Whole Exome Sequencing detects PYGM variants in two adults with McArdle disease

McArdle disease is a progressive and debilitating glycogen storage disease with typical onset in late childhood. Here we describe a former competitive athlete with early adult onset McArdle disease and a septuagenarian with a history of exercise-intolerance since adolescence who was evaluated for proximal muscle weakness. Exome sequencing identified bi-allelic variants in PYGM gene for both cases. The former athlete has the common, well-known pathogenic variant p.(Arg50Ter) in trans with a novel missense variant, p.(Asp694Glu). The second individual has a previously described homozygous missense variant, p.(Arg771Gln). Here, we describe the clinical course, enzyme-testing results using muscle tissue and molecular findings for the individuals, and add to the knowledge of the genotypic spectrum of this disorder.

Exosomal MicroRNAs as Potential Biomarkers of Hepatic Injury and Kidney Disease in Glycogen Storage Disease Type Ia Patients

Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α). Affected individuals develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma and kidney failure. The purpose of this study was to identify potential biomarkers of the evolution of the disease in GSDIa patients. To this end, we analyzed the expression of exosomal microRNAs (Exo-miRs) in the plasma exosomes of 45 patients aged 6 to 63 years. Plasma from age-matched normal individuals were used as controls. We found that the altered expression of several Exo-miRs correlates with the pathologic state of the patients and might help to monitor the progression of the disease and the development of late GSDIa-associated complications.

Loss of Depalmitoylation Exaggerates Synaptic Upscaling and Leads to Neuroinflammation in a Lysosomal Storage Disease

Palmitoylation and depalmitoylation are the dichotomic processes of lipid modification regulating protein trafficking, recycling, and degradation, thereby controlling proteostasis. Despite our understanding of palmitoylation, depalmitoylation is far less studied. Here, we study a lysosomal depalmitoylating enzyme, palmitoyl-protein thioesterase 1 (PPT1), associated with the devastating neurodegenerative condition CLN1 disease and show that dark-rearing Ppt1-/- mice, which induces synaptic upscaling in vivo, worsen the symptoms. In Ppt1-/- cortical neurons, upscaling induction triggers exaggerated responses of synaptic calcium-permeable AMPA receptors composed of palmitoylated GluA1 subunits. Consequently, Ppt1-/- visual cortex exhibits hypersynchrony in vivo. Remarkably, we also find an overload of palmitoylated A-kinase anchor protein 5 (Akap5) in Ppt1-/- mouse brains, leading to microglial activation through NFAT. These findings indicate Ppt1 acts as a gatekeeper of homeostatic plasticity by regulating the proteostasis of palmitoylated synaptic proteins. Moreover, our results suggest that perturbed depalmitoylation results in neuroinflammation, which is common to neurodegenerative diseases.

Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargo

Progranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia, while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interactions with prosaposin, another lysosomal protein, first occur within the lumen of the endoplasmic reticulum (ER) and are required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII-coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates that a network of interactions occurring early in the secretory pathway promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.

Positioning Head Tilt in Canine Lysosomal Storage Disease: A Retrospective Observational Descriptive Study

Positioning head tilt is a neurological sign that has recently been described in dogs with congenital cerebellar malformations. This head tilt is triggered in response to head movement and is believed to be caused by a lack of inhibition of the vestibular nuclei by the cerebellar nodulus and ventral uvula (NU), as originally reported cases were dogs with NU hypoplasia. We hypothesized that other diseases, such as lysosomal storage diseases that cause degeneration in the whole brain, including NU, may cause NU dysfunction and positioning head tilt. Videos of the clinical signs of canine lysosomal storage disease were retrospectively evaluated. In addition, post-mortem NU specimens from each dog were histopathologically evaluated. Nine dogs were included, five with lysosomal storage disease, two Chihuahuas with neuronal ceroid lipofuscinosis (NCL), two Border Collies with NCL, one Shikoku Inu with NCL, two Toy Poodles with GM2 gangliosidosis, and two Shiba Inus with GM1 gangliosidosis. Twenty-eight videos recorded the clinical signs of the dogs. In these videos, positioning head tilt was observed in seven of nine dogs, two Chihuahuas with NCL, one Border Collie with NCL, one Shikoku Inu with NCL, one Toy Poodle with GM2 gangliosidosis, and two Shiba Inus with GM1 gangliosidosis. Neuronal degeneration and loss of NU were histopathologically confirmed in all diseases. As positioning head tilt had not been described until 2016, it may have been overlooked and may be a common clinical sign and pathophysiology in dogs with NU dysfunction.

Anti-Inflammatory Mesenchymal Stromal Cell-Derived Extracellular Vesicles Improve Pathology in Niemann–Pick Type C Disease

Niemann–Pick type C (NPC) disease is a rare neurovisceral lipid storage disease with progressive neurodegeneration, leading to premature death. The disease is caused by loss-of-function mutations either in the NPC1 or NPC2 gene which results in lipid accumulation in the late endosomes and lysosomes. The involved disease mechanisms are still incompletely understood, making the design of a rational treatment very difficult. Since the disease is characterized by peripheral inflammation and neuroinflammation and it is shown that extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs) provide immunomodulatory capacities, we tested the potential of MSC-EV preparations to alter NPC1 disease pathology. Here, we show that the administration of an MSC-EV preparation with in vitro and in vivo confirmed immune modulatory capabilities is able to reduce the inflammatory state of peripheral organs and different brain regions of NPC1-diseased mice almost to normal levels. Moreover, a reduction of foamy cells in different peripheral organs was observed upon MSC-EV treatment of NPC1−/− mice. Lastly, the treatment was able to decrease microgliosis and astrogliosis, typical features of NPC1 patients that lead to neurodegeneration. Altogether, our results reveal the therapeutic potential of MSC-EVs as treatment for the genetic neurovisceral lipid storage disease NPC, thereby counteracting both central and peripheral features.