•GM2 gangliosidoses are a disease continuum dependent on residual enzyme activity.•Developmental and degenerative events are part of Infantile GM2 gangliosidoses.•Infantile GM2 gangliosidoses targets ...gray matter, white matter, and the retina.•Late-onset GM2 gangliosidoses targets preferentially the spinal cord and cerebellum.•Late-onset GM2 gangliosidoses has features akin to other neurodegenerative diseases.•Animal and cell-based GM2 gangliosidoses models inform biology and therapeutics.•Some clinical features may distinguishing late-onset Tay-Sachs from Sandhoff disease.•Impact of future therapies depends on pre-treatment disease burden.•The time from symptom onset to molecular diagnosis remains unacceptably protracted.
The sphingolipid (SL) metabolic pathway generates structurally diverse lipids that have roles as membrane constituents and as bioactive signaling molecules. The influence of the SL metabolic pathway ...in biology is pervasive; it exists in all mammalian cells and has roles in many cellular and physiological pathways. Human genetic diseases have long been recognized to be caused by mutations in the pathway, but until recently these mutational defects were only known to affect lysosomal SL degradation. Now, with a nearly complete delineation of the genes constituting the SL metabolic pathway, a growing number of additional genetic disorders caused by mutations in genes within other sectors of the pathway (de novo ceramide synthesis, glycosphingolipid synthesis, and nonlysosomal SL degradation) have been recognized. Although these inborn disorders of SL metabolism are clinically heterogeneous, some common pathogenic mechanisms, derived from the unique properties and functions of the SLs, underlie several of the diseases. These mechanisms include overaccumulation of toxic or bioactive lipids and the disruption of specific critical cellular and physiological processes. Many of these diseases also have commonalities in physiological systems affected, such as the nervous system and skin. While inborn disorders of SL metabolism are rare, gene variants in the pathway have been linked to increased susceptibility to Parkinson's disease and childhood asthma, implying that the SL metabolic pathway may have a role in these disorders. A more complete understanding of the inborn errors of SL metabolism promises new insights into the convergence of their pathogenesis with those of common human diseases. Display omitted
The inability of some seriously and chronically ill individuals to receive a definitive diagnosis represents an unmet medical need. In 2008, the NIH Undiagnosed Diseases Program (UDP) was established ...to provide answers to patients with mysterious conditions that long eluded diagnosis and to advance medical knowledge.
Patients admitted to the NIH UDP undergo a five-day hospitalization, facilitating highly collaborative clinical evaluations and a detailed, standardized documentation of the individual's phenotype. Bedside and bench investigations are tightly coupled. Genetic studies include commercially available testing, single nucleotide polymorphism microarray analysis, and family exomic sequencing studies. Selected gene variants are evaluated by collaborators using informatics, in vitro cell studies, and functional assays in model systems (fly, zebrafish, worm, or mouse).
In seven years, the UDP received 2954 complete applications and evaluated 863 individuals. Nine vignettes (two unpublished) illustrate the relevance of an undiagnosed diseases program to complex and common disorders, the coincidence of multiple rare single gene disorders in individual patients, newly recognized mechanisms of disease, and the application of precision medicine to patient care.
The UDP provides examples of the benefits expected to accrue with the recent launch of a national Undiagnosed Diseases Network (UDN). The UDN should accelerate rare disease diagnosis and new disease discovery, enhance the likelihood of diagnosing known diseases in patients with uncommon phenotypes, improve management strategies, and advance medical research.
•In 7 years, NIH’s Undiagnosed Diseases Program saw 863 individuals, undiagnosed after thorough evaluation elsewhere.•After record review, a one-week hospitalization included multiple consultations, targeted tests, and DNA sequencing.•9 vignettes with 20 patients illustrate successful diagnoses including arterial calcification due to deficiency of CD73.•The vignettes show relevance to common disorders, newly recognized disease mechanisms and the future of precision medicine.
Lysosomal storage diseases (LSDs) are a group of over 70 diseases that are characterized by lysosomal dysfunction, most of which are inherited as autosomal recessive traits. These disorders are ...individually rare but collectively affect 1 in 5,000 live births. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most LSDs have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. LSD-associated genes encode different lysosomal proteins, including lysosomal enzymes and lysosomal membrane proteins. The lysosome is the key cellular hub for macromolecule catabolism, recycling and signalling, and defects that impair any of these functions cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, 'storage') or impair the transport of molecules, which can result in cellular damage. Consequently, the cellular pathogenesis of these diseases is complex and is currently incompletely understood. Several LSDs can be treated with approved, disease-specific therapies that are mostly based on enzyme replacement. However, small-molecule therapies, including substrate reduction and chaperone therapies, have also been developed and are approved for some LSDs, whereas gene therapy and genome editing are at advanced preclinical stages and, for a few disorders, have already progressed to the clinic.
Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of β-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its ...substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses.
GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the
gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to ...the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult), based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the
gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the
murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three
gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).
Abstract
P/Q-type Ca
2+
currents mediated by Ca
V
2.1 channels are essential for active neurotransmitter release at neuromuscular junctions and many central synapses. Mutations in
CACNA1A
, the gene ...encoding the principal Ca
V
2.1 α
1A
subunit, cause a broad spectrum of neurological disorders. Typically, gain-of-function (GOF) mutations are associated with migraine and epilepsy while loss-of-function (LOF) mutations are causative for episodic and congenital ataxias. However, a cluster of severe Ca
V
2.1 channelopathies have overlapping presentations which suggests that channel dysfunction in these disorders cannot always be defined bimodally as GOF or LOF. In particular, the R1667P mutation causes focal seizures, generalized hypotonia, dysarthria, congenital ataxia and, in one case, cerebral edema leading ultimately to death. Here, we demonstrate that the R1667P mutation causes both channel GOF (hyperpolarizing voltage-dependence of activation, slowed deactivation) and LOF (slowed activation kinetics) when expressed heterologously in tsA-201 cells. We also observed a substantial reduction in Ca
2+
current density in this heterologous system. These changes in channel gating and availability/expression manifested in diminished Ca
2+
flux during action potential-like stimuli. However, the integrated Ca
2+
fluxes were no different when normalized to tail current amplitude measured upon repolarization from the reversal potential. In summary, our findings indicate a complex functional effect of R1667P and support the idea that pathological missense mutations in Ca
V
2.1 may not represent exclusively GOF or LOF.
As part of a late onset GM2 gangliosidosis natural history study, digital health technology was utilized to monitor a group of patients remotely between hospital visits. This approach was explored as ...a means of capturing continuous data and moving away from focusing only on episodic data captured in traditional study designs. A strong emphasis was placed on real-time capture of symptoms and mobile Patient Reported Outcomes (mPROs) to identify the disease impact important to the patients themselves; an impact that may not always correlate with the measured clinical outcomes assessed during patient visits. This was supported by passive, continuous data capture from a wearable device. Adherence rate for wearing the device and completing the mPROs was 84 and 91%, respectively, resulting in a rich multidimensional dataset. As expected for a six-month proof-of-concept study in a disease that progresses slowly, statistically significant changes were not expected or observed in the clinical, mPROs, or wearable device data. The study demonstrated that patients were very enthusiastic and motivated to engage with the technology as demonstrated by excellent compliance. The combination of mPROs and wearables generates feature-rich datasets that could be a useful and feasible way to capture remote, real-time insight into disease burden.
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