Fig 1 - uploaded by Carol Margolis
Content may be subject to copyright.
Mucopolysaccharidosis type VI Great Dane puppy. 4 months of age. The puppy has stunted growth and swollen joints and paws.
Source publication
Mucopolysaccharidoses are inherited metabolic disorders that result from a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans. Lysosomal glycosaminoglycan accumulation results in cell and organ dysfunction. This study characterized the phenotype and genotype of mucopolysaccharidosis VI in a Great Dane puppy with clini...
Contexts in source publication
Context 1
... proband (Fig. 1) was referred to the Pediatrics, Genetics and Reproduction Clinic at the School of Veterinary Medicine of the University of Pennsylvania. In addition to the previously noted clinicopathologic and imaging manifestations, mild cor- neal opacities, facial dysmorphia, and muzzle sloping, with a prominence of the rostral ventral mandible, ...
Context 2
... proband (Fig. 1) was referred to the Pediatrics, Genetics and Reproduction Clinic at the School of Veterinary Medicine of the University of Pennsylvania. In addition to the previously noted clinicopathologic and imaging manifestations, mild cor- neal opacities, facial dysmorphia, and muzzle sloping, with a prominence of the rostral ventral mandible, ...
Similar publications
Mucopolysaccharidosis are a group of rare inherited lysosomal storage disorder. The incidence of MPS type VI (Maroteaux-Lamy syndrome) is 0.36 to 1.30 per 100,000. It has autosomal recessive inheritance and is caused due to mutation in ARSB gene located on chromosome 5. This mutation causes absent or reduced production of N-acety-l galactosamine 6...
Enzyme replacement therapy shows remarkable clinical improvement in treating lysosomal storage disorders. However, this therapeutic approach is hampered by limitations in the delivery of the enzyme to cells and tissues. Therefore, there is an urgent, unmet clinical need to develop new strategies to enhance the enzyme delivery to diseased cells. Gra...
![Interpretation of the Berry spot test [17]](publication/332405207/figure/fig1/AS:961902272344092@1606346781824/Interpretation-of-the-Berry-spot-test-17_Q320.jpg)
Mucopolysaccharidosis VI is a rare autosomal recessive disorder caused by the deficiency of enzyme Arylsulfatase B. The enzyme deficiency leads to the accumulation of dermatan sulfate in connective tissue which causes manifestations related to MPS VI. Up to now, three different disease causing variants are reported in Iranian patients. In this stud...
Background
Mucopolysaccharidosis type VI (MPS VI) is a rare autosomal recessive inherited disease caused by mutations in the arylsulfatase B ( ARSB ) gene. MPS VI is a multisystemic disease resulting from a deficiency in arylsulfatase B causing an accumulation of glycosaminoglycans in the tissues and organs of the body.
In this report, we present t...
Mucopolysaccharidosis VI is a genetic disorder affecting multiple organs with sundry clinical presentations. The main etiological factor reflects the disturbances in mucopolysaccharide metabolism leading to deposition of acid mucopolysaccharide in various tissues. The pathognomonic features of the disease include a large head, short neck, corneal o...
Citations
... Mucopolysaccharidoses cause adverse effects to various tissues, while gangliosidoses mainly affect the central nervous system, being more severe and having early fatal forms. [98][99][100][101][102][103][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148] ...
... There are peroxisomal disorders (e.g., acatalasemia, primary hyperoxaluria type 1), 60,109 mitochondrial disorders (e.g., pyruvate dehydrogenase phosphatase deficiency) 18 and lysosomal disorders (e.g., glycogen storage diseases, mucopolysaccharidoses, neuronal ceroid lipofuscinoses). [55][56][57][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168][169][170][171][172] The various glycogen degradation disorders are called glycogenoses; oligosaccharide degradation disorders are oligosaccharidoses (e.g., beta-mannosidosis, fucosidosis) 63,81 ; glycosaminoglycans (mucopolysaccharides) degradation disorders are mucopolysaccharidoses; ganglioside degradation disorders are gangliosidoses; and so on. When the molecules mentioned are not degraded, they accumulate in lysosomes and the diseases they cause form a large group known as lysosomal storage diseases, which also includes diseases resulting from the storing of other molecules, such as Krabbe disease (globoid cell leukodystrophy), 193 Gaucher disease, 219 and Batten disease (neuronal ceroid lipofuscinoses). ...
... In disorders where there is a deficiency of molecules or defects in cell trafficking and processing, there may be a need for specific blood tests or the use of next-generation sequencing tools. 2,6,220 Examples of this group are mucopolysaccharidoses, [134][135][136][137][138][139][140][141][142][143][144][145][146][147][148] neuronal ceroid lipofuscinoses, 154-172 fucosidosis, 81 beta-mannosidosis, 63 glycogen storage diseases including Lafora disease 55-59 and intestinal lipid malabsorption. 119 Group 3-Energy Metabolism Disorders. ...
Inborn errors of metabolism are genetic disorders caused by a block in a metabolic pathway, affecting both humans and animals. Individually, they are rare diseases, but as a group they are relatively common. As most of them have recessive inheritance, a new case may seem like just a sporadic case. The high degree of inbreeding in dog breeds increases the frequency of heterozygotes in populations, maintaining mutations (variants) in healthy individuals and, consequently, increasing the risk of disease recurrence (homozygotes). General practitioners' familiarization with this subject is a significant factor in identifying new cases, contributing to increased knowledge about inborn errors of metabolism and their control. To help general practitioners, we use a clinical genetics approach covering key genetic, metabolic, diagnostic, and therapeutic aspects, offering an overview that integrates knowledge about these diseases in dogs and humans.
... Mutations in ARSB that result in a defective protein (i.e. enzyme deficiency) are known to be causal for the lysosomal storage disease known as Mucopolysaccharidosis (MPS) Type VI; with the concentration of urinary GAGs generally presenting as 5-100 times higher in patients with various forms of MPS (Pastores and Maegawa 2013;Sun et al. 2015;Vairo et al. 2015;Malekpour et al. 2018;Wang et al. 2018). Interestingly, the metabolism of GAGs is also known to be impaired in both humans and animals suffering from prion disease; with the degradation of GAGs disrupted by their interaction with PrP Sc , thus resulting in their accumulation and secretion in urine (Mayer-Sonnenfeld et al. 2005). ...
Despite implementation of enhanced management practices, chronic wasting disease in US white-tailed deer (Odocoileus virginianus) continues to expand geographically. Herein, we perform the largest genome-wide association analysis to date for chronic wasting disease (n = 412 chronic wasting disease-positive; n = 758 chronic wasting disease-nondetect) using a custom Affymetrix Axiom single-nucleotide polymorphism array (n = 121,010 single-nucleotide polymorphisms), and confirm that differential susceptibility to chronic wasting disease is a highly heritable (h2= 0.611 ± 0.056) polygenic trait in farmed US white-tailed deer, but with greater trait complexity than previously appreciated. We also confirm PRNP codon 96 (G96S) as having the largest-effects on risk (P ≤ 3.19E-08; phenotypic variance explained ≥ 0.025) across 3 US regions (Northeast, Midwest, South). However, 20 chronic wasting disease-positive white-tailed deer possessing codon 96SS genotypes were also observed, including one that was lymph node and obex positive. Beyond PRNP, we also detected 23 significant single-nucleotide polymorphisms (P-value ≤ 5E-05) implicating ≥24 positional candidate genes; many of which have been directly implicated in Parkinson's, Alzheimer's and prion diseases. Genotype-by-environment interaction genome-wide association analysis revealed a single-nucleotide polymorphism in the lysosomal enzyme gene ARSB as having the most significant regional heterogeneity of effects on chronic wasting disease (P ≤ 3.20E-06); with increasing copy number of the minor allele increasing susceptibility to chronic wasting disease in the Northeast and Midwest; but with opposite effects in the South. In addition to ARSB, 38 significant genotype-by-environment single-nucleotide polymorphisms (P-value ≤ 5E-05) were also detected, thereby implicating ≥ 36 positional candidate genes; the majority of which have also been associated with aspects of Parkinson's, Alzheimer's, and prion diseases.
... Although at the time of the first mouse generation, when both the cat and rat models were available, the small mouse model surely presented important advantages vs. the available larger models, in terms of lifespan and breeding [122]. [124]). (b) Siamese cat spontaneous mutant (reproduced with permission from [125]). ...
... Great Dane dog Spontaneous [124] Most models very much resemble the human MPS VI pathology, or at least many aspects of it [125]. Being the only model available for more than 15 years, the cat was the most used animal. ...
... Cytoplasmic vacuolation was found in corneal and uveal stroma, heart valves, Kupffer cells and spleen macrophages. Moreover, the trachea and ribs contained severe cytoplasmic vacuolation in chondrocytes and fibroblasts [124]. ...
Mucopolysaccharidosis type VI, or Maroteaux–Lamy syndrome, is a rare, autosomal recessive genetic disease, mainly affecting the pediatric age group. The disease is due to pathogenic variants of the ARSB gene, coding for the lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). The enzyme deficit causes a pathological accumulation of the undegraded glycosaminoglycans dermatan-sulphate and chondroitin-sulphate, natural substrates of ASB activity. Intracellular and extracellular deposits progressively take to a pathological scenario, often severe, involving most organ-systems and generally starting from the osteoarticular apparatus. Neurocognitive and behavioral abilities, commonly described as maintained, have been actually investigated by few studies. The disease, first described in 1963, has a reported prevalence between 0.36 and 1.3 per 100,000 live births across the continents. With this paper, we wish to contribute an updated overview of the disease from the clinical, diagnostic, and therapeutic sides. The numerous in vitro and in vivo preclinical studies conducted in the last 10–15 years to dissect the disease pathogenesis, the efficacy of the available therapeutic treatment (enzyme replacement therapy), as well as new therapies under study are here described. This review also highlights the need to identify new disease biomarkers, potentially speeding up the diagnostic process and the monitoring of therapeutic efficacy.
... It is an autosomal recessive lysosomal storage disease and is associated with early onset and progressive oculoskeletal signs. MPS VI has been described at the molecular genetic level in humans (Tomanin et al. 2018), rodents (Kunieda et al. 1995;Evers et al. 1996), cats (Crawley et al. 1998) and dogs (Jolly et al. 2012;Wang et al. 2018). Over the past two decades, MPS VI has been described in a few isolated dogs of different breeds (OMIA 000666-9615), such as one Miniature/Toy Poodle (Jolly et al. 2012), one Great Dane (Wang et al. 2018), Miniature Pinschers (Neer et al. 1995) and Miniature Schnauzers (P erez et al. 2015). ...
... MPS VI has been described at the molecular genetic level in humans (Tomanin et al. 2018), rodents (Kunieda et al. 1995;Evers et al. 1996), cats (Crawley et al. 1998) and dogs (Jolly et al. 2012;Wang et al. 2018). Over the past two decades, MPS VI has been described in a few isolated dogs of different breeds (OMIA 000666-9615), such as one Miniature/Toy Poodle (Jolly et al. 2012), one Great Dane (Wang et al. 2018), Miniature Pinschers (Neer et al. 1995) and Miniature Schnauzers (P erez et al. 2015). This study documents ARSB gene variants in Miniature Pinscher and Miniature Schnauzer dogs with MPS VI. ...
... Interestingly, the first exon of the ARSB gene appears to be a common site for disease-associated variants in dogs and in human patients. Specifically, the reported deletion in the MPS VI-affected Miniature/Toy Poodle (Jolly et al. 2012) and the nonsense variant in the affected Great Dane (Wang et al. 2018) were located in the first exon of ARSB. Likewise, 36 of the human pathogenic or likely pathogenic variants listed in CLINVAR are also in exon 1. ...
Mucopolysaccharidosis (MPS) VI is a lysosomal storage disease caused by a deficiency of N‐acetylgalactosamine‐4‐sulfatase, also called arylsulfatase B (ARSB, EC 3.1.6.12). Dogs with MPS VI show progressive predominantly oculoskeletal signs homologous to those in human and feline patients. We report herein two pathogenic ARSB gene variants in Miniature Pinscher and Miniature Schnauzer dogs with MPS VI and a genotyping survey in these breeds. All exons and adjacent regions of the ARSB gene were sequenced from three affected Miniature Pinschers and three affected Miniature Schnauzers. Allelic discrimination assays were used for genotyping. A missense variant (NM_001048133.1:c.910G>A) was found in exon 5 of MPS VI‐affected Miniature Pinschers that is predicted to result in a deleterious amino acid substitution of a highly conserved glycine to arginine (NP_001041598.1:p.Gly304Arg). In MPS VI‐affected Miniature Schnauzers, a 56 bp deletion (NM_001048133.1:c.‐24_32del) was found at the junction of exon 1 and its upstream region, predicting no enzyme synthesis. All clinically affected Miniature Pinschers and Miniature Schnauzers were homozygous for the respective variants, and screened healthy dogs in each breed were either heterozygous or homozygous for the wt allele. Whereas the Miniature Pinscher variant seemed to occur commonly (0.133 allele frequency), the Miniature Schnauzer variant was presumed to be rare. In conclusion, two breed‐specific pathogenic ARSB gene variants were identified in Miniature Pinscher and Miniature Schnauzer dogs with MPS VI, allowing for genotyping and informed breeding to prevent the production of affected offspring.
... There are up to 12 individual MPS types described in humans 1 and animals 2 with all but MPS II showing autosomal recessive inheritance. Genetic variants in dogs have been identified in the genes associated with MPS I 3 , IIIA 4,5 , VI 6,7 , and VII 8,9 . Clinical manifestations of MPS in dogs are most commonly ocular and musculoskeletal 2 . ...
Mucopolysaccharidosis (MPS) IIIB (Sanfilippo syndrome B; OMIM 252920), is a lysosomal storage disease with progressive neurological signs caused by deficient activity of alpha-N-acetylglucosaminidase (NAGLU, EC 3.2.1.50). Herein we report the causative variant in the NAGLU gene in Schipperke dogs and a genotyping survey in the breed. All six exons and adjacent regions of the NAGLU gene were sequenced from six healthy appearing and three affected Schipperkes. DNA fragment length and TaqMan assays were used to genotype privately owned Schipperkes. A single variant was found in exon 6 of MPS IIIB affected Schipperkes: an insertion consisting of a 40–70 bp poly-A and an 11 bp duplication of the exonic region preceding the poly-A (XM_548088.6:c.2110_2111ins[A(40_70);2100_2110]) is predicted to insert a stretch of 13 or more lysines followed by either an in-frame insertion of a repeat of the four amino acids preceding the lysines, or a frameshift. The clinically affected Schipperkes were homozygous for this insertion, and the sequenced healthy dogs were either heterozygous or homozygous for the wild-type allele. From 2003–2019, 3219 Schipperkes were genotyped. Of these, 1.5% were homozygous for this insertion and found to be clinically affected, and 23.6% were heterozygous for the insertion and were clinically healthy, the remaining 74.9% were homozygous for the wild-type and were also clinically healthy. The number of dogs homozygous and heterozygous for the insertion declined rapidly after the initial years of genotyping, documenting the benefit of a DNA screening program in a breed with a small gene pool. In conclusion, a causative NAGLU variant in Schipperke dogs with MPS IIIB was identified and was found at high frequency in the breed. Through genotyping and informed breeding practices, the prevalence of canine MPS IIIB has been drastically reduced in the Schipperke population worldwide.
... ARSB is the causative gene for the human disorder mucopolysaccharidosis type VI (Maroteaux Lamy Syndrome), which is associated with short stature and with facial dysmorphism (Azevedo et al. 2004). Similar phenotypes caused by mutations to an orthologous gene have also been noted in dogs (Wang et al. 2018). ...
Convergent evolution is often documented in organisms inhabiting isolated environments with distinct ecological conditions and similar selective regimes. Several Central America islands harbor dwarf Boa populations that are characterized by distinct differences in growth, mass, and craniofacial morphology, which are linked to the shared arboreal and feast-famine ecology of these island populations. Using high-density RADseq data, we inferred three dwarf island populations with independent origins and demonstrate that selection, along with genetic drift, has produced both divergent and convergent molecular evolution across island populations. Leveraging whole genome resequencing data for 20 individuals and a newly annotated Boa genome, we identify four genes with evidence of phenotypically-relevant protein-coding variation that differentiate island and mainland populations. The known roles of these genes involved in body growth (PTPRS, DMGDH, and ARSB), circulating fat and cholesterol levels (MYLIP), and craniofacial development (DMGDH and ARSB) in mammals link patterns of molecular evolution with the unique phenotypes of these island forms. Our results provide an important genome-wide example for quantifying expectations of selection and convergence in closely related populations. We also find evidence at several genomic loci that selection may be a prominent force of evolutionary change - even for small island populations for which drift is predicted to dominate. Overall, while phenotypically convergent island populations show relatively few loci under strong selection, infrequent patterns of molecular convergence are still apparent and implicate genes with strong connections to convergent phenotypes.
Hereditary neurological conditions documented in dogs encompass congenital, neonatal, and late-onset disorders, along with both progressive and non-progressive forms. In order to identify the causal variant of a disease, the main two approaches are genome-wide investigations and candidate gene investigation. Online Mendelian Inheritance in Animals currently lists 418 Mendelian disorders specific to dogs, of which 355 have their likely causal genetic variant identified. This review aims to summarize the current knowledge on the canine nervous system phenes and their genetic causal variant. It has been noted that the majority of these diseases have an autosomal recessive pattern of inheritance. Additionally, the dog breeds that are more prone to develop such diseases are the Golden Retriever, in which six inherited neurological disorders with a known causal variant have been documented, and the Belgian Shepherd, in which five such disorders have been documented. DNA tests can play a vital role in effectively managing and ultimately eradicating inherited diseases.
A 7-month-old Doberman Pinscher dog presented with progressive neurological signs and brain atrophy suggestive of a hereditary neurodegenerative disorder. The dog was euthanized due to the progression of disease signs. Microscopic examination of tissues collected at the time of euthanasia revealed massive accumulations of vacuolar inclusions in cells throughout the central nervous system, suggestive of a lysosomal storage disorder. A whole genome sequence generated with DNA from the affected dog contained a likely causal, homozygous missense variant in MAN2B1 that predicted an Asp104Gly amino acid substitution that was unique among whole genome sequences from over 4000 dogs. A lack of detectable α-mannosidase enzyme activity confirmed a diagnosis of a-mannosidosis. In addition to the vacuolar inclusions characteristic of α-mannosidosis, the dog exhibited accumulations of autofluorescent intracellular inclusions in some of the same tissues. The autofluorescence was similar to that which occurs in a group of lysosomal storage disorders called neuronal ceroid lipofuscinoses (NCLs). As in many of the NCLs, some of the storage bodies immunostained strongly for mitochondrial ATP synthase subunit c protein. This protein is not a substrate for α-mannosidase, so its accumulation and the development of storage body autofluorescence were likely due to a generalized impairment of lysosomal function secondary to the accumulation of α-mannosidase substrates. Thus, it appears that storage body autofluorescence and subunit c accumulation are not unique to the NCLs. Consistent with generalized lysosomal impairment, the affected dog exhibited accumulations of intracellular inclusions with varied and complex ultrastructural features characteristic of autophagolysosomes. Impaired autophagic flux may be a general feature of this class of disorders that contributes to disease pathology and could be a target for therapeutic intervention. In addition to storage body accumulation, glial activation indicative of neuroinflammation was observed in the brain and spinal cord of the proband.
The present case report describes the clinical signs of a 10-month-old, intact female, Domestic Shorthair cat presented with a history of chronic progressive difficulty to walk with the four limbs. The physical and neurological examinations revealed skeletal deformities, corneal opacity and a severe spastic non-ambulatory tetraparesis. Complete blood count and biochemistry profiles were unremarkable. Diffuse bone rarefaction, hyperostosis and an apparent fusion of the vertebral bodies were observed on spinal radiographs. A non-contrast computed tomography (CT) exam of the whole body of the patient was performed. Based on the medical history, clinical findings, laboratory analysis, spinal radiographs and CT findings, a lysosomal storage disorder was suspected. Genetic testing for mucopolysaccharidosis VI and VII revealed a genetic mutation, ARSB variant L476P, confirming the diagnosis of mucopolysaccharidosis type VI.
Genetic information is inherited from parents to offspring. Typically, this information provides instructions to produce proteins that determine chemical and physical traits, including hematologic diseases. The genetic basis for hematologic disease is determined by the inheritance of genes containing specific DNA mutations. DNA variations commonly used in genetic analyses include: single‐nucleotide polymorphisms and insertion/deletion polymorphisms. Reliable evaluation of regulation of gene expressions is required for the understanding of the connection between genotype and phenotype. Screening for a genetic disorder is indicated when there is familial disease presentation, young age of onset, or when routine CBC, biochemistry, or urinalysis suggest known inherited disorders. Genetic or DNA testing identifies disease‐causing mutations in genes. DNA mutation tests are laboratory assays that need to be validated; however, validation is not commonly documented for DNA tests of veterinary species.
