Non-autoimmune Diabetes Mellitus Research Articles

7316 A Unique Presentation of Diabetes Mellitus in an 8-Year-Old Male Positive For 3 Different Mutations Related to MODY

Abstract Disclosure: R. Senguttuvan: None. A. Pamfil: None. Background: Maturity-Onset Diabetes of the Young (MODY) is the most common form of inherited non-autoimmune diabetes mellitus, characterized by autosomal dominant inheritance, young age at onset and beta cell dysfunction. There are at least 14 MODY mutations and we present a pediatric case not meeting criteria for type 1[T1DM] or type 2 diabetes mellitus[T2DM], who tested positive for mutations in 3 different genes known to cause MODY. Case: An 8-year-old male, born full term, 2776 grams and 48.3 cm, without history of neonatal hypoglycemia or hyperglycemia, was referred for new onset diabetes mellitus management. While undergoing evaluation for abdominal pain and constipation, he was found to have a fasting glucose of 126 mg/dL (7 mmol/L) and hemoglobin A1C of 6.5%. He endorsed polyuria, but no polydipsia. He had no clinical signs of insulin resistance (e.g., acanthosis nigricans) and a BMI of 23.65 kg/m2, at the 97th percentile. Family history is positive for diabetes mellitus requiring insulin, in father (diagnosed at 11 years) and paternal grandmother and T2DM in paternal aunt. Laboratory evaluation was negative for all 5 antibodies (GAD, IA-2, Anti-islet cell antibody, Zinc Transporter 8 and Insulin antibodies) and revealed an insulin level of 15.9 uIU/mL (RR: <2.0-13.0) and C peptide: 2.3 ng/mL (RR: 1.1-4.4). Lacking diagnostic criteria for T1DM or T2DM, genetic testing was performed. Patient tested heterozygous for mutations in 3 genes known to cause MODY: GCK [(c.350 G>T p. (G117V)], ABCC8 [(c.2270 C>G p.(T757R)], and HNF1B [(c.68A>G p.(K23R)], all variant of uncertain significance. Over an 8-month period, patient's weight decreased from 98 lbs. (44.9 kg) to 90 lbs. (41.1 kg) after meeting with our dietician and implementing healthy dietary changes, and his beta cell function markers improved from diagnosis: Fasting insulin (4.5 uIU/mL), C peptide (1.3 ng/mL), and glucose 119 mg/dL; Hemoglobin A1C remained relatively stable at 6.1%. A kidney ultrasound was normal. No medical intervention were started yet, and patient is being monitored clinically and biochemically every 3-4 months. Discussion: Clinical monitoring over time, genetic testing in the parents, are critical in this patient’s long-term treatment plan and prognosis. To our knowledge, this may be the first case of diabetes mellitus in a pediatric patient, positive for mutations in 3 different genes known to cause MODY. South Texas has one of the highest incidences of T2DM in the USA. In addition to screening for genetic forms of diabetes, in patients with negative T1DM antibodies and atypical phenotype for T2DM, we should consider genetic screening in mildly obese pediatric and young adult patients without significant acanthosis nigricans, who were already diagnosed as T2DM. Presentation: 6/1/2024

Wolfram Syndrome 1: A Neuropsychiatric Perspective on a Rare Disease.

Wolfram syndrome 1 (WS1) is an uncommon autosomal recessive neurological disorder that is characterized by diabetes insipidus, early-onset non-autoimmune diabetes mellitus, optic atrophy, and deafness (DIDMOAD). Other clinical manifestations are neuropsychiatric symptoms, urinary tract alterations, and endocrinological disorders. The rapid clinical course of WS1 results in death by the age of 30. Severe brain atrophy leads to central respiratory failure, which is the main cause of death in WS1 patients. Mutations in the WFS1 gene, located on chromosome 4p16, account for approximately 90% of WS1 cases. The gene produces wolframin, a transmembrane glycoprotein widely distributed and highly expressed in retinal, neural, and muscular tissues. Wolframin plays a crucial role in the regulation of apoptosis, insulin signaling, and ER calcium homeostasis, as well as the ER stress response. WS1 has been designated as a neurodegenerative and neurodevelopmental disorder due to the numerous abnormalities in the ER stress-mediated system. WS1 is a devastating neurodegenerative disease that affects patients and their families. Early diagnosis and recognition of the initial clinical signs may slow the disease's progression and improve symptomatology. Moreover, genetic counseling should be provided to the patient's relatives to extend multidisciplinary care to their first-degree family members. Regrettably, there are currently no specific drugs for the therapy of this fatal disease. A better understanding of the etiology of WS1 will make possible the development of new therapeutic approaches that may enhance the life expectancy of patients. This review will examine the pathogenetic mechanisms, development, and progression of neuropsychiatric symptoms commonly associated with WS1. A thorough understanding of WS1's neurophysiopathology is critical for achieving the goal of improving patients' quality of life and life expectancy.

SAT079 A Novel Variant In The Carboxyl Ester Lipase (CEL) Gene Causing MODY

Abstract Disclosure: C.R. Medavarapu: None. M. McNutt: None. Introduction: Maturity-onset diabetes of the young (MODY) is a group of autosomal dominantly inherited disorders of non-autoimmune diabetes mellitus. Here, we report a patient initially diagnosed with type 2 DM and later found to have carboxyl ester lipase (CEL)-MODY. Case: A 51 year-old female was diagnosed with DM at the age of 44 and initially categorized as having type 2 DM based on normal GAD-65 antibodies. The patient’s DM was well controlled on semaglutide. The patient, however, reported chronic diarrhea/steatorrhea and intermittent dull abdominal pain which was not associated with semaglutide. The patient continued to have GI symptoms despite stopping the semaglutide. Abdominal imaging was unremarkable with a normal-appearing pancreas. Interestingly, the patient's daughter had similar gastric inflammatory symptoms and multiple members of the family have early-onset DM. Due to this symptom complex and similar presentation in the family, an inflammatory pathologic syndrome was suspected. A monogenetic auto-inflammatory syndrome was also considered in differential and the whole exome was analyzed. Genetic testing identified a novel, likely pathogenic heterozygous variant in CEL(NM_001807.5): c.1875del. Pathogenic variants in CEL are associated with MODY, type VIII. Discussion: Single-base deletions in the CEL gene can cause exocrine and endocrine pancreatic dysfunction. Our patient presented with a novel c.1875del variant in CEL that has not been reported in the literature as causative of disease nor as a variant in the general population. This variant lies in the variable number of tandem repeats (VNTR)-containing exon 11 of CEL. Two other single nucleotide deletions in this exon were described in the original report of CEL-MODY. The c.1875del variant results in the deletion of one nucleotide at position c.1875 of the CEL gene, causing a frameshift in the protein reading frame. Loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay is expected. The c.1875del CEL variant is classified as likely pathogenic, and it correlated with our patient's clinical and biochemical findings. Typically, patients with CEL-MODY develop pancreatic exocrine dysfunction in early childhood and later develop DM in their 40s. A genetic diagnosis helps in determining the choice of treatment, managing associated complications, and the need for further genetic counseling for the family. Insulin is the most appropriate treatment in CEL-MODY; however, other anti-DM drugs can also be used as seen in our patient. The risk of DM complications from CEL-MODY is unknown but patients can develop pancreatic cysts and clinicians should watch for these complications. Our case highlights the need for high suspicion for possible CEL-MODY and considering genetic testing in the setting of coexistent endocrine and exocrine pancreatic insufficiency. Presentation: Saturday, June 17, 2023

Contribution of ONECUT1 variants to different forms of non-autoimmune diabetes mellitus in Italian patients.

Contribution of ONECUT1 variants to different forms of non-autoimmune diabetes mellitus in Italian patients.

Clinical Peculiarities in a Cohort of Patients with Wolfram Syndrome 1.

Wolfram syndrome 1 is a rare, autosomal recessive, neurodegenerative, progressive disorder. Insulin-dependent, non-autoimmune diabetes mellitus and bilateral progressive optic atrophy are both sensitive and specific criteria for clinical diagnosis. The leading cause of death is central respiratory failure resulting from brainstem atrophy. We describe the clinical features of fourteen patients from seven different families followed in our Diabetes Center. The mean age at Wolfram syndrome 1 diagnosis was 12.4 years. Diabetes mellitus was the first clinical manifestation, in all patients. Sensorineural hearing impairment and central diabetes insipidus were present in 85.7% of patients. Other endocrine findings included hypogonadotropic hypogonadism (7.1%), hypergonadotropic hypogonadism (7.1%), and Hashimoto’s thyroiditis (21.4%). Neuropsychiatric disorders were detected in 35.7% of patients, and urogenital tract abnormalities were present in 21.4%. Finally, heart diseases were found in 14.2% of patients. Eight patients (57.1%) died at the mean age of 27.3 years. The most common cause of death was respiratory failure which occurred in six patients. The remaining two died due to end-stage renal failure and myocardial infarction. Our data are superimposable with those reported in the literature in terms of mean age of onset, the clinical course of the disease, and causes of death. The frequency of deafness and diabetes insipidus was higher in our patients. The incidence of urogenital diseases was lower although it led to the death of one patient. Long-term follow-up studies including large patient cohorts are necessary to establish potential genotype-phenotype correlation in order to personalize the most suitable clinical approach for each patient.

Urinary Tract Involvement in Wolfram Syndrome: A Narrative Review.

Wolfram Syndrome (WS) is a rare neurodegenerative disease with autosomal recessive inheritance and characterized by juvenile onset, non-autoimmune diabetes mellitus and later followed by optic atrophy leading to blindness, diabetes insipidus, hearing loss, and other neurological and endocrine dysfunctions. A wide spectrum of neurodegenerative abnormalities affecting the central nervous system has been described. Among these complications, neurogenic bladder and urodynamic abnormalities also deserve attention. Urinary tract dysfunctions (UTD) up to end stage renal disease are a life-threatening complication of WS patients. Notably, end stage renal disease is reported as one of the most common causes of death among WS patients. UTD have been also reported in affected adolescents. Involvement of the urinary tract occurs in about 90% of affected patients, at a median age of 20 years and with peaks at 13, 21 and 33 years. The aim of our narrative review was to provide an overview of the most important papers regarding urological impairment in Wolfram Syndrome. A comprehensive search on PubMed including Wolfram Syndrome and one or more of the following terms: chronic renal failure, bladder dysfunction, urological aspects, and urinary tract dysfunction, was done. The exclusion criteria were studies not written in English and not including urinary tract dysfunction deep evaluation and description. Studies mentioning general urologic abnormalities without deep description and/or follow-up were not considered. Due to the rarity of the condition, we considered not only papers including pediatric patients, but also papers with pediatric and adult case reports

Non-autoimmune diabetes mellitus and the risk of virus infections: a systematic review and meta-analysis of case-control and cohort studies

A significant number of studies invoked diabetes as a risk factor for virus infections, but the issue remains controversial. We aimed to examine whether non-autoimmune diabetes mellitus enhances the risk of virus infections compared with the risk in healthy individuals without non-autoimmune diabetes mellitus. In this systematic review and meta-analysis, we assessed case-control and cohort studies on the association between non-autoimmune diabetes and viruses. We searched PubMed, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Web of Science with no language restriction, to identify articles published until February 15, 2021. The main outcome assessment was the risk of virus infection in individuals with non-autoimmune diabetes. We used a random-effects model to pool individual studies and assessed heterogeneity (I2) using the χ2 test on Cochrane’s Q statistic. This study is registered with PROSPERO, number CRD42019134142. Out of 3136 articles identified, we included 68 articles (90 studies, as the number of virus and or diabetes phenotype varied between included articles). The summary OR between non-autoimmune diabetes and virus infections risk were, 10.8(95% CI: 10.3–11.4; 1-study) for SARS-CoV-2; 3.6(95%CI: 2.7–4.9, I2 = 91.7%; 43-studies) for HCV; 2.7(95% CI: 1.3–5.4, I2 = 89.9%, 8-studies;) for HHV8; 2.1(95% CI: 1.7–2.5; 1-study) for H1N1 virus; 1.6(95% CI: 1.2–2.13, I2 = 98.3%, 27-studies) for HBV; 1.5(95% CI: 1.1–2.0; 1-study) for HSV1; 3.5(95% CI: 0.6–18.3 , I2 = 83.9%, 5-studies) for CMV; 2.9(95% CI: 1–8.7, 1-study) for TTV; 2.6(95% CI: 0.7–9.1, 1-study) for Parvovirus B19; 0.7(95% CI: 0.3–1.5 , 1-study) for coxsackie B virus; and 0.2(95% CI: 0–6.2; 1-study) for HGV. Our findings suggest that, non-autoimmune diabetes is associated with increased susceptibility to viruses especially SARS-CoV-2, HCV, HHV8, H1N1 virus, HBV and HSV1. Thus, these viruses deserve more attention from diabetes health-care providers, researchers, policy makers, and stakeholders for improved detection, overall proper management, and efficient control of viruses in people with non-autoimmune diabetes.

Wolfram syndrome: clinical and genetic profiling of a cohort from a tertiary care centre with characterization of the primary gonadal failure.

Wolfram syndrome (WFS) is a rare, monogenic neurodegenerative syndrome characterised by insulin requiring non-autoimmune diabetes mellitus (DM) and optic atrophy which are usually the earliest and commonest manifestations. However, there are other features which are under-recognized, adding to morbidity and premature mortality in these patients. Five patients (three males, two females) with genetically confirmed WFS at a single tertiary care centre were prospectively followed up. Their symptomatology, clinical profile, genetic analysis and radiology were analyzed. Multidisciplinary approach was used for comprehensive clinical care of this cohort. Patients with primary gonadal failure were subjected to biopsy and immunohistochemistry (IHC) for wolframin was performed. DM was the earliest presenting manifestation at 6.2 ± 1.3 years followed by optic atrophy at 10.4 ± 2.3 years, diabetes insipidus at 12 ± 2.1 years and deafness at 12.8 ± 2.1 years. All patients were autoantibody negative with low C-peptide(<0.6 ng/ml). Hypoglycemic episodes were frequent (upto 60%) but there was no instance of diabetic ketoacidosis. Optic atrophy was present alongwith proliferative diabetic retinopathy and cataract in 40%. Uncommon manifestations included neuropsychiatric features, parasuicide, cystopathy, brainstem atrophy and hypergonadotropic hypogonadism only in adult males (n = 2). Testicular biopsy revealed partly hyalinised seminiferous tubules and prominence of Leydig cells. IHC confirmed the presence of mutated wolframin, which was not significantly different from normal testis specimen on protein quantification. WFS requires a multidisciplinary approach with special emphasis on early diagnosis and management of other endocrine and non-endocrine features so as to improve long-term outcomes. Gonadal functions need periodic assessment, especially in adult males.

Clinical and genetic analysis of two wolfram syndrome families with high occurrence of wolfram syndrome and diabetes type II: a case report

BackgroundMutations of the WFS1 gene are responsible for most cases of Wolfram syndrome (WS), a rare, recessively inherited neurodegenerative disorder characterized by juvenile-onset non-autoimmune diabetes mellitus and optic atrophy. Variants of WFS1 are also associated with non-syndromic hearing loss and type-2 diabetes mellitus (T2DM). Our study adds to literature significant associations between WS and T2DM.Case presentationIn this study, we analyzed the clinical and genetic data of two families with high prevalence of WS and T2DM. Genetic linkage analysis and DNA sequencing were exploited to identify pathogenic variants. One novel pathogenic variant (c.2243-2244insC) and one known pathogenic (c.1232_1233delCT) (frameshift) variant were identified in exon eight of WFS1 gene.ConclusionsThe mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. This study also confirms the role of WFS1 in T2DM.

An emerging, recognizable facial phenotype in association with mutations in GLI‐similar 3 (GLIS3)

Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. © 2016 Wiley Periodicals, Inc.

TRMA syndrome (thiamine-responsive megaloblastic anaemia): An example of rare monogenic diabetes: is thiamine a magic pill for anaemia and diabetes?

Thiamine-responsive megaloblastic anaemia (TRMA) is a rare syndrome presenting with early onset non-autoimmune diabetes mellitus, megaloblastic anaemia and sensorineural deafness. We report a 16-month-old male, a youngest case of genetically confirmed TRMA syndrome in Indian phenotype, born to consanguineous parents. We found a homozygous pathogenic variant in exon 2 of the SLC19A2 gene, c.314G>A (p.Gly105Glu). The anaemia showed a good response to daily thiamine doses and was able to avoid unwanted blood transfusion. There was no benefit with regard to insulin requirement. Early detection of hearing impairment and referral to audiological treatment was possible. The report indicates that TRMA should be considered as a differential diagnosis for patients presenting with suggestive clinical symptoms which would have tremendous impact on patient management if identified early.

Chromosome 6q24 methylation defects are uncommon in childhood-onset non-autoimmune diabetes mellitus patients born appropriate- or large-for-gestational age.

Methylation defects in the imprinting locus at chromosome 6q24 result in transient neonatal diabetes and small-for-gestational age (SGA) births (1). These phenotypes are primarily ascribed to the overexpression of PLAGL1, a paternally expressed gene on 6q24 that regulates cell cycle and apoptosis (2). Paternal uniparental disomy involving 6q24, as well as copy-number gains of paternal PLAGL1 alleles and epimutations in maternal alleles, have been identified as the causes of hypomethylation at the differentially methylated region (DMR) of PLAGL1 (3, 4). Recently, Yorifuji et al. reported the identification of 6q24 uniparental disomy in three patients with childhood-onset non-autoimmune diabetes mellitus (5). The three patients were identified through methylation-specific PCR analysis of the PLAGL1 DMR of 113 patients clinically suspected of having maturity-onset diabetes of the young (MODY). These results expanded the phenotypic consequences of 6q24 methylation defects to include MODY-like manifestations without a history of neonatal diabetes. However, the frequency of 6q24 methylation defects among patients with childhood-onset non-autoimmune diabetes remained unknown.

A vesicular protein important for puberty.

A vesicular protein important for puberty.

Novel Mutation in the SLC19A2 Gene in an Iranian Family with Thiamine-Responsive Megaloblastic Anemia: A Series of Three Cases

Thiamine-responsive megaloblastic anemia (TRMA) is a clinical triad characterized by megaloblastic anemia, non-autoimmune diabetes mellitus, and sensory-neural hearing loss. Mutations in the thiamine transporter gene, solute carrier family 19, member 2 (SLC19A2), have been associated with TRMA. Three pediatric patients from a large consanguineous Iranian family with hyperglycemia, anemia, and hearing loss were clinically diagnosed with TRMA. In all three patients, TRMA was confirmed by direct sequencing of the SLC19A2 gene that revealed a novel missense homozygous mutation c.382 G>A (p.E128K). This mutation results in the substitution of glutamic acid to lysine at position 128 in exon 2 and was not detected in 200 control chromosomes. Thiamine therapy reversed the anemia and alleviated the hyperglycemia in all three patients. We recommend sequence analysis of the SLC19A2 gene in individuals with a clinical triad of diabetes mellitus, hearing loss, and anemia. The administration of thiamine ameliorates the megaloblastic anemia and the hyperglycemia in patients with TRMA.Conflict of interest:None declared.

NOVEL MUTATION IN THE SLC19A2 GENE IN THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA (ROGERS’ SYNDROME)

Introduction: The Thiamine Transporter gene SLC19A2 is the only gene known to be associated with TRMA. This syndrome is a trial clinical characterized by megaloblastic anemia, nonautoimmune diabetes mellitus and sensory-neural hearing loss. Methods: Described here are three children from consanguineous Iranian families with thiamine – responsive megaloblastic anemia (TRMA) or Rogers' syndrome. Case one and two were siblings of healthy first-cousin parents and case three from a healthy second-cousin couple. These cases presented with hyperglycemia, anemia, and hearing loss. Thiamine reversed the anemia and there was a satisfactory response for the hyperglycemia as well. Results: In all three patients, direct sequencing revealed a homozygous mutation c.38 G>A (P.E.128K) resulting in the substitution of glutamic acid to lysine at position 128 in exon 2 of the SLC19A2 gene on chromosome 1q23.3. This novel mutation was confirmed by the PCR RFLP assay of more than 100 control alleles. Conclusion: TRMA or Rogers' syndrome should be considered for patients with diabetes (DM) and other symptoms, including hearing loss and anemia. Early diagnosis can assist families in planning future pregnancies. The administration of thiamine ameliorates the megaloblastic anemic condition and produces a better response in DM.

Endocrine manifestations related to inherited metabolic diseases in adults

Most inborn errors of metabolism (IEM) are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.). IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects), and metal (hemochromatosis) and storage disorders (cystinosis). Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes), whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction) and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure), congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last). This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses.

Presentation and clinical course of Wolfram (DIDMOAD) syndrome from North India

Wolfram syndrome, also known as DIDMOAD, is a relatively rare inherited neurodegenerative disorder, first evident in childhood as an association of juvenile-onset diabetes mellitus and optic atrophy, followed by diabetes insipidus and deafness. The aim of the study was to examine the clinical profile of patients with DIDMOAD syndrome presenting to a tertiary care hospital in north India. Clinical presentation of juvenile-onset diabetes mellitus fulfilling the diagnosis of Wolfram syndrome was studied using a prepared standardized form. Subjects with juvenile-onset non-autoimmune diabetes mellitus attending the diabetic clinic at a tertiary care centre in north India were followed for 10 years and a diagnosis of fully developed Wolfram syndrome was confirmed in seven individuals. The series consisted of five male and two female patients with a mean age of 17.5 ±7.34 years. Two subjects had consanguinity and none had any other family member affected. Optic atrophy was present in all, sensorineural hearing loss in 4/7, central diabetes insipidus in 4/7 and nephrogenic diabetes insipidus in 2/7 subjects. The new associations found were: spastic myoclonus, short stature with pancreatic malabsorption, nephrogenic diabetes insipidus, cyanotic heart disease and choledocholithiasis with cholangitis. Genetic analysis revealed mutation in exon 8 of the WFS1 gene in all the cases studied. The present clinical series of Wolfram syndrome reveals a varied clinical presentation of the syndrome and some new associations.

Male mice with deleted Wolframin (Wfs1) gene have reduced fertility

BackgroundWolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes.MethodsWfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt) male mice were mated with wt female mice. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analysed. Serum testosterone and FSH concentrations were also measured.ResultsThe pregnancy rate in wt females mated with Wfs1KO males was significantly lower than in the control group (15% vs. 32%; p < 0.05), but there was no significant difference in litter size. Analysis of male fertility showed that, in the Wfs1KO group, eight males out of 13 had pups whereas in the control group all 13 males had at least one litter. Sperm motility was not affected in Wfs1KO mice, but Wfs1KO males had less proximal bent tails (14.4 +/- 1.2% vs. 21.5 +/- 1.3 p < 0.05) and less abnormal sperm heads (22.8 +/- 1.8 vs. 31.5 +/- 3.5, p < 0.05) than wt males. Testes histology revealed significantly reduced number of spermatogonia (23.9 +/- 4.9 vs. 38.1 +/- 2.8; p < 0.05) and Sertoli cells (6.4 +/- 0.5 vs. 9.2 +/- 1.0; p < 0.05) in Wfs1KO mice. Serum testosterone and FSH concentrations did not differ between the two groups.ConclusionThe impaired fertility of Wfs1KO male mice is most likely due to changes in sperm morphology and reduced number of spermatogenic cells. The exact mechanism through which the Wfs1 gene influences sperm morphology needs to be clarified in further studies.

WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon

Most cases of juvenile-onset diabetes (JOD) are diagnosed as type 1 diabetes (T1D), for which genetic studies conducted in outbred Caucasian populations support the concept of multifactorial inheritance. However, this view may be partly challenged in particular population settings. In view of the suggestive evidence for a high prevalence of Wolfram syndrome (WFS) in Lebanon, the phenotypic variability associated with WFS1 mutations, and the high consanguinity rate in Lebanon, we aimed to evaluate the contribution of WFS1 mutations as monogenic determinants to JOD in Lebanon. We performed a family-based genetic study, with linkage analysis followed by systematic mutation screening of WFS1 exons in all JOD probands. The study population consisted of an unbiased recruitment of all juvenile-onset insulin-dependent diabetic patients from a specialized diabetes pediatric clinic in Beirut, Lebanon. Homozygous or compound heterozygous WFS1 mutations were found in 22 of the 399 JOD probands (5.5%), resulting in WFS (17 probands) or in non-syndromic non-autoimmune diabetes mellitus (DM, five probands). These accounted for 12.1% (21/174) of probands in consanguineous families, compared with 0.4% (1/225) in non-consanguineous families. Of the 38 patients identified with homozygous or compound heterozygous WFS1 mutations, 11 (29%) had non-syndromic DM, all of whom carried a particular WFS1 mutation, WFS1(LIB), encoding a protein with an extended C-terminal domain. This mutation resulted in a delayed onset or absence of extrapancreatic features. These results underscore the major impact of population-specific factors, such as population-specific mutations and founder effects, and family structure in the genetic determinism of JOD.

Thiamine-responsive megaloblastic anaemia: a cause of syndromic diabetes in childhood

Thiamine-responsive megaloblastic anaemia (TRMA) is a rare autosomal recessive condition, characterized by megaloblastic anaemia, non-autoimmune diabetes mellitus, and sensorineural hearing loss. We describe three infants with TRMA from two consanguineous Pakistani families, who were not known to be related but originated from the same area in Pakistan. All children were homozygous, and the parents were heterozygous for a c.196G>T mutation in the SLC19A2 gene on chromosome 1q23.3, which encodes a high-affinity thiamine transporter. The result is an abnormal thiamine transportation and vitamin deficiency in the cells. Thiamine in high doses (100-200 mg/d) reversed the anaemia in all our patients. Two patients discontinued insulin treatment successfully after a short period, while the third patient had to continue with insulin. The hearing loss persisted in all three children. The diagnosis of TRMA should be suspected in patients with syndromic diabetes including hearing loss and anaemia, even if the latter is only very mild and, particularly, in the case of consanguinity.