Metabolic Specialists Research Articles

Efficacy of continuous glucose monitoring for finding unusual causes of hyperglycemia: a clinical case

Diabetes is a chronic condition that requires constant blood glucose self-monitoring. The carbohydrate metabolism compensation is usually assessed by the level of glycated hemoglobin. But it does not always help reveal the true cause of poor glycemic control. The devices for continuous glucose monitoring allows to assess blood glucose level in real time and find unusual causes of hyper- and hypoglycemia. Achieving target glycemic levels is influen­ced by many factors: age of patients, duration of diabetes, eating habits and eating disorders, level of education, patient’s understan­ding of the diabetes course. One of the reasons for not reaching the target levels of glycemia can be hyperphagic eating disorders, such as night eating syndrome. According to the American Psychiatric Association classification, night eating syndrome belongs to the category of “Other specified eating disorders”. Diagnostic criteria in this syndrome include consumption of > 25 % of food from the daily diet after dinner or at least 2 cases per week of food consumption at night; awareness of these episodes; and at least 3 of the following: morning anorexia, uncontrollable desire to eat between dinner and sleep or at night, conviction that eating will help you fall asleep or return to sleep, insomnia and/or bad mood in the morning. The prevalence of night eating syndrome in the general population is 1.1 %, and in those who refer to metabolic surgery specialists, it is 2–20 %. The presence of night eating syndrome in diabetes adversely affects metabolic control and complicates the management of these patients, in particular, they have higher levels of HbA1c, blood pressure and body mass index compared to individuals without such eating disorder. In this case report, we describe a patient with poor glycemic control who used continuous glucose monitor and was diagnosed with night eating syndrome that helped change management and achieve normoglycemia in the evening and nighttime.

Osteogenesis Imperfecta: A study of the patient journey in 13 European countries

IntroductionOsteogenesis imperfecta (OI) is a heritable skeletal disorder and comprises various subtypes that differ in clinical presentation, with Type I considered the least severe and Types III/IV the most severe forms. The study aim was to understand the OI patient diagnostic and treatment journey across Europe.MethodsWe conducted a qualitative, descriptive study to understand the OI patient journey. A selection of people with OI/their caregivers and clinicians involved in OI-patient care from across Europe were interviewed using a specially developed questionnaire.ResultsBetween May 2022 and July 2022, 22 people with OI/caregivers and 22 clinicians (endocrinologists, orthopaedic surgeons, geneticists and metabolic specialists) from across Europe were interviewed. Our study showed various areas of concerns for the OI community. Timely diagnosis of OI is essential; misdiagnoses and a delay to treatment initiation are all too common. There are a lack of consensus guidelines regarding optimal treatments (including when bisphosphonate therapy should be initiated and the route of administration) and patient management throughout the duration of the patient’s life. Adult OI patients do not have a medical home and are often managed by endocrinologists and rheumatologists. Adult care is often reactive based on the development of new symptoms. The psychosocial burden of OI impacts on the patient’s quality of life.ConclusionsThere is an urgent need for increased awareness about OI and its wide range of symptoms. In particular, there is a need for consensus guidelines outlining the optimum care throughout the duration of the OI patient’s life.

Standardized emergency protocols to improve the management of patients with suspected or confirmed inherited metabolic disorders (IMDs): An initiative of the French IMDs Healthcare Network for Rare Diseases

ObjectivesPatients with inherited metabolic disorders (IMDs) may require emergency hospital care to prevent life-threatening situations such as metabolic decompensation. To date, over one thousand different rare IMDs have been identified, which means that healthcare professionals (HCPs) initiating emergency treatment may not be familiar with these conditions. The objective of this initiative was to provide HCPs with practical guidance for the acute management of children and adults with IMDs who need emergency care, regardless of the underlying reason. MethodsWe outline how a multidisciplinary working group from the French IMDs Healthcare Network for Rare Diseases, known as G2M, has created concise and standardized protocols _each consisting of a single double-sided A4 sheet _ focused on a specific disease, a group of diseases, or a particular symptom. Prior to validation, these protocols were reviewed by all French reference and competence centres for IMDs, as well as by medical experts from other specialities when necessary, physicians from emergency and intensive care units, and representatives from patient associations. Results and conclusionIn total, 51 emergency protocols containing essential information have been developed and provided to affected patients. All the emergency protocols are freely available in both French and English at https://www.filiere-g2m.fr/urgences. These standardized protocols aim to enhance the emergency care of patients without delay, while also assisting HCPs by increasing their confidence and efficiency, minimizing the risk of dosage errors when administering specialized treatments, saving time, and reducing the number of phone calls to metabolic medicine specialists on night duty. The protocols are scheduled for annual review to facilitate further improvements based on feedback from HCPs and patients, as well as to accommodate any changes in management practices as they evolve.

The natural history of dihydrolipoamide dehydrogenase deficiency in Israel.

Dihydrolipoamide dehydrogenase (DLD) deficiency is an ultra-rare autosomal-recessive inborn error of metabolism, affecting no less than five mitochondrial multienzyme complexes. With approximately 30 patients reported to date, DLD deficiency was associated with three major clinical presentations: an early-onset encephalopathic phenotype with metabolic acidosis, a predominantly hepatic presentation with liver failure, and a rare myopathic phenotype. To elucidate the demographic, phenotypic, and molecular characteristics of patients with DLD deficiency within the Israeli population, data were collected from metabolic disease specialists in four large tertiary medical centers in the center and south of Israel. Pediatric and adult patients with biallelic variants in DLD were included in the study. A total of 53 patients of 35 families were included in the cohort. Age at presentation ranged between birth and 10 years. Wide phenotypic variability was observed, from asymptomatic individuals in their sixth decade of life, to severe, neonatal-onset disease with devastating neurological sequelae. Six DLD variants were noted, the most common of which was the c.685G>T (p.G229C) variant in homozygous form (24/53 patients, 45.3%; 13/35 families), observed mostly among patients of Ashkenazi-Jewish descent, followed by the homozygous c.1436A>T (p.D479V) variant, found in 20 patients of Bedouin descent (37.7%; 16/35 families). Overall, patients did not necessarily present as one of the previously described distinct clinical phenotypes. DLD deficiency is a panethnic disorder, with significant phenotypic variability, and comprises a continuum, rather than three distinct clinical presentations.

P074 Diagnostic Journeys of Patients with Hypophosphatasia

Abstract Background/Aims Hypophosphatasia (HPP) is an ultra-rare genetic disorder characterised by low activity of tissue non-specific alkaline phosphatase (TNAP). Due to heterogeneity of clinical presentation and lack of definitive biochemical testing, misdiagnosis and diagnostic delay are common. Methods We used information reported by HPP patients to the Rare and Undiagnosed Diseases Study (RUDY) online registry (www.rudystudy.org). We included patients with a self-reported diagnosis of HPP and information on at least one of our outcomes. We described their diagnostic journey, including diagnostic delays, initial symptoms, incorrect diagnoses and healthcare professionals seen. Results 16 participants with a self-reported diagnosis of HPP were included in the analysis with 14/16 female. Of those reporting the date of initial symptom onset, 9/14 participants had symptom onset before the age of 18, whereas five had symptom onset in adulthood. The median time from symptom onset to HPP final diagnosis was 26.5 years (N = 8, IQR 11.2 to 34.6). From the first GP visit related HPP to final diagnosis the median time was 9.5 years (N = 6, IQR 6.2 to 11.1), and from the first hospital visit related to HPP, the median time to final diagnosis was 3.9 years (N = 10, IQR 0.8 to 10.5). Among participants reporting initial symptoms (N = 13), 16 categories of initial symptom were reported, with a median of two initial symptom categories per participant (IQR 1 to 2). The most prevalent initial symptom was pain (10/13, 77%). Of these 10 participants, four had lower limb pain, one had upper limb pain, one had back pain, and five had pain of unspecified location. Skeletal deformity at birth, dental manifestations, joint swelling, and infantile feeding problems were each present in 2/13 participants (15%). Among participants reporting whether they had received other diagnoses prior to that of HPP (N = 13), nine participants (75%) received at least one other diagnosis, with diagnoses of 10 different conditions reported across the cohort. The most common other diagnosis was fibromyalgia (4/13, 31%), followed by hypermobility (2/13, 15%). 21 different types of healthcare professionals were seen prior to final diagnosis. General Practitioners were the most commonly consulted (9/14, 64%). This was followed by allied health professionals (8/14, 57%). Of the eight participants seeing allied health professionals, all eight saw physiotherapists, and 4 (29% of total) also saw at least one other allied health professional. Other types of healthcare professional seen by multiple responders included orthopaedic surgeons (5/14, 36%), rheumatologists (5/14, 36%), geneticists (4/14, 29%), endocrinologists (3/14, 21%), metabolic specialists (3/14, 21%) and dentists (2/14, 14%). Conclusion Patients typically present with a cluster of symptoms, often including pain, and are often seen by general practitioners and physiotherapists before diagnosis. Increasing awareness of HPP in these professions may improve early recognition of the disease. Disclosure D. Marsden: None. R. Ridley: None.

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.

Team Approach: Bone Health Optimization in Orthopaedic Surgery

» Bone health optimization (BHO) has become an increasingly important consideration in orthopaedic surgery because deterioration of bone tissue and low bone density are associated with poor outcomes after orthopaedic surgeries.» Management of patients with compromised bone health requires numerous healthcare professionals including orthopaedic surgeons, primary care physicians, nutritionists, and metabolic bone specialists in endocrinology, rheumatology, or obstetrics and gynecology. Therefore, achieving optimal bone health before orthopaedic surgery necessitates a collaborative and synchronized effort among healthcare professionals.» Patients with poor bone health are often asymptomatic and may present to the orthopaedic surgeon for reasons other than poor bone health. Therefore, it is imperative to recognize risk factors such as old age, female sex, and low body mass index, which predispose to decreased bone density.» Workup of suspected poor bone health entails bone density evaluation. For patients without dual-energy x-ray absorptiometry (DXA) scan results within the past 2 years, perform DXA scan in all women aged 65 years and older, all men aged 70 years and older, and women younger than 65 years or men younger than 70 years with concurrent risk factors for poor bone health. All women and men presenting with a fracture secondary to low-energy trauma should receive DXA scan and bone health workup; for fractures secondary to high-energy trauma, perform DXA scan and further workup in women aged 65 years and older and men aged 70 years and older.» Failure to recognize and treat poor bone health can result in poor surgical outcomes including implant failure, periprosthetic infection, and nonunion after fracture fixation. However, collaborative healthcare teams can create personalized care plans involving nutritional supplements, antiresorptive or anabolic treatment, and weight-bearing exercise programs, resulting in BHO before surgery. Ultimately, this coordinated approach can enhance the success rate of surgical interventions, minimize complications, and improve patients' overall quality of life.

Uncertain significance mutation in the POLR3B gene in a Syrian boy with leukodystrophy: a case report.

A 4-year-old boy presented in the neurologic clinic with delayed psychomotor development and progressive neurologic symptoms that started from the age of 20 months. Physical examination revealed ataxic features and a global development delay. The MRI was significant for hypomyelination. The most common causes of leukodystrophy were rolled out. He was referred to an inherited metabolic disease specialist under suspect of inborn metabolic errors because of laboratory analysis, which showed elevated levels of lactic acid, pyruvate, 4-Hydroxy-Phenylactic acid, 3-Hydroxy propionic acid, and decreased levels of PCO2, HCO3, total CO2, 25-Hydroxyvitamin D. These results were unspecific and mitochondrial disease was highly suspected. However, the genetic study was requested to get a defined diagnosis and treatment; the whole exon sequencing result showed a homozygous variant of uncertain significance mutation; related to an amino acid change from Ile to Thr at position 1002 in the POLR3B gene, which helped us to reveal the final diagnosis, and the genetic counseling were recommended for the next pregnancies. POLR3-related Leukodystrophy is a very rare disease. The early diagnosis should be raised depending on clinical history and MRI findings after other conditions were rolled out, and the confirmed diagnosis depends on the genetic study.

Multidisciplinary and multidimensional approaches to transplantation in children with rare genetic kidney diseases.

In this review, we describe the multidisciplinary, multidimensional care required to optimize outcomes for pediatric transplant recipients with rare genetic kidney diseases. Transplant success, recipient survival, and improvement in quality of life depend on collaboration between patients, families, and a team of specialists with medical, as well as nonmedical expertise. A multidisciplinary transplant team composed of experts from medicine, surgery, nursing, nutrition, social services, transplant coordination, psychology, and pharmacology, is now standard in most transplant centers and is critical to the success of a transplant. In addition to these professionals, other specialists, such as cardiologists, urologists, geneticists, metabolic disease specialists, occupational therapists, case management, child life, chaplain, and palliative care services, have a crucial role to play in the preparation, surgery, and follow-up care, especially when a pediatric patient has a rare genetic disorder leading to renal involvement, and the need for transplantation. In order to describe this multidisciplinary care, we divide the genetic renal diseases into five subgroups-metabolic and tubular disorders, glomerular diseases, congenital anomalies of the kidney and urinary tract, ciliopathies including cystic diseases, and miscellaneous renal conditions; and describe for each, the need for care beyond that provided by the standard transplant team members.

Expert opinion on patient journey, diagnosis and clinical monitoring in acid sphingomyelinase deficiency in Turkey: a pediatric metabolic disease specialist's perspective.

This review by a panel of pediatric metabolic disease specialists aimed to provide a practical and implementable guidance document to assist clinicians in best clinical practice in terms of recognition, diagnosis and management of patients with acid sphingomyelinase deficiency (ASMD). The participating experts consider the clinical suspicion of ASMD by the physician to be of utmost importance in the prevention of diagnostic delay and strongly suggest the use of a diagnostic algorithm including/starting with dried blood spots assay in the timely diagnosis of ASMD in patients presenting with hepatosplenomegaly and a need for increased awareness among physicians in this regard to consider ASMD in the differential diagnosis. In anticipation of the introduction of enzyme replacement therapy, raising awareness of the disease among physicians to prevent diagnostic delay and further investigation addressing natural history of ASMD across the disease spectrum, potential presenting characteristics with a high index of suspicion, as well as biomarkers and genotype-phenotype correlations suggestive of poor prognosis seem important in terms of implementation of best practice patterns.

Perspectives of adult patients with lysosomal storage diseases on the transition from pediatric to adult healthcare in Turkey

AimIn many countries, adult clinics specifically dedicated to adult patients with lysosomal storage diseases (LSDs) do not exist. In Turkey, these patients are managed either by pediatric metabolic specialists or adult physicians who do not specifically specialize in LSDs. In this study, we aimed to identify the unmet clinical needs of these adult patients and their suggestions. MethodsThe focus group participants were 24 adult LSD patients. Interviews were conducted in person. ResultsA total of 23 LSD patients and parents of a patient with mucopolysaccharidosis type-3b with intellectual deficit were interviewed, with 84.6% of patients diagnosed after the age of 18 years and 18% of patients diagnosed before the age of 18 years desiring management by adult physicians. Patients with particular physical characteristics or severe intellectual deficit declined the transition. Patients reported structural problems in the hospital and social problems associated with pediatric clinics. They made suggestions to facilitate the possible transition. ConclusionWith improved care, more patients with LSDs survive into adulthood or receive the diagnosis in adulthood. Children with chronic diseases need to transition to the care of adult physicians when they reach adulthood. Thus, there is an increasing need for adult physicians to manage these patients. In this study, most LSD patients accepted a well-planned and organized transition. Problems were related to stigmatization and social isolation in the pediatric clinic or adult issues with which pediatricians are not familiar. There is a need for adult metabolic physicians. Thus, health authorities should adopt necessary regulations for training of physicians in this field.

Lumasiran (Oxlumo)


 CADTH recommends that Oxlumo be reimbursed by public drug plans for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients if certain conditions are met.
 Oxlumo should only be covered to treat those with a genetically confirmed diagnosis of PH1 and whose urine oxalate excretion is not normalized with standard of care therapy (including 3 to 6 months of vitamin B6).
 Oxlumo should only be reimbursed if its cost is reduced and it is initially prescribed by a nephrologist or metabolic diseases specialist experienced in the diagnosis and management of PH1.

Epistemologies of Living With and Treating Rare Metabolic Disorders

ABSTRACT Treatment of a child diagnosed with an inherited metabolic disease is a demanding task both for the clinicians and for the parents. The metabolic pediatricians and dietitians have to deal with scarce and dispersed clinical knowledge, while the parents must actively participate in its treatment, the bulk of which consists of a stringent diet and managing the risk of metabolic decompensation or intoxication. In this article, I characterize the medical epistemologies of a particular kind of “metabolic living,” discussing differences and similarities between the clinical/expert knowledge of metabolic specialists, and the lay knowledge of parents of affected children.

Therapeutic thoroughfares for adults living with Pompe disease.

Pompe disease is caused by autosomal recessive mutations in the acid α-glucosidase gene leading to a multiorgan deficiency of the enzyme acid glucosidase alfa. To recover to a nondiseased status, a lift over a threshold of 25% acid glucosidase alfa enzyme activity is required. This update on therapeutic thoroughfares for adult Pompe disease aims to assist neuromuscular and metabolic specialists. We reviewed the recent studies covering enzyme replacement therapy, gene therapy, and substrate reduction therapy in adult Pompe disease. Results of phase 3 studies and the first sets of long-term data of both novel enzyme replacement therapies, avalglucosidase alfa, and ciplaglucodsidase alfa combined with miglustat, are public. First gene therapy trials are ongoing. Substrate reduction therapy is in early transition to the clinical trial phase. We still miss dose escalation and intensification of frequency trials on enzyme replacement therapy in adults, probably suitable to echo current results in infantile and juvenile Pompe disease. Therapy of Pompe disease reaches new thoroughfares reducing the overall disease burden of patients; however, individualization of these novel therapeutic options remains challenging. Consensus-based and shared decision-based recommendations need to be established based on reliable real-world data to allow the best standards of care worldwide.

Genome and proteome analyses show the gaseous alkane degrader Desulfosarcina sp. strain BuS5 as an extreme metabolic specialist.

The metabolic potential of the sulfate-reducing bacterium Desulfosarcina sp. strain BuS5, currently the only pure culture able to oxidize the volatile alkanes propane and butane without oxygen, was investigated via genomics, proteomics and physiology assays. Complete genome sequencing revealed that strain BuS5 encodes a single alkyl-succinate synthase, an enzyme which apparently initiates oxidation of both propane and butane. The formed alkyl-succinates are oxidized to CO2 via beta oxidation and the oxidative Wood-Ljungdahl pathways as shown by proteogenomics analyses. Strain BuS5 conserves energy via the canonical sulfate reduction pathway and electron bifurcation. An ability to utilize long-chain fatty acids, mannose and oligopeptides, suggested by automated annotation pipelines, was not supported by physiology assays and in-depth analyses of the corresponding genetic systems. Consistently, comparative genomics revealed a streamlined BuS5 genome with a remarkable paucity of catabolic modules. These results establish strain BuS5 as an exceptional metabolic specialist, able to grow only with propane and butane, for which we propose the name Desulfosarcina aeriophaga BuS5. This highly restrictive lifestyle, most likely the result of habitat-driven evolutionary gene loss, may provide D. aeriophaga BuS5 a competitive edge in sediments impacted by natural gas seeps. Etymology: Desulfosarcina aeriophaga, aério (Greek): gas; phágos (Greek): eater; D. aeriophaga: a gas eating or gas feeding Desulfosarcina.

Organic Acidemias.

Organic Acidemias.

Reproducibility, stochasticity, and geometry in a lattice of cross-feeding microbial cells

Bacteria often exchange metabolites to achieve together what they cannot alone. Chemically-exchanging cells can survive, even as metabolic specialists in poor environments; perform decentralized chemistry; and regulate phenotypic heterogeneity. Connecting the microscopic features of transport and physiology–often stochastic and heterogeneous–with reproducible, large-scale behaviors is key to advancing microbial ecology. Here we investigate the growth of cross-feeding strains at single-cell, stochastic resolution.

Mitochondrial hepatopathy: Anticipated difficulties in management of fatty acid oxidation defects and urea cycle defects.

Fatty acid oxidation defects (FAOD) and urea cycle defects (UCD) are among the most common metabolic liver diseases. Management of these disorders is dotted with challenges as the strategies differ based on the type and severity of the defect. In those with FAOD the cornerstone of management is avoiding hypoglycemia which in turn prevents the triggering of fatty acid oxidation. In this review, we discuss the role of carnitine supplementation, dietary interventions, newer therapies like triheptanoin, long-term treatment and approach to positive newborn screening. In UCD the general goal is to avoid excessive protein intake and indigenous protein breakdown. However, one size does not fit all and striking the right balance between avoiding hyperammonemia and preventing deficiencies of essential nutrients is a formidable task. Practical issues during the acute presentation including differential diagnosis of hyperammonemia, dietary dilemmas, the role of liver transplantation, management of the asymptomatic individual and monitoring are described in detail. A multi-disciplinary team consisting of hepatologists, metabolic specialists and dieticians is required for optimum management and improvement in quality of life for these patients.

Identifying features of a mobile-based application for self-care of people living with T2DM

IntroductionDiabetes self-care requires support to empower patients to improve self-monitoring and maintain the necessary self-care behaviors. We aimed to identify features of a mobile-based application as a technology-based device for self-care of people living with T2DM. MethodThis study was conducted in two main phases in 2020. In the first phase, a literature review study was performed to identify the data elements and technical features of the T2DM self-care application. In the second phase, using the information obtained from the review of similar articles, a questionnaire was designed to validate identified requirements. The statistical population of the present study consisted of 22 endocrinologists and metabolic specialists. ResultsIdentification of 55 data elements and technical features for mobile-based self-care application for people with T2DM, and according to the statistical population, 15data elements for demographic requirements, 16 data elements for clinical requirements, and 17 features for the technical capability of this app were selected. ConclusionBlood sugar monitoring, exercise, nutrition, weight monitoring, and educational capabilities were the most highlighted technical features of the T2DM self-care application. Software designers can use these requirements to design a self-care app for people with type-2 diabetes that can help manage and improve patients' health status.

Hormonal dysfunction in adult patients affected with inherited metabolic disorders.

Inherited metabolic disorders (IMDs ) are a rare and diverse group of metabolic conditions mainly caused by enzyme deficiencies, and in some of these, hormonal dysfunction is a relatively common complication. It may present in childhood and subsequently hormonal replacement is required throughout their life. Endocrinopathies can be a presenting symptom of an IMD in adulthood, which should be suspected when associated with multiorgan involvement (neurological, musculoskeletal or liver, etc.). A single IMD can affect any gland with hypogonadism, adrenal insufficiency, diabetes mellitus and thyroid dysfunction being the most common. In some cases, however, it is diagnosed later in their adult life as a secondary complication of previous therapies such as chemotherapy used during Haematopoietic Stem Cell Transplantation (HSCT) in childhood.The mechanisms of endocrine dysfunction in this group of conditions are not well understood. Regardless, patients require ongoing clinical support from the endocrine, metabolic, bone metabolism and fertility specialists throughout their life.Hormonal profiling should be part of the routine blood test panel to diagnose asymptomatic endocrine disorders with delayed manifestations. It is also worth considering screening for common hormonal dysfunction when patients exhibit atypical non-IMD related symptoms. In some adult-onset cases presenting with multiple endocrinopathies, the diagnosis of an IMD should be suspected.Given that new therapies are in development (e.g. gene therapies, stem cell therapies, pharmacological chaperone and substrate reduction therapies), clinicians should be aware of their potential long-term effect on the endocrine system.