This review discusses a selection of congenital disorders of glycosylation that show peculiar features, such as an unusual presentation, different phenotypes, a novel biochemical/genetic mechanism, a relatively high frequency or a relatively efficient treatment.
Isolated methylmalonic acidurias represent a heterogeneous genetic group of inborn errors of propionate metabolism with the common biochemical hallmark of elevated methylmalonic acid present in tissues and body fluids. It was first described in the 1960s and over the years better understanding of the disease and its presentation, earlier diagnosis, and most importantly advances in treatment have resulted in extended survival of patients. With that an expanding spectrum of complications is emerging which requires attention and regular monitoring to facilitate early intervention and reduce disease burden.
Over the last two decades, gene therapy has been successfully translated to many rare diseases. The number of clinical trials is rapidly expanding and some gene therapy products have now received market authorisation in the western world. Inherited metabolic diseases (IMD) are orphan diseases frequently associated with a severe debilitating phenotype with limited therapeutic perspective. Gene therapy is progressively becoming a disease-changing therapeutic option for these patients. In this review, we aim to summarise the development of this emerging field detailing the main gene therapy strategies, routes of administration, viral and non-viral vectors and gene editing tools. We discuss the respective advantages and pitfalls of these gene therapy strategies and review their application in IMD, providing examples of clinical trials with lentiviral or adeno-associated viral gene therapy vectors in rare diseases. The rapid development of the field and implementation of gene therapy as a realistic therapeutic option for various IMD in a short term also require a good knowledge and understanding of these technologies from physicians to counsel the patients at best.
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.
Chronically ill young people must transition to the adult health care service after their 18th birthday. The transition from child centred paediatric care to the adult health care service is not simply limited to the change from familiar structures to something unknown, but includes the entire process of growing up, of individuals becoming independent from their parents and taking responsibility for their own disease management. Young people are at particular risk of losing the connection to medical care during this phase and the transition of young people with chronic conditions is associated with a high risk of declining adherence and worsening health status. Studies suggest that transition programs might be helpful, yet there is no evidence as to whether risks can be reduced or which intervention components are particularly conducive to better outcome. This study aimed to identify transition-specific interventions and evaluate their effect on the improvement of psychosocial parameters, such as health related quality of life and adherence of patients. A systematic literature review was conducted. Electronic databases (Cochrane, Embase, Pubmed, Web of Science) were searched by two independent reviewers for intervention studies aiming to improve transition. Grey literature was also searched. Studies were included if they evaluated transition-specific interventions aiming to improve psychosocial or adherence parameters of participants aged 12 years and older suffering from a chronic condition. Both controlled trials and studies with measurements before an after the intervention were included. The GRADE approach was used to assess the quality of evidence. The inclusion criteria was met by forty studies. Patients suffered from different chronic conditions, such as inflammatory bowel disease, type 1 diabetes or juvenile idiopathic arthritis. Transition interventions used several program components, such as transition coordinators, patient education programs or web-based interventions. Outcomes included quality of life, transition-specific knowledge, adherence and loss to follow up. Thirty-eight studies showed beneficial effects in the intervention group, respectively after intervention. The overall study quality was low. A large number of studies evaluating transition-specific interventions was included. Transition-specific interventions seem to have beneficial effects on psychosocial outcomes and adherence. The promotion of health literacy, appointment arrangement service and the use of technical elements (websites, SMS) seem to be particularly helpful in the transition process. As the patient population was diverse, the results can be transferred to other diseases. Even though the overall study quality was poor, it is possible to draw some conclusions. Future studies should aim to include large numbers of patients over extended periods of time in order to assess long-term outcomes.
Pompe disease is an autosomal recessive lysosomal glycogen storage disorder caused by the deficiency of acid alpha-glucosidase and subsequent progressive glycogen accumulation due to mutations in the GAA gene. Pompe disease manifests with a broad spectrum of disease severity, ranging from severe infantile-onset diseases such as hypotonia and hypertrophic cardiomyopathy to late-onset diseases such as myopathy and respiratory compromise. The diagnosis requires demonstration of deficiency of the lysosomal acid alpha-glucosidase enzyme, which can be assayed in dried blood spot or liquid blood samples, together with supportive biomarker tests, and confirmed with molecular genetic analysis. Targeted screening of at-risk populations and universal newborn screening can result in earlier diagnosis and enable earlier treatment initiation, which result in the potential improvement of clinical outcomes. Disease-modifying treatment with enzyme replacement therapy has partially altered the natural history of the disease, but more efficacious novel therapies are under evaluation including second-generation enzyme replacement therapies, molecular chaperones and gene therapy approaches. Long-term survivors with Pompe disease are now manifesting novel aspects of the disease including widespread vascular disease, smooth muscle and central nervous system involvement, and these emerging phenotypes will require additional specific therapeutic approaches.
Diagnosis, treatment, and care of inborn errors of metabolism require well organized interdisciplinary teams. Holistic approaches comprise the system of all elements and relations between elements necessary for an optimal function of the system.
Following the rule “structure follows function” based on scientific, academic, and clinical experience the elements of the system providing diagnosis, treatment, and care for inborn errors of metabolism are defined and described.
A holistic approach to inborn errors of metabolism comprising 10 elements is suggested, established, and controlled by an interdisciplinary metabolic team organized as a disease, and a case management program based on evidence-based guidelines is suggested. Quality assurance and quality control will not only improve the treatment of the individual but also the health system.
The holistic approach is a joint project of the team of health care professionals and the person with a condition, allowing them to see the patient’s individual medical, behavioral, social, legal, and economic context. For practical, technical, and economic reasons this will only be possible in centers caring for a critical number of individuals.