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Objective: Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as "borderline." Methods: Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the "borderline" individual with moderate anxiety and obsessive-compulsive traits. Results: The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a "borderline" phenotype that, if combined with a heterozygous missense variant in ZNF92, is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. Conclusions: Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92.
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Abstract Introduction: Neuronal ceroid lipofuscinosis (NCLs) is an autosomal recessive neurodegenerative disorders group. We report the first case in Colombia involving a new genetically confirmed variant of a homozygous CLN6 mutation. Case report: 12-year-old male, history of blood parents and average growth until 5 years of age. At this age began focal crises, progressive regression of neurodevelopment, severe cognitive deficit, and swallowing disorder that led to gastrostomy. Clinical exome + CNVs + mitochondrial DNA genetic study identified variant NM_017882.3 (CLN6): c. 22C>T, p. (Gln8*) in homozygous, deleterious. Late-onset infantile neuronal ceroid lipofuscinosis was diagnosed. Discussion: Mutations in the CLN6 gene are associated with late-onset infantile lipofuscinosis of autosomal recessive inheritance. This variant has not been previously described in the medical literature nor is it listed in the population databases, which indicates that it is extremely rare. The treatment focuses on the control of seizures, sleep disturbances, extrapyramidal symptoms, behavioral disorders, anxiety, and psychosis. Conclusion: To date, this variant of the CLN6 gene has not been reported in the world. There are currently no etiological or disease-specific therapeutic approaches. The use of exome/whole genome sequencing can be very useful for etiological diagnosis and differential diagnosis. An early diagnosis opens the door to future care and treatment.
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Abstract Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare autosomal recessive neurodegenerative disorder caused by mutations in the CLN2/TPP1 gene, leading to a deficiency in tripeptidyl peptidase 1 activity. Enzyme replacement therapy with cerliponase alfa (recombinant human TPP1 [rhTPP1]; Brineura®) was approved in the United States and Europe for the treatment of CLN2 disease in 2017. We retrospectively report a cohort of 19 patients with CLN2 assisted in a specialized center in Argentina, including 8 newly diagnosed cases. Speech disorders and white matter changes/ventricular system enlargement were the most frequent clinical and imaging findings at CLN2 disease onset, respectively. Patients treated with cerliponase alfa presented a stable or improved course of the disease in this Latin American real world setting, as described in clinical trials.
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ABSTRACT Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of inherited lysosomal storage disorders characterized by the intracellular accumulation of ceroid-lipofuscin compounds and neurodegeneration. Fourteen genes are currently recognized with disease-causing DNA variants: PPT1/CLN1, TPP1/CLN2, CLN3, DNAJC5/CLN4, CLN5, CLN6, MFSD8/CLN7, CLN8, CTSD/CN10, GRN/CLN11, ATP13A2/CLN12, CTSF/CLN13, KCTD7/CLN14, TBCK/CLN15. In the frame of the Cordoba cohort, we studied N=51 cases. The aim of this paper is the observational and retrospective analysis of the "atypical" phenotypes. PCR-Sanger sequencing and/or massive exome sequencing were used as a screening methodology. One CLN1 subject showed an atypical prolonged (P) phenotype with null PPT1 activity and a heterozygous compound genotype: E5 c.451C>T, p.Arg151*/g.6302T>G (I3 c.363-3T>G). Other 11 CLN2 individuals (except one girl) showed TPP1 activity decreased to around 10% of the minimum value of the reference interval in leukocytes and saliva. The DNA variants E7 c.827A>T, p.Asp276Val and I7 c.887-10A>G were the most prevalent. One CLN8 individual showed an atypical congenital phenotype with a heterozygous combination of DNA variants: E2 c.1A>G, p.?/E3 c.792C>G, p.Asn264Lys. Massive sequencing was installed as a screening methodology for the precision diagnosis of atypical CLN1, CLN2, and CLN8 phenotypes. A genetic/phenotypic local registry is under construction.
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Objective To analyze the clinical symptoms and hereditary information of suspicious juvenile neuronal ceroid-lipofuscinosis (JNCL) and determine the genotype in order to explore the diagnosis clues in the patients with ophthalmologic manifestations being initial symptom.Methods A case-control study was performed in this study.Two families were included in Eye Hospital of Wenzhou Medical in 2013 and 2017,respectively.Medical histories were collected and all participants underwent comprehensive ophthalmologic examinations,and the best corrected visual acuity (BCVA) was obtained.Fundus photography and optical coherence tomography (OCT) were used to image the retinal signs,and visual electrophysiology was recorded to evaluate the visual function.Genomic DNA of 3 patients who initially visited to ophthalmologists and 5 unaffected family members were extracted.Whole exome sequencing (WES),targeted exome sequencing (TES),Sanger sequencing and comprehensive analyses of pathogenicity were performed to determine the genetic cause of the patients.This study was approved by Ethics Committee of Eye Hospital of Wenzhou Medical University (KYK-2017-7),and written informed consent was obtained from each subject prior to any medical examination.Results All patients presented bull eye sign and disorder of pigment on the fundus photograph,and the retinas were thinning on the OCT image,indicating the diffuse retinal pigment epithelium atrophy of macula and loss of outer layer structure of retina.Three mutations in CLN3 gene were identified by WES,TES,Sanger validation and assessments of pathogenicity,including c.154T＞C (p.Y52H),c.982G＞C (p.A328P) and c.906+5G＞A,among which p.A328P was a novel mutation.Patients of F1 family harbored the compound heterozygous mutations c.154T＞C (p.Y52H) and c.982G＞C (p.A328P),while proband of F2 family harbored the homozygous splice site mutation c.906+5G＞A,which was reported to be a pathogenic mutation of JNCL.Co-segregation and comprehensive pathogenicity analysis revealed that the compound heterozygous mutations in F1 family and the homozygous mutation in a splice site in F2 family were the genetic causes of their phenotypes.Conclusions A novel mutation in CLN3 gene for JNCL is identified,which expands the mutation spectrum of CLN3 gene.Considering the high clinical heterogeneity of inherited retinal diseases,especially syndromic cases,genetic test through next generation plays a vital role in diagnosis,guiding future treatment and prognostic evaluation.
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Abstract Given the lack of standardized guidance for follow-up of patients with neuronal ceroid lipofucsinosis-2 disease in Latin-American countries and the heterogeneity of the region, an expert panel was created with the participation of 11 pediatric neurologists from Colombia, Argentina, Brazil and Chile. The aim of the expert panel was to describe a framework for standardized follow-up in patients with neuronal ceroid lipofucsinosis-2 disease, on or off therapy, that could benefit patients and treating physicians alike. Experts made recommendations in the following areas: seizures, abnormal movements and ataxia, sleep disorders and pain, cognitive function, visual function, hearing and speech, cardiac function, quality of life, and motor function. Recommendations include the most appropriate tools for use in the Latin-American context and health care systems, and provide feasible follow-up guidance, applicable in public and private healthcare facilities. They take into consideration the availability of clinical assessment resources, tools (scales, questionnaires, paraclinical tests) and access to these tools in Latin-American countries, as well as other regional and local needs defined by the participating experts.
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Abstract Neuronal ceroid lipofuscinoses (NCLs), also referred as "Batten disease", are a group of thirteen rare genetic conditions, which are part of the lysosomal storage disorders. CLN type 2 (CLN2) is caused by the deficient activity of the tripeptidyl peptidase I (TPP1) enzyme, encoded by the TPP1 gene, most frequently leading to the classic late infantile phenotype. Nearly 140 CLN2-causing mutations have been described. In this case report, we describe the identification of a new disease-causing mutation and highlight the importance of appropriate laboratory investigation based on clinical suspicion. The collection of dried blood spots (DBS) on filter paper, which is a convenient sample, can be used to measure the TPP1 enzyme activity and detect CLN2-related mutations. Since the biochemical and genetic diagnoses are possible and as the disease progression is fast and the therapeutic window is short, the investigation of CLN2 should be always considered when this diagnostic hypothesis is raised in order to enable the patients to benefit from the specific pharmacological treatment.
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Abstract Limited research has investigated the challenges faced by families caring for children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Face-to-face, mixed-method, in-depth surveys were conducted with 19 families (23 children) in the UK (n=9) and Germany (n=10) to assess the impact of caring for children with CLN2 disease, using national wellbeing and quality of life (QoL) measures. Primary (n=19) and secondary (n=10) caregivers, adult siblings (n=2), and child siblings (n=2) were included. Caregivers reported reduced health-related QoL compared with age and gender-matched controls (mean utility scores 0.08 and 0.11 lower in Germany and the UK, respectively). Hours of caregiving were significantly higher relative to that provided to a child of normal health, with stress, back pain, and reductions in sleep being recorded. Lower life satisfaction and happiness with partners were also reported, along with significant financial burden. Those caring for children in the late stage of disease were more greatly impacted than those with children in the rapidly progressive stage, or who were bereaved. The results of this study make clear the importance of emotional and practical support for caregivers and siblings coping with CLN2 disease.
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Objective@#To analyze the clinical symptoms and hereditary information of suspicious juvenile neuronal ceroid-lipofuscinosis (JNCL) and determine the genotype in order to explore the diagnosis clues in the patients with ophthalmologic manifestations being initial symptom.@*Methods@#A case-control study was performed in this study.Two families were included in Eye Hospital of Wenzhou Medical in 2013 and 2017, respectively.Medical histories were collected and all participants underwent comprehensive ophthalmologic examinations, and the best corrected visual acuity (BCVA) was obtained.Fundus photography and optical coherence tomography (OCT) were used to image the retinal signs, and visual electrophysiology was recorded to evaluate the visual function.Genomic DNA of 3 patients who initially visited to ophthalmologists and 5 unaffected family members were extracted.Whole exome sequencing (WES), targeted exome sequencing (TES), Sanger sequencing and comprehensive analyses of pathogenicity were performed to determine the genetic cause of the patients.This study was approved by Ethics Committee of Eye Hospital of Wenzhou Medical University (KYK-2017-7), and written informed consent was obtained from each subject prior to any medical examination.@*Results@#All patients presented bull eye sign and disorder of pigment on the fundus photograph, and the retinas were thinning on the OCT image, indicating the diffuse retinal pigment epithelium atrophy of macula and loss of outer layer structure of retina.Three mutations in CLN3 gene were identified by WES, TES, Sanger validation and assessments of pathogenicity, including c. 154T>C(p.Y52H), c.982G>C(p.A328P) and c. 906+ 5G>A, among which p. A328P was a novel mutation.Patients of F1 family harbored the compound heterozygous mutations c. 154T>C (p.Y52H) and c. 982G>C(p.A328P), while proband of F2 family harbored the homozygous splice site mutation c. 906+ 5G>A, which was reported to be a pathogenic mutation of JNCL.Co-segregation and comprehensive pathogenicity analysis revealed that the compound heterozygous mutations in F1 family and the homozygous mutation in a splice site in F2 family were the genetic causes of their phenotypes.@*Conclusions@#A novel mutation in CLN3 gene for JNCL is identified, which expands the mutation spectrum of CLN3 gene.Considering the high clinical heterogeneity of inherited retinal diseases, especially syndromic cases, genetic test through next generation plays a vital role in diagnosis, guiding future treatment and prognostic evaluation.
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OBJECTIVE: To collect the clinical features and gene mutation types of children with neuronal ceroid lipofuscinosis(NCLs)in China,and to help to make genetic diagnosis of NCLs patients. METHODS: The clinical manifestations and examinations of one case with complaints of language disorder for 1.5 years,dyskinesia for 0.5 years and repeated convulsions for one week were collected,and literatures of NCLs from China were reviewed. RESULTS: The electroencephalogram(EEG)showed multiple spikes and slow-wave discharges bilaterally. The brain MRI scan showed high hyperintensities adjacent to the bilateral posterior horns of the lateral ventricles on T2-weighted images and broadened cerebellar fissures. The "leukoencephalopathies and symptomatic epilepsy" was diagnosed. The genetic analysis showed that the proband had a homozygous missense point mutation c.892 G>A(p.Glu298 Lys)(reference sequence:NM＿017882.2)in exon 7 of CLN6 and that both his parents were heterozygous for the mutation. The diagnosis of late infantile neuronal ceroid lipofuscinosis(LINCLs)was confirmed according to the clinical features and genetic analysis results. In CNKI,WANFANG and WIPP Databases,we reviewed the relevant domestic reports about NCLs(28 articles). A total of 3 cases of CLN6 gene mutation were reported,including 2 cases of LINCLs caused by heterozygous mutation and 1 case of JNCLs caused by homozygous mutation. Here we reported the first case of LINCLs caused by a CLN6 homozygous mutation in China. CONCLUSION: This is the first case of LINCLs caused by CLN6 homozygous mutation reported in China. Our report expands the genotype data for NCLs.The mutant genes reported in NCLs patients are CLN1,CLN2,CLN3,CLN5,CLN6 and CLN7,and the clinical manifestations are intractable epilepsy,decreased vision,decreased intelligence,mental and motor dysfunction,personality and behavior changes,and memory decline. A gene sequencing panel for investigating unexplained seizures,leukoencephalopathies and inherited metabolic disorder can help to make the diagnosis.
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Abstract CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, genetic, paediatric-onset, neurodegenerative lysosomal storage disorder characterised by seizures, ataxia, rapid loss of motor function and language ability, dementia, visual loss and early death. Physiotherapy plays an important role in the management of CLN2 disease, aiming to maintain the best possible functioning and autonomy of the child, support the child's participation in everyday life, limit secondary complications and maintain or improve quality of life. This article discusses the physiotherapeutic treatment of children diagnosed with CLN2 disease. Based on the author's clinical experience, frequent muscular impairments associated with CLN2 disease, their impact on affected children's sensorimotor abilities and autonomy, and physiotherapy interventions are described. Common muscular deficits included abnormal muscle tone leading to poor trunk control, difficulty standing upright, often accompanied by equinus contractures and movement disorders such as myoclonus. The use of orthotic and adaptive medical devices that support an erect posture in locomotion and positioning appear to be particularly beneficial for prolonging sensorimotor control, communication and food intake. In conclusion, early initiation of physiotherapy is recommended and should include the provision of adaptive walking, standing, sitting and positioning aids.
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Abstract Neuronal ceroid lipofuscinosis type-2 (CLN2) disease is a rare, autosomalrecessive,pediatric-onset,neurodegenerative lysosomal storage disease caused by mutations in the TPP1 gene. Cerliponase alfa (Brineura®), a recombinant form of human tripeptidyl peptidase-1, was recently developed as a treatment for CLN2 disease. In clinical trials, the primary end point to evaluate treatment effect was the aggregate score for the motor and language (ML) domains of the CLN2 Clinical Rating Scale, an adaptation of the Hamburg scale's component items that include anchor point definitions to allow consistent ratings in multinational, multisite, clinical efficacy studies. Psychometric analyses demonstrated that the ML score of the CLN2 Clinical Rating Scale and individual item scores are well defined and possess adequate measurement properties (reliability, validity, and responsiveness) to demonstrate a clinical benefit over time. Additionally, analyses comparing the CLN2 Clinical Rating Scale ML ratings to the Hamburg scale's ML ratings demonstrated adequate similarity.
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Objective To observe the effect of electroacupuncture (EA) pretreatment of different durations on the expressions of AQP4 and CLN5 in the blood-brain barrier after cerebral ischemia and reperfusion Methods Sixty-four male Sprague-Dawley (SD) rats were randomly divided into a model group,a sham operation group,a 7-day EA-pretreatment group (EAP-7 group) and a 15-day EA-pretreatment group (EAP-15 group),each of 16.After EA-pretreatment on the baihui and shuigou acupoints for 7 days or 15 days,a model of unilateral middle cerebral artery embolism (MCAO) model was induced in the rats of the model,EAP-7 and EAP-15 group using a modified Longa method.In the sham operation group the carotid artery was separated without middle cerebral artery embolism.The reperfusion was begun 90 min after the MCAO modeling.Immunohistochemical methods and fluorescence quantitative PCR were applied to detect the expression of AQP4,CLN5 and their mRNAs expression in the blood brain barrier (BBB) 24h after the operation.Results Compared with the sham operation group,the expression of AQP4 positive cells and AQP4 mRNA in the BBB in the other three groups had increased significantly,while the expression of CLN5 positive cells and CLN5 mRNA was significantly less.Compared with the model group,the expression of AQP4 positive cells and AQP4 mRNA in the EAP-7 and EAP-15 groups was significantly reduced,while the expression of CLN5 positive cells and CLN5 mRNA was significantly increased.Moreover,the expression of AQP4 positive cells and AQP4 mRNA in the EAP-15 group were significantly higher than in the EAP-7 group,while the expression of CLN5 positive cells and CLN5 mRNA were significantly lower.Conclusions EA-pretreatment on the baihui and shuigou acupoints can restrain the expression of AQP4-positive cells and AQP4 mRNA and promote that of CLN5-positive cells and CLN5 mRNA in the BBB after cerebral ischemia and reperfusion,at least in rats.The BBB protection effect is better when the EA-pretreatment lasts longer.The mechanisms of cerebral ischemia tolerance may be related to the regulation of AQP4,CLN5 and their mRNAs in the blood-brain barrier after cerebral injury.
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Objective: Batten disease (BD), the juvenile form of neuronal ceroid lipofuscinosis (NCLs), is pathological characterized by finding lysosomal storage of autofluorescent lipofuscins with unique ultrastructural profiles. The gene underlying BD is designated CLN3 and encodes a protein, Battenin, of unknown function that localizes in lysosomes and/or mitochondria. Previously, we hypothesized that Battenin associates with other membrane protein(s) to form a membrane complex. Dysfunction of this complex could result in the pathological changes of BD, and possibly in other NCLs. Two such membranous proteins, the slow and fast Battenin-interactive proteins (BIPs and BIPf) of unknown functions, have been identified. In this study, we have characterized the functional domains of Battenin that interact with both BIP proteins. Methods: Protein-protein interactions with a yeast two-hybrid system were employed. A "deletion assay" was employed to localize the interactive segment(s). Different lengths of cDNA sequences lacking exon 1-5 were used to express CLN3-encoded proteins lacking N-terminal segments in the yeast two-hybrid system. N-terminal exons of CLN3 were deleted with PCR-cloning strategies.Results: We eliminated the possibility of interacting domains from the exon 7-encoded region because both Battenin and mBattenin interact with the BIP proteins. We have shown that peptide sequences encoded by exons 2 and 4 of CLN3 gene include the functional domains by which Battenin interacts with the BIP proteins. Conclusion: Our studies provide evidence that the N-terminus of Battenin is the functional domain for these protein interactions.
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Objective:Genotype-phenotype associations were studied in 517 subjects clinically affected by classical neuronal ceroid lipofuscinosis (NCL). Methods:Genetic loci CLN1-3 were analyzed in regard to age of onset, initial neurological symptoms, and electron microscope (EM) profiles. Results: The most common initial symptom leading to a clinical evaluation was developmental delay (30%) in NCL1, seizures (42.4%) in NCL2, and vision problems (53.5%) in NCL3. Eighty-two percent of NCL1 cases had granular osmiophilic deposits (GRODs) or mixed-GROD-containing EM profiles; 94% of NCL2 cases had curvilinear (CV) or mixed-CV-containing profiles; and 91% of NCL3 had fingerprint (FP) or mixed-FP-containing profiles. The mixed-type EM profile was found in approximately one-third of the NCL cases. DNA mutations within a specific CLN gene were further correlated with NCL phenotypes. Seizures were noticed to associate with common mutations 523G>A and 636C>T of CLN2 in NCL2 but not with common mutations 223G>A and 451C>T of CLN1 in NCL1. Vision loss was the initial symptom in all types of mutations in NCL3. Surprisingly, our data showed that the age of onset was atypical in 51.3% of NCL1 (infantile form) cases, 19.7% of NCL2 (late-infantile form) cases, and 42.8% of NCL3 (juvenile form) cases.Conclusion:Our data provide an overall picture regarding the clinical recognition of classical childhood NCLs. This may assist in the prediction and genetic identification of NCL1-3 via their characteristic clinical features.
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CLN3 gene product is an antiapoptotic membrane protein, the expressions of CLN3 in normal tissues and cells are at very low level. Juvenile-Batten disease is a neurodegenerative disease caused by accelerated apoptosis of photoreceptors and neurons resulting from deletion of 1.02 kb in the CLN3 gene. A number of observations showed that CLN3 mRNA and protein are overexpressed in a variety of human cancer cell lines. Blocking of CLN3 expression using an adenovirus-expressing antisense CLN3 inhibited growth and viability of cancer cells. CLN3 may regulate apoptosis through modulating ceramide synthesis or the expression of some down stream genes. More importantly, these results suggested that CLN3 is a novel molecular target for the etiology, progression and theraputics of cancer.
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AIM: To determine whether overexpression of CLN3 is involved in the tumorigenesis of ovarian cacinoma. METHODS: 10 specimens of ovarian carcinoma were screened for CLN3 gene expression level by semiquantitative RT-PCR and Western blotting. RESULTS: Overexpression of CLN3 mRNA and protein was found in all ovarian tumor tissues as compared with normal tissues. CONCLUSION: The overexpression of CLN3 may contribute to tumor development of ovarian cancer.