodes a histone acetyltransferase has been recently found to be associated with a neurodevelopmental disorder autosomal dominant mental retardation 32 (OMIM: no. 616268). Features of this disorder are nonspecific, which makes it difficult to characterize the condition based on the clinical symptoms alone. Therefore, our findings confirm the utility of whole exome sequencing to quickly and reliably identify the etiology of such conditions.

scholarly journals Kabuki Syndrome: Identification of Two Novel Variants in KMT2Dand KDM6A

2021 ◽  
pp. 1-9
Author(s):  
Mehrnoosh Khodaeian ◽  
Ehsan Jafarinia ◽  
Fatemeh Bitarafan ◽  
Shohreh Shafeii ◽  
Navid Almadani ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Kabuki Syndrome ◽  
Functional Studies ◽  
Large Deletions ◽  
Whole Exome ◽  
Functionally Impaired ◽  
And Function

Kabuki syndrome (KS) is a rare genetic disorder characterized by the following 5 crucial symptoms: dysmorphic facial features, growth retardation, skeletal abnormalities, intellectual disability, and dermatoglyphic malformations. Studies show that most of the KS cases are caused by mutations or large deletions in the KMT2D gene, while the other cases show mutations in KDM6A. We studied 2 patients with suspected KS in 2 unrelated families by whole-exome sequencing to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants and check the segregation in other members of the families. Finally, the potential effects of the variants on the structure and function of respective proteins were tested using in silico predictions. Both affected members of the families showed typical manifestations of KS including intellectual disability, developmental delay, and abnormal facial characteristics. A novel heterozygous frameshift variant in the KMT2D gene, c.4981del; p.(Glu1661Serfs*61), and a novel hemizygote missense variant in the KDM6A gene, c.3301G>A; p.(Glu1101Lys), were detected in patients 1 and 2, respectively. The frameshift variant identified in the first family was de novo, while in the second family, the mother was also heterozygous for the missense variant. The frameshift variant in KMT2D is predicted to lead to a truncated protein which is functionally impaired. The Glu1101 residue of KDM6A (UTX) affected in the second patient is located in a conserved region on the surface of the Jumonji domain and predicted to be causative. Our findings provide evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.

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