Overcoming challenges in rare genetic diseases

In the past few years, substantial progress has been made towards effective treatment of Batten disease, a family of paediatric neurodegenerative lysosomal storage disorders. In this Review, the authors discuss new therapies for Batten disease, including cerliponase alfa, the first globally approved agent, and considers promising new therapeutic avenues for future treatments.

This Review presents our current understanding of C3 glomerulopathy. Smith et al. discuss the histopathological diagnosis and the crucial pathogenic role of complement dysregulation. Genetic and acquired drivers of C3 glomerulopathy, potential biomarkers and available treatments are highlighted.

Haemolytic anaemia, thrombocytopenia and microthrombi are hallmarks of thrombotic thrombocytopenic purpura (TTP), a rare microangiopathy that can cause severe ischaemic organ damage. The majority of cases have an autoimmune aetiology and, therefore, can be managed with immunosuppressive drugs, in addition to plasma therapy.

Anaemia, thrombosis and smooth muscle dystonias are manifestations of paroxysmal nocturnal haemoglobinuria, a rare but potentially life-threatening haematological disorder. Inhibition of complement activation is the treatment of choice; stem cell transplantation is recommended for patients who also develop severe bone marrow failure.

Several macromolecular structures coexist in the intercalated discs, which connect cardiomyocytes and control cell-to-cell communication. In this Perspectives article, Moncayo-Arlandi and Brugada suggest that the structures of the intercalated disc form an interactive 'connexome'. They also propose a link between arrhythmogenic cardiomyopathy and Brugada syndrome on the basis of overlapping genetic, molecular, and pathophysiological mechanisms.

Although anaplastic thyroid carcinoma (ATC) is a rare form of thyroid cancer, the limited efficacy of conventional treatment options and challenges in histological diagnosis make this an almost invariably lethal disease. In this Review, the authors describe the clinical and pathological features of ATC, highlight recent advances in uncovering the genetics and molecular biology of this disease, and discuss both conventional and future treatment modalities.

Lafora disease is an autosomal recessive, progressive myoclonus epilepsy caused by loss of function of laforin or malin, leading to impaired glycogen metabolism. The authors review the clinical and molecular features of Lafora disease and discuss current and emerging treatment options.

Here, Lam and colleagues review advances in understanding the pathogenesis of tuberous sclerosis complex (TSC). Although rapalogues are effective cytostatic treatments for TSC, the unique metabolic vulnerabilities of cells lacking hamartin and/or tuberin might represent opportunities for developing cytocidal treatments.

Wilson disease is an inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. This Primer describes the pathogenesis of this disorder and outlines diagnostic and management strategies.

Childhood-onset craniopharyngioma is a rare embryonic tumour of low-grade malignancy that has traditionally been treated by radical resection. Here, Müller and colleagues review recent advances in the molecular pathogenesis of the disease and treatment strategies that could lead to novel targeted therapies and more-limited surgeries.

In this Review, Krismer and Wenning discuss the risk factors for and the clinical presentation and neuropathology of multiple system atrophy (MSA) — a devastating and fatal neurodegenerative disorder. They provide an overview of ongoing trials and international efforts to improve care in patients with MSA.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a variable rate of cyst development, variable kidney function decline and variable presentation of renal and extrarenal manifestations. In this Review, the authors discuss pharmacological and non-pharmacological interventions for the treatment of patients with ADPKD and provide recommendations for the management of renal complications.

Lysosomal storage diseases (LSDs) are a diverse group of disorders that can manifest at any stage of life. This Primer by Platt and colleagues provides an overview of the LSDs, including how lysosomal dysfunction gives rise to disease and how these disorders are diagnosed and treated. An overview of future therapeutic targets for LSDs is also provided.

Dysfunction of endolysosomal pathways can lead to generalized dysfunction of the proximal tubule. Here, De Matteis and colleagues describe the role of the inositol polyphosphate 5-phosphatase, OCRL, in the endolysosomal pathway and how mutations in the encoding gene lead to the clinical manifestations of Lowe syndrome and Dent disease 2.

Osteogenesis imperfecta — also known as brittle bone disease — is a heterogeneous group of inherited bone dysplasias characterized by skeletal deformity and bone fragility. In this Primer, Marini et al. provide an overview of the epidemiology, genetics, pathophysiology, diagnosis and management of osteogenesis imperfecta.

One of the first manifestations of cystinosis is a renal Fanconi syndrome, characterized by severe dysfunction of proximal tubule cells. This Review describes the pathogenesis of renal Fanconi syndrome in cystinosis, focusing on the importance of cystinosin in the maintenance of cellular homeostasis beyond its function in cystine transport.

Neurofibromatosis type 1 is caused by mutations in the NF1 tumour suppressor gene. This Primer by Gutmann and colleagues discusses the genetics underlying the development of this disease, and describes the diagnosis and treatment of the widespread clinical manifestations.

Gilles de la Tourette syndrome (GTS) is a childhood-onset neurodevelopmental disorder that is characterized by several motor tics and at least one phonic tic. In this Primer, Robertson et al. describe the epidemiology, pathophysiology, diagnosis and management of GTS in detail.

The past 5 years have seen an unprecedented rate of discovery of genes that cause rare diseases and with it a commensurate increase in the number of diagnosable but nevertheless untreatable disorders. Here, we discuss the increasing opportunity for diagnosis and therapy of rare diseases and how to tackle the associated challenges.

A proportion of neurodevelopmental disorder and congenital anomaly cases remain without a genetic diagnosis. Here, the authors study aberrations of DNA methylation in such cases and find that epivariations might provide an explanation for some of these undiagnosed patients.

This Consensus Statement gives recommendations for the diagnosis and management of patients with pseudohypoparathyroidism and related disorders. A coordinated and multidisciplinary approach from infancy through adulthood is recommended to improve the care of these patients.

In this Review, a group of experts in fragile X syndrome analyses why the considerable drug development effort based on robust preclinical findings describing the mechanisms underlying this neurodevelopmental disorder has failed to translate into effective treatment and offers possible solutions to improve clinical trial design and therapeutic approaches.

Hirschsprung disease is a serious and potentially fatal condition affecting the enteric nervous system and defined by the absence of enteric neurons in the distal bowel. This Review provides an update on the basic science discoveries that link to clinical manifestations of the disease.

Rare neurological diseases require widely distributed networks of centres, investigators and patients to foster multidisciplinary investigations and recruit sufficient numbers of patients for research studies and clinical trials. In this article, Jen and colleagues highlight the role of two networks, the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and the Clinical Research Consortium for Studies of Cerebellar Ataxias (CRC-SCA), in bringing together the various stakeholders in patient-oriented research into rare neurological channelopathies.

Scientific advances, in combination with government incentives and commercial opportunity, have fuelled strong investment in orphan drugs, resulting in many innovative therapies. Here, we discuss the approach of the FDA to a range of issues that remain crucial to maintaining this momentum, such as the use of the totality of evidence in evaluating orphan drugs.

The emerging field of paediatric genomics has leveraged the power of next-generation sequencing technologies to improve the diagnostic rates of rare disease in children. This Review addresses key considerations for safe and effective implementation of genomics in the clinic.

The correction of genetic defects in utero could allow for improved outcomes of gene therapy. Here, the authors demonstrate safe delivery of nanoparticles to fetal mouse tissues, and show that nanoparticles containing peptide nucleic acids to edit the beta-globin gene are effective in a mouse model of beta-thalassemia.

Gene editing of a single gene in the brain of an adult mouse model of fragile X syndrome, achieved via the intracranial injection of a nonviral Cas9 delivery vehicle, rescues mice from the exaggerated repetitive behaviours caused by the disease.

Beckwith–Wiedemann syndrome is an overgrowth disorder characterized by variable clinical phenotypes and a complex molecular aetiology. This Consensus Statement summarizes recommendations for clinical indications, molecular diagnosis and management of the newly defined Beckwith–Wiedemann spectrum.

Genomic medicine approaches are increasingly used for diagnosis of kidney disease. Here, the authors discuss sequencing modalities, the interpretation and clinical application of genetic data, and the challenges that must be overcome to realize the potential of genomic medicine in nephrology.

This article discusses how integrating different omics data types — such as DNA sequencing, transcriptomics and metabolomics — can provide a rich view of healthy and disease states, including novel clinical diagnoses. The authors discuss the value of the different data types, as well as strategies, considerations and challenges for multi-omic integration in various disease contexts.

New therapies in development for haemophilia — including gene therapies, proteins with extended half-lives and inhibitors of natural anticoagulants — look poised to change the management of this disease. In this Review, Peters and Harris discuss recent progress, including the hurdles that still need to be overcome in order to translate these advances into routine clinical use.

The limb-girdle muscular dystrophies (LGMDs) comprise more than 30 genetically defined neuromuscular diseases that share the determining features of weakness and wasting of the pelvic and shoulder girdle muscles. Next-generation sequencing (NGS) technologies are continuing to expand the range of genes and phenotypes associated with the LGMDs. In this article, Thompson and Straub review the international collaborations that are addressing translational research issues in the LGMDs, and the lessons learned from large-scale NGS programmes.

Genome-wide sequencing (GWS) is the most sensitive test available for detecting pathogenic genetic variants but it generates complex results. It is important, therefore, that individuals undergoing GWS are offered both pre-test and post-test genetic counselling.

Hereditary colorectal cancer syndromes are associated with a high risk of developing malignancies. Despite compelling data from preclinical models, clinical studies of promising chemopreventive agents often yield conflicting results. Here, the authors discuss critical issues related to previous chemopreventive trial designs, focusing on common pitfalls and how future interventions might be improved.

For clinical cases of Mendelian disease that lack a genetic diagnosis, genome and exome sequencing are increasingly used for seeking the genetic cause. This Review discusses the strategies and computational tools for prioritizing the many genetic variants identified in each genome into those that are most likely to be causal for disease. The authors discuss how diverse types of biochemical, evolutionary, pedigree and clinical-phenotype information are used, and they highlight common pitfalls to be aware of for responsible variant prioritization.

Skeletal muscle disorders of glycogenolysis and glycolysis account for most of the conditions collectively termed glycogen storage diseases. Godfrey and Quinlivan outline the distinguishing features of these disorders, and they describe a large European registry, EUROMAC, that has been established to pool and transfer knowledge regarding McArdle disease and other rare disorders of carbohydrate metabolism.

Recent studies show that structural variation can alter the genome architecture, leading to changes in the regulation of gene expression that cause disease. The authors review the role of genetic structural variation in disease and the pathogenic potential of changes to the 3D genome.

Current approaches for diagnosing mitochondrial disorders involve specialist clinical assessment, biochemical analyses and targeted molecular genetic testing. There is now a strong rationale for undertaking first-line genome-wide sequencing, accelerating the speed of diagnosis and avoiding the need for expensive and invasive investigations.

Next-generation sequencing is fuelling a rise in the number of genomic diagnostic tests, which compete with existing interventions for limited health-care budgets. This Perspective presents key approaches and challenges that must be considered by decision-makers assessing the relative cost-effectiveness of new genomic tests.