Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

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.

CLN6 Variant of Late Infantile Neuronal Ceroid Lipofuscinosis Caused by a Homozygous Mutation: Case Report in Colombia

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.

Late infantile neuronal ceroid lipofuscinosis caused by a CLN6 homozygous mutation:One case report and the literature review / 中国实用儿科杂志

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.