Clouds over IEMs? Perspectives for Inborn Errors of Metabolism in adults from a retrospective cohort studies in two Swiss adult metabolic Clinics

Background: Inborn errors of metabolism (IEMs) are complex medical conditions. Thanks to improvements in diagnostics and treatment, a growing number of pediatric IEM patients reach adulthood. Thus, clinical care for adults with IEM has become an emerging and challenging reality. This purpose of this study of adults with IEM in an adult metabolic clinic at two academic hospitals (Lausanne and Geneva) was to help make informed decisions on the future organization of health care for this group of patients. Methods: All adult patients with a biochemical and/or genetic diagnosis of IEM followed at the Clinic were included in the study. Electronic patient records were reviewed for clinical features, diagnostic studies, treatment and long-term outcome. Data of undiagnosed patients referred for IEM suspicion were analyzed separately. Results: 126 patients were included in the study. The most prevalent group of diseases was small molecules disorders with 83 (66%) patients, followed by energy defects disorders with 28 (22%) patients and complex molecules disorders with 15 (12%) patients. Overall, 64% of patients were diagnosed before, and 37 % after the age 16 years. Among the 126 IEM, 51% suffered from medical complications. 79% of the patients were receiving a specific treatment for their disease. Among the 140 undiagnosed patients referred for suspicion of IEM, investigations lead to a diagnosis in 29 (21%) patients. 24 had confirmation of an IEM and 5 were found to have another genetic condition. Conclusions. This retrospective study reveals significant features of adult IEM cohort. The disorders are heterogeneous, and there is no one-size-fits-all approach – treatment must be tailored to fit each specific disorder in each individual patient. Even patients who are followed tightly are not protected from metabolic decompensations and/or chronic organ-specific complications. While it is commonly assumed that patients with IEMs are more stable once they become adults, our data show that the diseases continue to exact a lifelong toll. A coordinated monitoring of target organs by a multidisciplinary team is needed. To ensure that the success in diagnosis and treatment of individuals with IEMs is sustained, there is a clear requirement for adequately staffed adult IEM clinics. for and availability of genetic testing remains fragmentary among physicians caring for adult patients.


Introduction
Inborn errors of metabolism (IEMs) are genetic disorders resulting from an enzyme defect in metabolic pathways affecting proteins, fat, carbohydrate metabolism or impaired organelle function, and presenting as complex medical conditions involving multiple organ systems (1). The most recent nosology of IEM includes well over 1000 disorders (2). Even though they are individually rare, their collective prevalence is estimated today at more than 1:800 individuals (3). Improvements in screening programs, disease awareness, diagnostic tests and therapeutic interventions in IEM have led to increasing patient survival and better prognosis but also to the detection of milder or late-onset forms that present in adulthood (4)(5)(6)(7). A recent survey of the metabolic European reference network showed that 50% of patients with inherited metabolic diseases (IMD) are adults (Scientific report, Board annual meeting 2018, MetabERN).
In the past, IEM medicine has been considered as a pediatric discipline and no formal training has been offered for adult medicine. As a result, many of these patients are still under the care of their pediatricians as young adults. (8,9). As with other chronic illnesses, numerous obstacles are known (i.e. lack of support system, unfamiliarity with IEM, poor adherence to treatment) which may interfere with the transition process (10,11). Little is known on long-term outcomes of childhood IEM as many of the "first survivors" currently approach middle age. Exploring the long-term outcomes of these patients is, nonetheless, important from the viewpoint of developing the optimal treatment strategy over a lifetime (12). In order to meet this growing demand, programs with a higher level of formal training in adult IEM are underway in several countries (13) leading to adult metabolic physicians specializing in this new and expanding medical discipline (14). However, according to a recent survey, most of the centers following adult patients with IEM felt the current state of available education and training in this field were insufficient (15).
In our country, an Adult Metabolic Clinic was established in 2013 at the Centre for Molecular Diseases of the University Hospital of Lausanne and was extended in 2015 by an affiliation with the Division of Endocrinology, Diabetology, Hypertension and Nutrition of the University Hospitals of Geneva. This study was intended to establish a database of the current health of adult patients with IEM in order to better understand the clinical course of these patients, their response to treatment and their complication rate, and to obtain a basis upon which to organize the future organization of health care for these patients.

Statistical analysis
All data were analyzed using Excel statistical functions for Office 365 for Mac and for Windows 2016.
Frequency was calculated for classification of patients according to the metabolic subtype. Prevalence was reported as percentage of the total group or subgroup of patients depending on the studied outcome.

Results General
A total of 126 adult patients with IEM including 64 men (51%) and 62 women (49%) were enrolled in the study. One hundred (79%) of the patients were transitioned from the pediatric metabolic clinic whereas 26 (21%) were referred from another specialty.

Disease frequencies
The most prevalent group of diseases was small molecules disorders with 83 (66%) patients, followed by energy defect disorders with 28 (22%) patients and complex molecules disorders with 15 (12%) patients. Disorders of phenylalanine metabolism were the most represented disease with 16 patients having classical phenylketonuria and seven mild hyperphenylalaninemia (Supplementary Table 1).
The most prevalent group in complex molecule disorders was sphingolipidosis (LSD) with Gaucher and Niemann-Pick type B diseases representing eight patients in total. Patients with Fabry disease were not included in the study as they were followed by a specific and separate clinic. The most prevalent diseases in the energy defect disorders were Chronic Progressive External Ophthalmoplegia (CPEO) and Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes (MELAS) with in total 11 patients.

Age group at diagnosis
Overall about a third was diagnosed during the infantile period (from birth to 1 year; 32%), one third during childhood and adolescence (from age 1 to 15 years; 32%) and one third after the age of 16 years (37%). For the 83 patients in the small molecules disorders group, 39 (47%) had an infantile diagnosis, twenty-three (28%) were diagnosed between 1 to 15 years of age and 21 (25%) patients were diagnosed after age 16 years. Age at diagnosis in complex molecule disorders was widely distributed with 9 (60%) patients diagnosed between 1 to 15 years of age and 6 (40%) patients after 16 years of age. In the energy defect disorders group, 19 (68%) were diagnosed after 16 years and only one had an infantile diagnosis (glycogenosis type 1A). Factors associated with diagnosis in adulthood were: (1) true late-onset form of the disease. Some gene variants are known to be associated with a milder, later onset phenotype (ex. the c.-32-13T > G variant found in one of our patient is reported in approx. 80-90% of late-onset Pompe disease (17)), (2) Delayed diagnosis of infantile forms. Some of the adult patients diagnosed lately had their first symptoms in infancy (i.e. splenomegaly in Niemann-Pick B), and (3) genotypes known to be associated with variable cinical presentation, such as in mitochondrial disease.

Molecular Genetic studies
The diagnosis was based solely on biochemical results in 50% of the cohort, while molecular genetic confirmation was obtained in the other 50%. Of the 63 patients with genetic confirmation of the pathogenic mutation, 29 (46%) had small molecule, 24 (38%) energy defect and 10 (16%) complex molecule disorders.

Disease-related complications
During the study period (4 years, 2 months), 64 (51%) of the 126 patients experienced a worsening of a previously known complication, or manifested a new complication directly linked to their IEM diagnosis. The proportions were thirty-nine (61%) with small molecule disorders, 17 (27%) energy defect and 8 (13%) complex molecule disorders. Among these complications, 19% were due to an acute metabolic decompensation, 69% were worsening of pre-existing complications and 12% were newly detected. Among the 64 patients, 54 (84%) of them were receiving a specific treatment. In total, 45 (36%) patients had at least one hospitalization and for 33 (73%) of them it was for complications related to the metabolic condition (i.e. acute metabolic decompensation, cardiac decompensation, epilepsy, leukoencephalopathy). The characteristics of disease-related complications are summarized in Table 1. Lost to follow-up During the time of the study, 15 patients (12%) were lost to follow-up. Five of them had been seen only once in clinic and none of these patients had regular follow-up primarily. Two of them relocated to another area with an orderly transition to another adult metabolic clinic. For two of them, it was due to lack of coordination between the different specialists in a multidisciplinary context. Finally, six patients freely decided to discontinue regular follow-up in our Clinic. Factors associated with loss of follow-up were poor adherence to treatment, independence from parental control after transition, integration in working life with limited availability, and living at longer distance from our Clinic.
A summary of all the data is reported in supplementary Table 2.

New adult referrals
One hundred and forty (63 men and 77 women) were referred to the metabolic clinic for a suspicion of IEM. One hundred and thirty-three patients were referred due to symptoms suggestive of IEM and 7 because of a positive family history. The ones in which an IEM was confirmed were included in the statistics of the general results. Of the 140 referrals for IEM suspicion, a genetic diagnosis was reached in 29 (21%): 19 with a genuine IEM, and 10 with a non-IEM genetic disease ( Table 2). Most of the diagnoses were made in patients who had positive family history or neurological symptoms with clear neurological findings (i.e. abnormal electroneuromyography, elevated creatine kinase (CK), signs of myopathy). Rare genetic but non-IEM diseases were found using whole exome sequencing.
Investigations were inconclusive for all the patients referred for chronic fatigue syndrome, myalgia (with no elevation of CK), chronic/joint pain but normal clinical examination (data not shown). Which are the limitations of our study? Firstly, patients with Fabry disease were not included in this study as they were followed at a parallel dedicated clinic. However, previous studies showed that Fabry disease was one of the most prevalent IEMs in adults with diagnosis almost exclusively in adulthood (12,18). This may affect the interpretation of the disease frequencies and age group at diagnosis in our cohort and its comparison with previous studies. Secondly, some patients with IEMs in the French-speaking Switzerland may be followed by other specialists or centres and therefore were not included in our results; this may be particularly true for individuals with less severe forms. Thirdly, classification of IEM is variable according to the textbooks and literature. We based our criteria on a reference textbook for inherited metabolic disease in adult (19), the Vademecum Metabolicum (20) and the Saudubray classification (16) but are aware that it may differ from other classifications such as the MetabERN diseases group (European Reference Network for Inherited Metabolic Disorders) (21). Fourthly, not all the IEM are represented in our cohort (i.e. congenital disorders of glycosylation, some urea cycle disorders, few subtypes of mucopolysaccharidosis, glycogenosis and β-oxidation defect) which also significantly biases the interpretation of the results. For these reasons, we do not suggest that our figures are necessarily applicable to other settings and other countries. In spite of these shortcomings, we feel that our study offers some insights that may be worthy of reflection.
Comparison of the size of our clinic and its disease distribution to other clinics around the world cases of adult patients with IEM from Reference Centers in Spain were reviewed (12). The high prevalence of PKU may also be due to the fact that it has been the first disorder included in newborn screening programs (22). The prevalence of the other IEMs in this study is comparable to previous studies, notably with amino acid (protein) metabolism disorders being the most prevalent group (18).
The lysosomal group was underrepresented on our cohort as Fabry patients are taken care of in a parallel dedicated clinic.
IEMs diagnosed in adulthood account for more than 30% of all diagnoses 37% of the patients were diagnosed after 16 years of age. This observation was similar to the SSIEM adult group report (42%) (18) and included mainly patients from the energy defect disease group and storage disorders. Adult-onset is frequent in mitochondrial disease where individual level of heteroplasmy and variable environment can trigger the disease at any age. In contrast, the majority of the patients in the small molecule disorders group were diagnosed in the neonatal period which is likely explained by newborn screening and the frequent onset of symptoms in the neonatal period. Of note, many of our historical patients had been diagnosed solely on biochemical grounds; with the advent of quasi-universal application of next-generation sequencing techniques, the recognition of variant forms with juvenile or adult onset will increase significantly (23,24). Here, it must be remarked that many of these "adult" diagnoses were made because of astute observations or intuitions of individual physicians; we suspect that a large number of individuals still go unrecognized.
Awareness of the indication for and availability of genetic testing remains fragmentary among physicians caring for adult patients.
More than 50% of patients present with medical complications The challenge continues after transition from pediatric to adult care The transition process has been effective for the majority of patients in our cohort however a minority of patients has been lost to follow-up thereafter, highlighting that this period is fragile and needs careful attention such as described previously for other genetic and/or endocrine conditions (11,26,27). In summary, the overall pattern emerging from these observations are the following: patients diagnosed in the neonatal or paediatric period are diagnosed and treated much better today than was the case 50 years ago and many patients reach adolescence and adulthood; however, these patients have to navigate through a transition process that is fraught with perils. In addition, there is a growing number of patients who are diagnosed with an IEM in adult age. As adults, all these patients may enjoy periods of stability but decompensations are possible at any time and late-onset complications tend to appear as the patient with age. The chronic genetic disease continues to exact its toll inexorably.
Ongoing efforts to coordinate diagnosis and care of individuals with IEMs Switzerland was one of the first countries to implement newborn screening 50 years ago (28); and in 2017, Switzerland was considered to have the third best standard of healthcare in the world (29).
Despite this remarkable track record, the observations above indicate that there is much room for improvement. Specific programmes for rare diseases have been or are being implemented in several European countries. The majority of these programmes include a specific section on IEMs. In Switzerland, The National Coordination for Rare Diseases (Kosek) is mandated with the establishment of networks to improve the care of individuals affected by rare diseases. One of the pilot groups within the Kosek programme is focused on IEM. One of the requisites of the networking progress is to make sure that dedicated centers meet high standards of organization and accountability (30).
Ultimately, national recognition should enable reference centers to integrate European reference networks (31). Nevertheless, we would like to suggest that national coordination will not work unless the individual centers are improved and strengthened.

Conclusions
In the 21st century, we welcome the fact that improved diagnosis and treatment are making IEM morbidity and mortality a relic of the past, giving way to a growing adult population. However these advances also bring challenges for medicine and society. In spite of the limitations discussed above, this retrospective study may give some indications on the outcome of these patients and indicate where the health system might be improved further: (1) adults with IEM are clearly an emerging population in Switzerland and may soon outnumber the pediatric population. Both children and adults with IEM require specific management and expertise from the health care providers, but the requirements are different and the setting is different (pediatric clinics vs. adult clinics); (2) as more than half of our patients developed organ-specific complications, a multidisciplinary team and disease-specific personalized health plans are necessary to monitor target organs and (3) as no patient is protected from metabolic decompensations, IEM clinics must be connected to tertiary hospitals offering intensive care units as well as availability of specific drugs (e.g. sodium benzoate and other). Hence the need for coordination at national and then ideally at international level for the management of these rare diseases.