A rare cause of epileptic encephalopathy: case report of a novel patient with PEHO-like phenotype and CCDC88A gene pathogenic variants.

BACKGROUND: The Coiled-Coil Domain-Containing Protein 88 A (CCDC88A) gene encodes the actin-binding protein Girdin, which plays important roles in maintaining the actin cytoskeleton and in cell migration and was recently associated with a specific form of epileptic encephalopathy. Biallelic protein-truncating variants of CCDC88A have been considered responsible for progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome. To date, only three consanguineous families with loss-of-function homozygous variants in the CCDC88A gene have been reported. The described patients share many clinical features, such as microcephaly, neonatal hypotonia, seizures, profound developmental delay, face and limb edema, and dysmorphic features, with a similar appearance of the eyes, nose, mouth, and fingers. CASE PRESENTATION: We report on a child from a nonconsanguineous family who presented with profound global developmental delay, severe epilepsy, and brain malformations, including subcortical band heterotopia. The patient harbored two heterozygous pathogenic variants in the trans configuration in the CCDC88A gene, which affected the coiled-coil and C-terminal domains. CONCLUSIONS: We detail the clinical and cerebral imaging data of our patient in the context of previously reported patients with disease-causing variants in the CCDC88A gene, emphasizing the common phenotypes, including cortical malformations, that warrant screening for sequence variants in this gene.

Phenotypic variability related to dominant UCHL1 mutations: about three families with optic atrophy and ataxia.

INTRODUCTION: Ubiquitin C-terminal hydrolase L1 (UCHL1) has been associated with a severe, complex autosomal recessive spastic paraplegia (HSP79) [1] [2] [3] [4]. More recently, UCHL1 loss of function (LoF) variants have been associated to an autosomal dominant disease characterized by late-onset spastic ataxia, neuropathy, and frequent optic atrophy [5]. METHODS: Routine clinical care whole-genome (WGS) and exome (ES) sequencing. RESULTS: We present three families with autosomal dominant UCHL1-related disorder. The clinical phenotype mainly associated optic atrophy, mixed cerebellar and sensory ataxia, and possible hearing loss. We delineated two major phenotypes, even within the same family: (1) juvenile severe optic atrophy followed by a later-onset ataxia, or (2) late-onset ataxia with asymptomatic or mild optic atrophy. The families harboured three novel heterozygous variants in UCHL1: two loss of function (p.Lys115AsnfsTer40; c.171_174 + 7del11), and one missense (p.Asp176Asn) involving the catalytic site of the protein and potentially altering the adjacent splice site. DISCUSSION: We confirm the existence of dominantly inherited UCHL1 pathogenic variants. We describe a considerable intrafamilial phenotypic variability, with two main phenotypes. Optic atrophy was consistently present, but with varying degrees of severity. Neither delayed motor or intellectual development, nor dysmorphic features were part of the dominant phenotype in comparison with the autosomal recessive form. The molecular mechanism appears to be haploinsufficiency. UCHL1 monoallelic variants should therefore be considered in any case of early-onset optic atrophy or in late-onset complex ataxic syndrome with asymptomatic optic atrophy.

Wolfram Syndrome Type I Case Report and Review-Focus on Early Diagnosis and Genetic Variants.

Background and Objectives: Wolfram syndrome type 1 (OMIM# 222300; ORPHAcode 3463) is an extremely rare autosomal recessive syndrome with a 25% recurrence risk in children. It is characterized by the presence of juvenile-onset diabetes mellitus (DM), progressive optic atrophy (OA), diabetes insipidus (DI), and sensorineural deafness (D), often referred to by the acronym DIDMOAD. It is a severe neurodegenerative disease with a life expectancy of 39 years, with death occurring due to cerebral atrophy. For a positive diagnosis, the presence of diabetes mellitus and optic nerve atrophy is sufficient. The disease occurs because of pathogenic variants in the WFS1 gene. The aim of this article is to present a case report of Wolfram Syndrome Type I, alongside a review of genetic variants, clinical manifestations, diagnosis, therapy, and long-term management. Emphasizing the importance of early diagnosis and a multidisciplinary approach, the study aims to enhance understanding and improve outcomes for patients with this complex syndrome. Materials and Methods: A case of a 28-year-old patient diagnosed with DM at the age of 6 and with progressive optic atrophy at 26 years old is presented. Molecular diagnosis revealed the presence of a heterozygous nonsense variant WFS1 c.1943G>A (p.Trp648*), and a heterozygous missense variant WFS1 c.1675G>C (p.Ala559Pro). Results: The molecular diagnosis of the patient confirmed the presence of a heterozygous nonsense variant and a heterozygous missense variant in the WFS1 gene, correlating with the clinical presentation of Wolfram syndrome type 1. Both allelic variants found in our patient have been previously described in other patients, whilst this combination has not been described before. Conclusions: This case report and review underscores the critical role of early recognition and diagnosis in Wolfram syndrome, facilitated by genetic testing. By identifying pathogenic variants in the WFS1 gene, genetic testing not only confirms diagnosis but also guides clinical management and informs genetic counseling for affected families. Timely intervention based on genetic insights can potentially reduce the progressive multisystem manifestations of the syndrome, thereby improving the quality of life and outcomes for patients.

CNV Analysis through Exome Sequencing Reveals a Large Duplication Involved in Sex Reversal, Neurodevelopmental Delay, Epilepsy and Optic Atrophy.

BACKGROUND: Duplications on the short arm of chromosome X, including the gene NR0B1, have been associated with gonadal dysgenesis and with male to female sex reversal. Additional clinical manifestations can be observed in the affected patients, depending on the duplicated genomic region. Here we report one of the largest duplications on chromosome X, in a Lebanese patient, and we provide the first comprehensive review of duplications in this genomic region. CASE PRESENTATION: A 2-year-old female patient born to non-consanguineous Lebanese parents, with a family history of one miscarriage, is included in this study. The patient presents with sex reversal, dysmorphic features, optic atrophy, epilepsy, psychomotor and neurodevelopmental delay. Single nucleotide variants and copy number variants analysis were carried out on the patient through exome sequencing (ES). This showed an increased coverage of a genomic region of around 23.6 Mb on chromosome Xp22.31-p21.2 (g.7137718-30739112) in the patient, suggestive of a large duplication encompassing more than 60 genes, including the NR0B1 gene involved in sex reversal. A karyotype analysis confirmed sex reversal in the proband presenting with the duplication, and revealed a balanced translocation between the short arms of chromosomes X and 14:46, X, t(X;14) (p11;p11) in her/his mother. CONCLUSIONS: This case highlights the added value of CNV analysis from ES data in the genetic diagnosis of patients. It also underscores the challenges encountered in announcing unsolicited incidental findings to the family.

DDX58 variant triggers IFN-ß-induced autophagy in trabecular meshwork and influences intraocular pressure.

Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.

Childhood fever and hearing loss associated with CAPOS syndrome.

CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is a rare genetic disorder caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. CAPOS syndrome involves a characteristic episode in which neuropathy develops after a fever in childhood, and here, we describe the case of a patient with CAPOS syndrome. The patient had repeated episodes of a fever around 74 months of age. Although he could speak at 23 months of age, he presented with hearing difficulty after the fever. Pure-tone audiometry revealed moderate-to-severe bilateral sensorineural hearing loss, and auditory brainstem response (ABR) showed poor response in the both ears. Auditory stead-state response (ASSR) produced relatively consistent results compared to pure-tone audiometry. A mutation in the ATP1A3 gene was detected through genetic testing. In CAPOS syndrome, a genetic mutation leads to desynchronization during neural firing. We believe that this desynchronization in neural firing is responsible for the lack of response in the ABR and the presence of a response in the ASSR. In this patient, we attribute the response detection in ASSR to its greater tolerance for errors in the timing of neural firing compared to ABR.

Genetic underpinnings explored: OPA1 deletion and complex phenotypes on chromosome 3q29.

BACKGROUND: Copy number variations (CNVs) have emerged as significant contributors to the elusive genetic causality of inherited eye diseases. In this study, we describe a case with optic atrophy and a brain aneurysm, in which a de novo CNV 3q29 deletion was identified. CASE PRESENTATION: A 40-year-old female patient was referred to our department after undergoing aneurysm transcatheter arterial embolization for a brain aneurysm. She had no history of systemic diseases, except for unsatisfactory best-corrected visual acuity (BCVA) since elementary school. Electrophysiological tests confirmed the findings in retinal images, indicating optic nerve atrophy. Chromosomal microarray analysis revealed a de novo deletion spanning 960 kb on chromosome 3q29, encompassing OPA1 and six neighboring genes. Unlike previously reported deletions in this region associated with optic atrophy, neuropsychiatric disorders, and obesity, this patient displayed a unique combination of optic atrophy and a brain aneurysm. However, there is no causal relationship between the brain aneurysm and the CNV. CONCLUSION: In conclusion, the optic atrophy is conclusively attributed to the OPA1 deletion, and the aneurysm could be a coincidental association. The report emphasizes the likelihood of underestimating OPA1 deletions due to sequencing technology limitations. Recognizing these constraints, healthcare professionals must acknowledge these limitations and consistently search for OPA1 variants/deletions in Autosomal Dominant Optic Atrophy (ADOA) patients with negative sequencing results. This strategic approach ensures a more comprehensive exploration of copy-number variations, ultimately enhancing diagnostic precision in the field of genetic disorders.

A Wolfram-like syndrome family: Case report.

BACKGROUND: Wolfram-like syndrome (WFLS) is an autosomal dominant inherited disease characterized by a single heterozygous pathogenic variant in the WFS1 gene. Its clinical presentation is similar to autosomal recessive Wolfram syndrome. CASE PRESENTATION: We reported a case of a 10-year-old boy and his family members who initially experienced hearing impairment (HI), followed by optic atrophy. Genetic testing revealed the presence of a WFS1 variant (chr4-6302385 exon8 NM_006005.3: c.2590G > A, p. Glu864Lys). CONCLUSION: Wolfram-like syndrome, a rare neurodegenerative genetic disorder, manifested as deafness, optic atrophy, and diabetes mellitus. There hasn't been a definite treatment yet. Early identification of the variant in the WFS1 gene is beneficial for genetic counseling.

Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy.

The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux.

Comprehensive overview of disease models for Wolfram syndrome: toward effective treatments.

Wolfram syndrome (OMIM 222300) is a rare autosomal recessive disease with a devastating array of symptoms, including diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss, and neurological dysfunction. The discovery of the causative gene, WFS1, has propelled research on this disease. However, a comprehensive understanding of the function of WFS1 remains unknown, making the development of effective treatment a pressing challenge. To bridge these knowledge gaps, disease models for Wolfram syndrome are indispensable, and understanding the characteristics of each model is critical. This review will provide a summary of the current knowledge regarding WFS1 function and offer a comprehensive overview of established disease models for Wolfram syndrome, covering animal models such as mice, rats, flies, and zebrafish, along with induced pluripotent stem cell (iPSC)-derived human cellular models. These models replicate key aspects of Wolfram syndrome, contributing to a deeper understanding of its pathogenesis and providing a platform for discovering potential therapeutic approaches.

[Clinical features of CAPOS syndrome caused by maternal ATP1A3 gene variation: a case report].

CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A（Glu818Lys） heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.

[Wolfram-like syndrome: a case report].

Different from classical autosomal recessive Wolfram syndrome, Wolfram-like syndrome is an autosomal dominant disorder caused by a heterozygous mutation in the WFS1 gene. In this case, a 7-year-old male child presented to the eye clinic due to vision loss that could not be corrected, discovered during a routine examination. The child had experienced hearing impairment since early childhood, leading to cochlear implantation. Ophthalmic examination revealed optic disc atrophy in both eyes. Optical coherence tomography imaging demonstrated a distinctive thickening of the outer plexiform layer with abnormal layering, characteristic of a single mutation in the WFS1 gene. Subsequent genetic testing identified a de novo heterozygous missense mutation c.2051C>T (p.A684V) in the WFS1 gene, which ultimately led to the diagnosis of Wolfram-like syndrome.

Recurrent MECR R258W causes adult-onset optic atrophy: A case report.

MECR-related neurologic disorder, also known as mitochondrial enoyl CoA reductase protein-associated neurodegeneration (MEPAN) or dystonia with optic atrophy and basal ganglia abnormalities in childhood (MIM: #617282), is an autosomal recessive inherited disease characterized by a progressive childhood-onset movement disorder and optic atrophy. Here we report a 19-year-old male, presented with progressive visual failure, nystagmus, and right orbital pain, with no history of movement or eye disorder in his childhood. His visual decline started at age 18 years, whereas nystagmus emerged seven months later. Analysis of whole-exome sequencing (WES) revealed a homozygous recurrent variant (NM_016011.5:c.772C > T, p.Arg258Trp) in MECR. These findings suggest phenotypic heterogeneity in MECR-related neurologic disorder, thus, more relevant case screening, will help to delineate the genotype-phenotype correlation of the MECR gene.

A Homozygous NDUFS6 Variant Associated with Neuropathy and Optic Atrophy.

Background: The NADH dehydrogenase [ubiquinone] iron-sulfur protein 6 (NDUFS6) gene encodes for an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Bi-allelic NDUFS6 variants have been linked with a severe disorder mostly reported as a lethal infantile mitochondrial disease (LMID) or Leigh syndrome (LS). Objective: Here, we identified a homozygous variant (c.309 + 5 G > A) in NDUFS6 in one male patient with axonal neuropathy accompanied by loss of small fibers in skin biopsy and further complicated by optic atrophy and borderline intellectual disability. Methods: To address the pathogenicity of the variant, biochemical studies (mtDNA copy number quantification, ELISA, Proteomic profiling) of patient-derived leukocytes were performed. Results: The analyses revealed loss of NDUFS6 protein associated with a decrease of three further mitochondrial NADH dehydrogenase subunit/assembly proteins (NDUFA12, NDUFS4 and NDUFV1). Mitochondrial copy number is not altered in leukocytes and the mitochondrial biomarker GDF15 is not significantly changed in serum. Conclusions: Hence, our combined clinical and biochemical data strengthen the concept of NDUFS6 being causative for a very rare form of axonal neuropathy associated with optic atrophy and borderline intellectual disability, and thus expand (i) the molecular genetic landscape of neuropathies and (ii) the clinical spectrum of NDUFS6-associated phenotypes.

Infantile epileptic spasm syndrome as a new NR2F1 gene phenotype.

INTRODUCTION: NR2F1 pathogenetic variants are associated with the Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Recent studies indicate that BBSOAS patients not only have visual impairments but may also have developmental delays, hypotonia, thin corpus callosum and epileptic seizures. However, reports of BBSOAS occurrence along with infantile epileptic spasm syndrome (IESS) are rare. METHODS: Here, we report three cases involving children with IESS and BBSOAS caused by de novo NR2F1 pathogenetic variants and summarize the genotype, clinical characteristics, diagnosis and treatment of them. RESULTS: All three children experienced epileptic spasms and global developmental delays, with brain Magnetic Resonance Imaging (MRI) suggesting abnormalities (thinning of the corpus callosum or widened extracerebral spaces) and two of the children exhibiting abnormal visual evoked potentials. CONCLUSIONS: Our findings indicate that new missense NR2F1 pathogenetic variants may lead to IESS with abnormal visual evoked potentials. Thus, clinicians should be aware of the Bosch-Boonstra-Schaaf optic atrophy syndrome and regular monitoring of the fundus, and the optic nerve is necessary during follow-up.

Refining the phenotypic spectrum of CCDC88A-related PEHO-like syndrome.

Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and PEHO-like syndromes are very rare infantile disorders characterized by profound intellectual disability, hypotonia, convulsions, optic, and progressive brain atrophy. Many causative genes for PEHO and PEHO-like syndromes have been identified including CCDC88A. So far, only five patients from two unrelated families with biallelic CCDC88A variants have been reported in the literature. Herein, we describe a new family from Egypt with a lethal epileptic encephalopathy. Our patient was the youngest child born to a highly consanguineous couple and had a family history of five deceased sibs with the same condition. She presented with postnatal microcephaly, poor visual responsiveness, and epilepsy. Her brain MRI showed abnormal cortical gyration with failure of opercularization of the insula, hypogenesis of corpus callosum, colpocephaly, reduced white matter, hypoplastic vermis, and brain stem. Whole exome sequencing identified a new homozygous frameshift variant in CCDC88A gene (c.1795_1798delACAA, p.Thr599ValfsTer4). Our study presents the third reported family with this extremely rare disorder. We also reviewed all described cases to better refine the phenotypic spectrum associated with biallelic loss of function variants in the CCDC88A gene.

Wolfram syndrome type 1: a case series.

BACKGROUND: Wolfram syndrome (WS) is a rare autosomal recessive multisystem neurodegenerative disease characterized by non-autoimmune insulin-dependent diabetes mellitus, optic atrophy, sensorineural deafness, and diabetes as the main features. Owing to clinical phenotypic heterogeneity, the misdiagnosis rate is high. However, early accurate diagnosis and comprehensive management are key to improving quality of life and prolonging life. RESULTS: Eleven patients from seven WS pedigrees with 10 mutation sites (c.1314_1317delCTTT, c.C529T, c.C529A, c.G2105A, c.C1885T, c.1859_1860del, c.G2020A, c.C529A, c.G2105A, and c.G1393C) in the WFS1 gene were included. We conducted further expert department analysis to clarify the diagnosis and analyze the correlation between genes and phenotypes. CONCLUSIONS: The genotypes of these patients were closely associated with their phenotypes. The clinical data of the patients were analyzed to provide a basis for the diagnosis and clinical management of the disease.

Variants in the WDR45 Gene Within the OPA-2 Locus Associate With Isolated X-Linked Optic Atrophy.

Purpose: To describe clinical and molecular findings of two families with X-linked optic atrophy and present two new pathogenic variants in the WDR45 gene. Methods: Case series and molecular analysis of two families of Jewish Ashkenazi descent with early onset bilateral optic atrophy. Whole-exome sequencing (WES) and bioinformatic analysis were performed, followed by Sanger sequencing and segregation analysis. Results: In both families, male siblings (three in family 1, two in family 2) had early-onset isolated bilateral optic atrophy. The sibling's healthy mother (and in the second family also one healthy sister) had a mild presentation, suggesting a carrier state and an X-linked inheritance pattern. All participants were otherwise healthy, apart from mild learning disabilities and autism spectrum disorder in two siblings of the second family. Variants in known optic atrophy genes were excluded. Analysis revealed a point variant in the WDR45 gene-a missense variant in the first family, NM_001029896.2:c.107C>A; NP_001025067.1:p.Pro36His (variant ID: 1704205), and a splice site variant in the second family, NM_001029896.2:c.236-1G>T; NP_009006.2:p.Val80Leu (variant ID: 1704204), located on Xp11.23 (OPA2 locus). Both variants are novel and predicted as pathogenic. In both families, the variant was seen with full segregation with the disease, occurring in all affected male participants and in one allele of the carrier females, as well as none of the healthy participants. Conclusions: Among two families with isolated X-linked optic atrophy, molecular analysis revealed novel variants in the WDR45 gene in full segregation with the disease. This gene resides within the OPA2 locus, previously described to associate with X-linked optic atrophy. Taken together, these findings suggest that certain pathogenic variants in the WDR45 gene are associated with isolated X-linked optic atrophy.

Next generation sequencing identifies a pathogenic mutation of WFS1 gene in a Moroccan family with Wolfram syndrome: a case report.

BACKGROUND: Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by juvenile onset diabetes, optic nerve atrophy and other systemic manifestations. Symptoms of the disease arise mostly in early childhood with a high mortality rate due to severe neurological complications. Two causative genes have been identifed in this syndrome; the classical form is caused by autosomal recessive mutations of the WFS1 gene, and a smaller portion of patients has mutations in the CIDS2 gene, which are responsible for autosomal recessive Wolfram syndrome 2. CASE PRESENTATION: We report the case of a 28-year-old Moroccan boy born from consanguineous parents referred to the department of medical genetics at the National Institute of Health in Rabat. The diagnosis of Wolfram syndrome was made based on insulin-dependent diabetes, optic nerve atrophy, sensorineural deafness, urological abnormalities and psychiatric illness. To establish the diagnosis at a molecular level, we performed next-generation sequencing in the index patient, which revealed compound heterozygous WFS1 mutations: c.1113G > A (p.Trp371Ter) and c.1223_1224insGGAACCACCTGGAGCCCTATGCCCATTT (p.Phe408fs). This second variant has never been described in patients with Wolfram syndrome. CONCLUSION: The identification of the genetic substrate in our patient confirmed the clinical diagnosis of Wolfram syndrome and allowed us to provide him an appropriate management and genetic counseling to his family.

Genomics of Wolfram Syndrome 1 (WFS1).

Wolfram Syndrome (WFS) is a rare, autosomal, recessive neurogenetic disorder that affects many organ systems. It is characterised by diabetes insipidus, diabetes mellites, optic atrophy, and deafness and, therefore, is also known as DIDMOAD. Nearly 15,000-30,000 people are affected by WFS worldwide, and, on average, patients suffering from WFS die at 30 years of age, usually from central respiratory failure caused by massive brain atrophy. The more prevalent of the two kinds of WFS is WFS1, which is a monogenic disease and caused by the loss of the WFS1 gene, whereas WFS2, which is more uncommon, is caused by mutations in the CISD2 gene. Currently, there is no treatment for WFS1 to increase the life expectancy of patients, and the treatments available do not significantly improve their quality of life. Understanding the genetics and the molecular mechanisms of WFS1 is essential to finding a cure. The inability of conventional medications to treat WFS1 points to the need for innovative strategies that must address the fundamental cause: the deletion of the WFS1 gene that leads to the profound ER stress and disturbances in proteostasis. An important approach here is to understand the mechanism of the cell degeneration after the deletion of the WFS1 gene and to describe the differences in these mechanisms for the different tissues. The studies so far have indicated that remarkable clinical heterogeneity is caused by the variable vulnerability caused by WFS1 mutations, and these differences cannot be attributed solely to the positions of mutations in the WFS1 gene. The present review gives a broader overview of the results from genomic studies on the WFS1 mouse model.