Sandra Sirrs

Background: New gene therapy medicinal products [GTMP] are being considered as alternatives to liver transplant [LTx] for some patients with inherited metabolic diseases [IMDs] but pose unique challenges for health policy makers. Methods: Published data on LTx and GTMP in human patients with urea cycle defects [UCD], glycogen storage disease type 1a [GSD1a], methylmalonic aciduria [MMA] and propionic aciduria [PA] were reviewed for efficacy, safety, data quality and health policy considerations. Results: LTx can reduce [MMA, PA] or eliminate [UCD, GSD1a] metabolic decompensation and improve quality of life. Risk of death peaks in the first year but long-term survival post LTx is similar to medical management. Initial data for GTMP show reduction in metabolic decompensation [MMA, PA, UCD] with more modest impacts in GSD1a. Long-term safety and efficacy data [available for LTx] may not be available at the time of market authorization for GTMP. Age is one health policy challenge as clinical trials for GTMP may target one age group but other age groups may request consideration for treatment. Quality concerns regarding data analysis exist for both modalities. Cost effectiveness of LTx is likely to be significantly more favorable than for GTMP. Access limitations are severe for both treatments, with high opportunity costs [price for GTMP, organ availability for LTx] mandating the need to engage the public as stakeholders in addition to patients, families, manufacturers and clinicians. Conclusions: LTx remains an effective treatment choice in the era of GTMP given the significant health policy challenges associated with these novel therapies.

The number of inherited metabolic diseases (IMDs) in newborn screening (NBS) programs has increased significantly in the past decades. For some of the IMDs included in NBS (e.g., tyrosinemia type I), there are clear and substantial health benefits of NBS, while for others (e.g., very long chain acyl CoA dehydrogenase deficiency and 3‐methylcrotonyl CoA carboxylase 1 deficiency), this is less clear as NBS identifies individuals who are asymptomatic or have milder forms of the disease. Therefore, knowledge of the full disease spectrum (including later onset forms) is needed when setting diagnostic metabolite cut‐offs for NBS. Insights into the clinical, genetic and biochemical characteristics of different patient subsets can be used to redefine NBS protocols to identify patients with more severe forms of the disease who are most likely to benefit from identification in the newborn period. These insights require life‐long monitoring of individuals identified based on symptoms versus those identified by NBS to determine long‐term health outcomes and quantify the benefits of NBS. Adult metabolic specialists should be included in the development of NBS programs to provide data from this long‐term monitoring and to contribute specific knowledge about later onset phenotypes of the IMDs included in NBS programs. The goal should be to develop NBS programs that identify newborns that benefit from early disease detection and treatment, without increasing psychological, social and management burden for individuals who may develop disease in adulthood with milder phenotype or potentially even not at all.

The rapid expansion of the number of adult patients with inherited metabolic diseases (IMDs) has created demand for physicians with expertise in the field of adult metabolic medicine (AMM). Unfortunately, existing accredited training programs in this field are rare, and training programs in pediatric metabolic medicine cannot fully meet the needs of AMM physicians as the types of patients and the problems they face are different in the adult setting. We surveyed a group of working practitioners in AMM for input on what medical expert competencies they feel should be included as part of training programs in AMM. Through a modified Delphi process, 66 physicians from six continents reached consensus on a comprehensive list of training competencies in AMM. This list includes competencies from the fields of adult internal medicine, neurology, medical genetics, and pediatric metabolic medicine but also includes competencies not found in any of those programs, leading to the conclusion that the training needs for specialists in AMM cannot be met from any of these existing programs. We propose that AMM be considered a subspecialty separate from pediatric metabolic medicine and that accredited training programs in AMM be created using these medical expert competencies as part of a broader program design.

Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy. NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location.

Transplantation is an established disease modifying therapy in selected children with certain inherited metabolic diseases (IMDs). Transplantation of hematopoietic stem cells or solid organs can be used to partially correct the underlying metabolic defect, address life threatening disease manifestations (such as neutropenia) or correct organ failure caused by the disease process. Much less information is available on the use of transplantation in adults with IMDs. Transplantation is indicated for the same IMDs in adults as in children. Despite similar disease specific indications, the actual spectrum of diseases for which transplantation is used differs between these age groups and this is partly related to the natural history of disease. There are diseases (such as urea cycle defects and X‐linked adrenoleukodystrophy) for which transplantation is recommended for selected symptomatic patients as a treatment strategy in both adults and children. In those diseases, the frequency with which transplantation is used in adults is lower than in children and this may be related in part to a reduced awareness of transplantation as a treatment strategy amongst adult clinicians as well as limited donor availability and allocation policies which may disadvantage adult patients with IMDs. Risks of transplantation and disease‐specific prognostic factors influencing outcomes also differ with age. We review the use of transplantation as a disease modifying strategy in adults focusing on how this differs from use in children to highlight areas for future research.

Background: Glycogen storage disease type 1 is an autosomal recessive disorder with an incidence of 1 in 100,000. Long-term complications include chronic blood glucose lability, lactic academia, short stature, osteoporosis, delayed puberty, gout, progressive renal insufficiency, systemic or pulmonary hypertension, hepatic adenomas at risk for malignant transformation, anemia, vitamin D deficiency, hyperuricemic nephrocalcinosis, inflammatory bowel syndrome (type 1b), hypertriglyceridemia, and irregular menstrual cycles. We describe hypogonadotropic hypogonadism as a novel complication in glycogen storage disease (GSD) type 1. Case Studies and Methods: Four unrelated patients with GSD 1a (N = 1) and 1b (N = 3) were found to have hypogonadotropic hypogonadism diagnosed at different ages. Institutional Research Ethics Board approval was obtained as appropriate. Participant consent was obtained. A retrospective chart review was performed and clinical symptoms and results of investigations summarized as a case series. Results: All patients were confirmed biochemically to have low luteinizing hormone (LH) and follicular stimulating hormone (FSH), and correspondingly low total testosterone. Clinical symptoms of hypogonadism varied widely. Investigations for other causes of hypogonadotropic hypogonadism were unremarkable. In addition, all patients were found to have disproportionately low bone mineral density at the lumbar spine compared to the hip. Common to all patients was erratic metabolic control, including recurrent hypoglycemia and elevated lactate levels. Discussion: Recurrent elevations in cortisol in response to hypoglycemia may be the underlying pathology leading to suppression of gonadotropin-releasing hormone (GnRH) release. Incorporating clinical and/or biochemical screening of the hypothalamic–pituitary–gonadal axis may be important in the management of this disease. Testosterone therapy however needs to be carefully considered because of the risk of hepatic adenomas.

Fatty acid amide hydrolase 2 (FAAH2) is a hydrolase that mediates the degradation of endocannabinoids in man. Alterations in the endocannabinoid system are associated with a wide variety of neurologic and psychiatric conditions, but the phenotype and biochemical characterization of patients with genetic defects of FAAH2 activity have not previously been described. We report a male with autistic features with an onset before the age of 2 years who subsequently developed additional features including anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities but was otherwise cognitively intact as an adult. Whole exome sequencing identified a rare missense mutation in FAAH2, hg19: g.57475100G > T (c.1372G > T) resulting in an amino acid change (p.Ala458Ser), which was Sanger confirmed as maternally inherited and absent in his healthy brother. Alterations in lipid metabolism with abnormalities of the whole blood acyl carnitine profile were found. Biochemical and molecular modeling studies confirmed that the p.Ala458Ser mutation results in partial inactivation of FAAH2. Studies in patient derived fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. We propose that genetic alterations in FAAH2 activity contribute to neurologic and psychiatric disorders in humans.