Pancreatic agenesis and altered m6A methylation in the pancreas of PDX1-mutant cynomolgus macaques.

As an essential transcriptional activator, PDX1 plays a crucial role in pancreatic development and ß-cell function. Mutations in the PDX1 gene may lead to type 4 maturity-onset diabetes of the young (MODY4) and neonatal diabetes mellitus. However, the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models. In this study, three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology, all of which succumbed shortly postpartum, exhibiting pancreatic agenesis. Notably, one tri-allelic PDX1-mutant cynomolgus macaque (designated as M4) developed a pancreas, whereas the two mono-allelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation. RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions, indicating developmental delay and PDX1 haploinsufficiency. A marked change in m6A methylation was identified in the M4 pancreas, confirmed through cultured PDX1-mutant islet organoids. Notably, overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids. This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.

Causal effects of smoking, alcohol consumption, and coffee intake on hepatobiliary and pancreatic diseases: A Mendelian randomization study.

BACKGROUND: Hepatobiliary and pancreatic diseases, such as cirrhosis, hepatocellular carcinoma, cholelithiasis, and pancreatitis, are major global health challenges. Lifestyle factors like smoking, alcohol consumption, and coffee intake are commonly studied for their health impacts. However, observational studies often face issues with confounding factors and reverse causality, making it difficult to establish causal relationships. METHODS: This research uses Mendelian randomization (MR) to investigate the causal effects of smoking, alcohol use, and coffee intake on 10 hepatobiliary and pancreatic diseases. Genetic data from the Sequencing Consortium of Alcohol and Nicotine Use (GSCAN) and self-reported GWAS were used to derive instrumental variables (IVs). The outcomes were obtained from the FinnGen and UK Biobank cohorts. Univariable and multivariable MR analyses were conducted to assess the associations. RESULTS: Genetic predisposition to tobacco use was associated with increased risks of acute pancreatitis, alcoholic hepatitis, chronic pancreatitis, cirrhosis, gallstones, liver cancer, and pancreatic cancer. Alcohol consumption was linked to acute pancreatitis, chronic pancreatitis, alcoholic liver disease, hepatic cancer, and cholangitis. Coffee intake showed minimal associations, with a slight protective effect against non-alcoholic steatohepatitis. CONCLUSIONS: This study confirms the harmful effects of inhaling tobacco and consuming alcohol on hepatobiliary and pancreatic diseases. It highlights the need for public health strategies to reduce tobacco use and heavy alcohol consumption. Coffee intake showed minimal effects, suggesting further research is needed to understand its relationship with hepatobiliary health.

Stellate cells are in utero markers of pancreatic disease in cystic fibrosis.

BACKGROUND: Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use a sheep model of CF (CFTR-/-) to examine the evolution of pancreatic disease through gestation. METHODS: Fetal pancreas was collected at six time points from 50-days of gestation through to term, which is equivalent to ~ 13 weeks to term in human. RNA was extracted from tissue for bulk RNA-seq and single cells were prepared from 80-day, 120-day and term samples for scRNA-seq. Data were validated by immunochemistry. RESULTS: Transcriptomic evidence from bulk RNA-seq showed alterations in the CFTR-/- pancreas by 65-days of gestation, which are accompanied by marked pathological changes by 80-days of gestation. These include a fibrotic response, confirmed by immunostaining for COL1A1, αSMA and SPARC, together with acinar loss. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CFTR-/- animals at 80- and 120-days gestation, as are stellate cells at term. CONCLUSION: The transcriptomic changes and cellular imbalance that we observe likely have pivotal roles in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent pancreatic destruction in CF.

The neurological core features of the infantile-onset multisystem neurologic, endocrine, and pancreatic disease: A novel nonsense mutation in an Italian family.

AIM: Biallelic mutations in the PTRH2 gene have been associated with infantile multisystem neurological, endocrine, and pancreatic disease (IMNEPD), a rare autosomal recessive disorder of variable expressivity characterized by global developmental delay, intellectual disability or borderline IQ level, sensorineural hearing loss, ataxia, and pancreatic insufficiency. Various additional features may be included, such as peripheral neuropathy, facial dysmorphism, hypothyroidism, hepatic fibrosis, postnatal microcephaly, cerebellar atrophy, and epilepsy. Here, we report the first Italian family presenting only predominant neurological features. METHODS: Extensive neurological and neurophysiological evaluations have been conducted on the two affected brothers and their healthy mother since 1996. The diagnosis of peripheral neuropathy of probable hereditary origin was confirmed through a sural nerve biopsy. Exome sequencing was performed after the analysis of major neuropathy-associated genes yielded negative results. RESULTS: Whole-exome sequencing analysis identified the homozygous substitution c.256C>T (p.Gln86Ter) in the PTRH2 gene in the two siblings. According to American College of Medical Genetics and Genomics (ACMG) guidelines, the variant has been classified as pathogenic. At 48 years old, the proband's reevaluation confirmed a demyelinating sensorimotor polyneuropathy with bilateral sensorineural hearing loss that had been noted since he was 13. Additionally, drug-resistant epileptic seizures occurred when he was 32 years old. No hepatic or endocrinological signs developed. The younger affected brother, 47 years old, has an overlapping clinical presentation without epilepsy. INTERPRETATION: Our findings expand the clinical phenotype and further demonstrate the clinical heterogeneity related to PTRH2 variants. We thereby hope to better define IMNEPD and facilitate the identification and diagnosis of this novel disease entity.

Relationship of TNFα-238 G/A (rs 361525) genotypes with TNFα gene expression in liver and pancreas disorders in sample of beta thalassemia major adult Iraqi patients.

BACKGROUND: Tumor necrosis factor-α (TNFα) is a crucial physiologic regulator of immune responses, and several disorders have been associated with its dysregulation. OBJECTIVE: This study aimed to understand TNFα gene expression in adult patients with liver and pancreas disorders and examine the impact of TNFα-238 genotypes on this population. METHODS: At the Ibn Al-Baladi Hospital in Baghdad, blood samples were collected from forty patients who were diagnosed with beta thalassemia together with pancreatic disease, forty patients who were diagnosed with thalassemia together with liver disorder, and forty patients who were diagnosed with thalassemia without pancreas or liver disorder. For the purpose of establishing a control group, forty samples were collected from persons who were of the same age and gender and seemed to be in good health. All of these individuals were deemed to be older than 18 years old. Through the utilization of real-time polymerase chain reaction (PCR), the level of TNF-α gene expression was investigated and assessed. The T-ARMS-PCR method was performed for detection and genotyping of TNFα-238 in thalassemia patients and healthy control samples. RESULTS: The result showed that TNF α gene expression assessment showed that group B (thalassemia patients with liver disorder) had higher folding than other groups while the lowest gene expression was in group D (as control group). Furthermore, the relationship between TNFα gene expressions folding with TNFα-238 genotypes in beta thalassemia major patients, discovered a considerable increase at GA genotype patients in TNFα gene expression level, followed by AA genotype compared to the GG genotype. Furthermore, the results of the current study showed an association between the presence of the mutant (A) allele whether heterozygous (GA) and homozygous (AA) with the TNF-α gene expression in thalassemia patients with liver and pancreatic disorders. CONCLUSION: Based on the results, it can be concluded that there is a relationship between the presence of the mutant (A) allele, whether heterozygous (GA) or homozygous (AA) of TNF-α 238, and TNF-α gene expression in liver and pancreatic diseases as well as in patients with thalassemia.

Liver Transplantation in a Woman with Mahvash Disease.

Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.

Overexpression of Pdx1, reduction of p53, or deletion of CHOP attenuates pancreas hypoplasia in mice with pancreas-specific O-GlcNAc transferase deletion.

Deletion of O-GlcNAc transferase (Ogt) in pancreatic epithelial progenitor cells results in pancreatic hypoplasia at birth, partly due to increased apoptosis during embryonic development. Constitutive loss of Ogt in ß-cells results in increased ER stress and apoptosis, and in the Ogt-deficient pancreas, transcriptomic data previously revealed both tumor suppressor protein p53 and pancreatic duodenal homeobox 1 (Pdx1), key cell survival proteins in the developing pancreas, as upstream regulators of differentially expressed genes. However, the specific roles of these genes in pancreatic hypoplasia are unclear. In this study, we explored the independent roles of p53, ER stress protein CHOP, and Pdx1 in pancreas development and their use in the functional rescue of pancreatic hypoplasia in the context of Ogt loss. Using in vivo genetic manipulation and morphometric analysis, we show that Ogt plays a key regulatory role in pancreas development. Heterozygous, but not homozygous, loss of pancreatic p53 afforded a partial rescue of ß-cell, α-cell, and exocrine cell masses, while whole body loss of CHOP afforded a partial rescue in pancreas weight and a full rescue in exocrine cell mass. However, neither was sufficient to fully mitigate pancreatic hypoplasia at birth in the Ogt-deficient pancreas. Furthermore, overexpression of Pdx1 in the pancreatic epithelium resulted in partial rescues in pancreas weight and ß-cell mass in the Ogt loss background. These findings highlight the requirement of Ogt in pancreas development by targeting multiple proteins such as transcription factor Pdx1 and p53 in the developing pancreas.

PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.

Hom ozygous variants in the peptidyl-tRNA hydrolase 2 gene (PTRH2) cause infantile-onset multisystem neurologic, endocrine, and pancreatic disease. The objective is to delineate the mechanisms underlying the core cerebellar phenotype in this disease. For this, we generated constitutive (Ptrh2LoxPxhCMVCre, Ptrh2-/- mice) and Purkinje cell (PC) specific (Ptrh2LoxPxPcp2Cre, Ptrh2ΔPCmice) Ptrh2 mutant mouse models and investigated the effect of the loss of Ptrh2 on cerebellar development. We show that Ptrh2-/- knockout mice had severe postnatal runting and lethality by postnatal day 14. Ptrh2ΔPC PC specific knockout mice survived until adult age; however, they showed progressive cerebellar atrophy and functional cerebellar deficits with abnormal gait and ataxia. PCs of Ptrh2ΔPC mice had reduced cell size and density, stunted dendrites, and lower levels of ribosomal protein S6, a readout of the mammalian target of rapamycin pathway. By adulthood, there was a marked loss of PCs. Thus, we identify a cell autonomous requirement for PTRH2 in PC maturation and survival. Loss of PTRH2 in PCs leads to downregulation of the mTOR pathway and PC atrophy. This suggests a molecular mechanism underlying the ataxia and cerebellar atrophy seen in patients with PTRH2 mutations leading to infantile-onset multisystem neurologic, endocrine, and pancreatic disease.

Hyperinsulinemic Hypoglycemia Diagnosed in Childhood Can Be Monogenic.

CONTEXT: Congenital hyperinsulinism (HI) is characterized by inappropriate insulin secretion despite low blood glucose. Persistent HI is often monogenic, with the majority of cases diagnosed in infancy. Less is known about the contribution of monogenic forms of disease in those presenting in childhood. OBJECTIVE: We investigated the likelihood of finding a genetic cause in childhood-onset HI and explored potential factors leading to later age at presentation of disease. METHODS: We screened known disease-causing genes in 1848 individuals with HI, referred for genetic testing as part of routine clinical care. Individuals were classified as infancy-onset (diagnosed with HI < 12 months of age) or childhood-onset (diagnosed at age 1-16 years). We assessed clinical characteristics and the genotypes of individuals with monogenic HI diagnosed in childhood to gain insights into the later age at diagnosis of HI in these children. RESULTS: We identified the monogenic cause in 24% (n = 42/173) of the childhood-onset HI cohort; this was significantly lower than the proportion of genetic diagnoses in infancy-onset cases (74.5% [n = 1248/1675], P < 0.00001). Most (75%) individuals with genetically confirmed childhood-onset HI were diagnosed before 2.7 years, suggesting these cases represent the tail end of the normal distribution in age at diagnosis. This is supported by the finding that 81% of the variants identified in the childhood-onset cohort were detected in those diagnosed in infancy. CONCLUSION: We have shown that monogenic HI is an important cause of hyperinsulinism presenting outside of infancy. Genetic testing should be considered in children with persistent hyperinsulinism, regardless of age at diagnosis.

[Analysis of a child with Johanson-Blizzard syndrome due to novel compound heterozygous variants of UBR1 gene].

OBJECTIVE: To analyze the clinical and genetic characteristics of a boy featuring unexplained developmental delay, malnutrition and distinct facial appearance. METHODS: Physical examination was carried out for the child. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA and trio-whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The patient had facial dysmorphism including nasal alae aplasia, scalp defect and teeth deformities, in addition with recurrent diarrhea due to pancreatic exocrine insufficiency. DNA sequencing revealed that he has harbored compound heterozygous variants of the UBR1 gene, namely c.3167C>G (p.S1056X) and c.1911+14C>G, which were inherited from his father and mother, respectively. Database search has suggested the c.3167C>G to be a novel nonsense variant and c.1911+14C>G a known splicing variant. Based on the guidelines of the American College of Medical Genetics and Genomics, the two variants were predicted to be pathogenic and likely pathogenic, respectively. CONCLUSION: The child was diagnosed with Johanson-Blizzard syndrome due to the compound heterozygous variants of the UBR1 gene. Above finding has enriched the mutational spectrum of the UBR1 gene and provided a basis for genetic counseling for this family.

[Clinical phenotypes and genotypic spectrum of cystic fibrosis with pancreatic insufficiency in children].

Objective: To investigate the clinical phenotypes and genotypic spectrum of exocrine pancreatic insufficiency in children with cystic fibrosis. Methods: This was a retrospective analysis of 12 children with cystic fibrosis who presented to Children's Hospital of Fudan University from December 2017 to December 2021. Clinical features, fecal elastase-1 level, genotype, diagnosis and treatment were systematically reviewed. Results: A total of 12 children, 7 males and 5 females, diagnosis aged 5.4 (2.0, 10.6) years, were recruited. Common clinical features included chronic cough in 12 cases, malnutrition in 7 cases, steatorrhea in 7 cases, bronchiectasis in 5 cases and electrolyte disturbance in 4 cases. Exocrine pancreatic insufficiency were diagnosed in 8 cases,the main clinical manifestations were steatorrhea in 7 cases, of which 5 cases started in infancy; 6 cases were complicated with malnutrition, including mild in 1 case, moderate in 2 cases and severe in 3 cases; 3 cases had abdominal distension; 2 cases had intermittent abdominal pain; 4 cases showed fatty infiltration or atrophy of pancreas and 3 cases showed no obvious abnormality by pancreatic magnetic resonance imaging or B-ultrasound. All 8 children were given pancreatic enzyme replacement therapy, follow-up visit of 2.3 (1.2,3.2) years. Diarrhea significantly improved in 6 cases, and 1 case was added omeprazole due to poor efficacy. A total of 20 variations of CFTR were detected in this study, of which 7 were novel (c.1373G>A,c.1810A>C,c.270delA,c.2475_2478dupCGAA,c.2489_c.2490insA, c.884delT and exon 1 deletion). Conclusions: There is a high proportion of exocrine pancreatic insufficiency in Chinese patients with cystic fibrosis. The main clinical manifestations are steatorrhea and malnutrition. Steatorrhea has often started from infancy. Pancreatic enzyme replacement therapy can significantly improve the symptoms of diarrhea and malnutrition.

A unique pancreatic phenotype in a child with a WDR19-related ciliopathy: A case report and literature review of pancreatic involvement in ciliopathies.

Ciliopathies are a group of genetic disorders caused by ciliary dysfunction. Thirty-five distinct multi-organ phenotypes have been recognized, with 187 genes associated. We performed a literature review of pancreatic involvement in ciliopathies and found that pancreatic disease is an uncommon phenotype described in only a handful of these genetic disorders. We present a case report of a pediatric patient with WDR19-related ciliopathy whose degree of pancreatic disease exceeds what has previously been reported in the literature for WDR19-related ciliopathies. WDR19 is one member of the nephronophthisis (NPHP)-related ciliopathy gene family and encodes an intra-flagellar transport protein (IFT144). Our patient presented with restrictive and obstructive lung disease, short rib thoracic dysplasia, end-stage renal disease (ESRD), developmental delay, hepatic fibrosis, and severe recurrent pancreatitis. Whole-exome sequencing (GeneDx) showed two likely pathogenic WDR19 variants in trans (maternally inherited: c.742G > A, p.G248S; paternally inherited: c.617 T > C, p.L206P). Among WDR19-related ciliopathies, pancreatic involvement is rarely reported and there have been no cases of severe, recurrent pancreatitis. Through this case report and literature review we hope to emphasize that pancreatic involvement is a rare yet important clinical phenotype to recognize in ciliopathies, especially in WDR19-related ciliopathies.

Liquid biopsy, using a novel DNA methylation signature, distinguishes pancreatic adenocarcinoma from benign pancreatic disease.

We tested the ability of a novel DNA methylation biomarker set to distinguish metastatic pancreatic cancer cases from benign pancreatic cyst patients and to monitor tumor dynamics using quantitative DNA methylation analysis of cell-free DNA (cfDNA) from blood samples. The biomarkers were able to distinguish malignant cases from benign disease with high sensitivity and specificity (AUC = 0.999). Furthermore, the biomarkers detected a consistent decline in tumor-derived cfDNA in samples from patients undergoing chemotherapy. The study indicates that our liquid biopsy assay could be useful for management of pancreatic cancer patients.

Mutations and variants of ONECUT1 in diabetes.

Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.

Multiple endocrine neoplasia type 1 with a frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas: case report.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by pituitary neoplasia, primary hyperparathyroidism and pancreatic endocrine tumor. Here we show a case of MEN1 with a germline frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas. CASE PRESENTATION: A 28-year-old man noticed the decreased visual acuity of both eyes and visited our institution. Since he was diagnosed as visual disturbance and brain computer tomography (CT) showed a mass in the pituitary fossa, he was hospitalized in our institution. Endoscopic trans-sphenoidal hypophysectomy and total parathyroidectomy with auto-transplantation were performed, and a giant cervical lipoma was resected. Furthermore, in genetic search, we found a germline frameshift mutation in MEN1 gene leading to the appearance of a new stop codon. CONCLUSIONS: We should bear in m ind that giant skin lipoma and multiple abnormal fatty deposits in the pancreas could be complicated with MEN1.

TGF-ß Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer.

Genetic alterations affecting transforming growth factor-ß (TGF-ß) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-ß signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-ß pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.

METTL3 is required for maintaining ß-cell function.

N6-methyladenosine (m6A) mRNA methylation has been shown to regulate obesity and type 2 diabetes. However, whether METTL3, the key methyltransferase for m6A mRNA methylation, regulates ß-cell failure in diabetes has not been fully explored. Here, we show that METTL3 is downregulated under the inflammatory and oxidative stress conditions, and islet ß-cell-specific deletion of Mettl3 induces ß-cell failure and hyperglycemia, which is likely due to decreased m6A modification and reduced expression of insulin secretion-related genes. Overall, METTL3 might be a potential drug target for the treatment of ß-cell failure in diabetes.

Biallelic deletion in a minimal CAPN15 intron in siblings with a recognizable syndrome of congenital malformations and developmental delay.

Calpainopathies constitute a heterogeneous group of disorders resulting from deficiencies in calpains, calcium-specific proteases that modulate substrates by limited proteolysis. Clinical manifestations depend on tissue-specific expression of the defective calpain and substrate specificity. CAPN15, encoding the Drosophila small optic lobes (sol) homolog, was recently found to cause various eye defects in individuals carrying bi-allelic missense variants. Here we report on two siblings with manifestations reminiscent of Johanson-Blizzard syndrome including failure to thrive, microcephaly, global developmental delay, dysmorphic features, endocrine abnormalities and congenital malformations, in addition to eye abnormalities. Exome sequencing identified a homozygous 47 base-pair deletion in a minimal intron of CAPN15, including the splice donor site. Sequencing of cDNA revealed single exon skipping, resulting in an out-of-frame deletion with a predicted premature termination codon. These findings expand the phenotypic spectrum associated with CAPN15 variants, and suggest that complete loss-of-function is associated with a recognizable syndrome of congenital malformations and developmental delay, overlapping Johanson-Blizzard syndrome and the recently observed brain defects in Capn15 knockout (KO) mice. Moreover, the data highlight the unique opportunity for indel detection in minimal introns.

Diabetes mellitus in an adolescent girl with intellectual disability caused by novel single base pair duplication in the PTRH2 gene: Expanding the clinical spectrum of IMNEPD.

BACKGROUND: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) is an extremely rare autosomal recessive disorder with variable expressivity, caused by biallelic mutations in the PTRH2 gene. Core features are global developmental delay or isolated speech delay, intellectual disability, sensorineural hearing loss, ataxia, and pancreatic insufficiency (both exocrine and endocrine). Additional features may include postnatal microcephaly, peripheral neuropathy, facial dysmorphism, and cerebellar atrophy. In literature, there are only a few anecdotal case reports and none of the previous cases presented with diabetic ketoacidosis. METHODS: We are reporting a 12-year old adolescent girl with mild intellectual disability who presented with fever, pain abdomen for 2 days, and fast breathing for one day. RESULTS: Her random blood sugar was 472 mg/dl and arterial blood gas revealed high anion gap metabolic acidosis. Urine examination showed ketonuria. On further evaluation, she was found to have demyelinating sensorimotor polyneuropathy and sensorineural hearing loss. Neuroimaging and other ancillary investigations were normal. Whole exome sequencing revealed a novel homozygous single base pair duplication in exon 1 of the PTRH2 gene (c.127dupA, p.Ser43LysfsTer11), confirming the diagnosis of IMNEPD. CONCLUSIONS: Apart from describing a novel single base pair duplication causing protein truncation in the PTRH2 gene for the first time, our case also expanded the clinical spectrum of IMNEPD, as this is the first case with seemingly pure neurodevelopmental phenotype, who later developed diabetes mellitus, without any exocrine pancreatic abnormality. IMNEPD should be considered in children or adolescents with global developmental delay or intellectual disability when they develop diabetes mellitus.