blackboard codon calcification

What is the most common mutation in NGD?

The most common mutation is Asn409Ser amino acid substitution . It is empirically regarded as associated exclusively with nonneuronopathic disease, and the clinical manifestations can be relatively mild, particularly in homozygotes. 47 Patients who are either homozygous or compound-heterozygous for certain mutations, such as Leu483Pro and Asp448His, are at high risk of developing central nervous system (CNS) involvement. Homozygosity for Leu483Pro is the most common NGD genotype. 48 In Japan, Leu483Pro accounts for 41% of all disease alleles. 17 Sixteen consecutive patients with progressive myoclonic encephalopathy had a total of 14 different genotypes. 28 However, mutations Val433Leu, Asn227Ser, and Gly416Ser are often associated with progressive myoclonic encephalopathy, although each has been seen with other forms of Gaucher disease. 28 On the other hand, mutation Arg502Cys and homozygosity for Leu483Pro are rarely associated with myoclonic seizures. The reason for this phenotypic selectivity is unknown. A form of Gaucher disease type 3 with cardiac valvular and aortic calcifications, hydrocephalus, corneal opacity occur only in p.Asp448His/p.Asp448His – previously known as D409H/D409H.

What is the other consistent feature in NGD?

The other consistent feature in NGD is an abnormality of brainstem auditory evoked potentials. Waveforms are poor and show progressive deterioration over time. 36 Apart from reflecting brainstem dysfunction, the significance of this finding is unclear, as most patients have normal peripheral hearing.

What are the clinical aspects of NGD?

The two main clinical aspects of NGD should guide the differential diagnosis. Other disorders that present with liver or spleen involvement are one important group. Besides acquired malignancy or infections such as Epstein–Barr virus-associated infectious mononucleosis, other lysosomal storage disorders such as Niemann–Pick A, B, or C often present with organomegaly, although the liver often is relatively more enlarged than the spleen. The neurological differential diagnosis should include disorders associated with supranuclear gaze palsy such as Niemann–Pick in all its neurologic variants (especially C, in which the vertical movements are predominantly affected), ataxia telangiectasia, cerebellar hypoplasia such as Joubert syndrome, Huntington disease, as well as acquired diseases. 67 Diseases that are associated with progressive myoclonic epilepsy should be considered in the differential diagnosis of the myoclonic variant of Gaucher disease including the disorder (with or without renal dysfunction) related to SCARB2 (scavenger receptor class B member 2 protein) gene mutations encoding lysosomal integral membrane protein type 2 (LIMP2). 42., 68.

What is cathepsin D in neuronal loss?

Cathepsin D elevation in microglia of the nestin- flox/flox neuronopathic Gaucher mouse was found in areas where neuronal loss, astrogliosis, and microgliosis were observed, such as in layer 5 of the cerebral cortex, the lateral globus pallidus, various thalamic nuclei, and other brain regions known to be affected in NGD. 62 In the same animal model, levels of mRNA expression of IL-1β, TNF-α, TNF-α receptor, macrophage colony-stimulating factor, and transforming growth factor-β were elevated by up to −30-fold. 63 The chemokines CCL2, CCL3, and CCL5 were very much elevated and all in a time course that paralleled the disease severity. 63 Blood–brain barrier and excess oxidative stress were also found. Based on these results, the authors suggested that once a critical threshold of glucosylceramide storage is reached in neurons, a signaling cascade is triggered that activates microglia, which in tum release inflammatory cytokines that amplify the inflammatory response, contributing to neuronal death. 57 Neuro-inflammation and neuronal loss in susceptible brain areas were detected prior to the noticeable behavioral signs, linking these to early pathogenic stages. 53., 63.

What is the first mouse model of Gaucher disease?

Generation of the first genetic mouse model of Gaucher disease was based on the production of a null glucocerebrosidase allele ( the gba −I− mouse). However, this mouse died soon after birth due to a skin permeability disorder before significant CNS damage occurred, and this model, therefore, was not useful for studying the long-term effects of glucosylceramide accumulation. 24 Another Gaucher disease mouse model, the Leu483Pro mouse, which carries a mutation most commonly leading to neuronopathic Gaucher in humans, did not accumulate significant glucosylceramide levels and did not display CNS pathology. 57., 58. Mouse models of NGD have been particularly useful for elucidating the cascade of events between the primary defect and cellular death. The most useful model has been the Gba flox/flox; nestin-Cre mouse. 52 Hematopoietic derived cells of this mouse model have normal glucocerebrosidase activity, thus producing a mouse in which glucocerebrosidase deficiency is limited to neurons and astrocytes. Interestingly, this mouse model survives 1 week longer (3 weeks vs 2) thus confirming the clinical impression that normal glucocerebrosidase activity in macrophages does not appreciably modify the course of neurological Gaucher disease. 52 A nongenetic biochemical manner of obtaining a Gaucher model has been the use of conduritol-B-epoxide (CBE), an irreversible inhibitor of glucocerebrosidase, both in cultured cells and in wild-type mice. Various concentrations of CBE lead to correspondingly different residual enzyme activity levels. 53 Recent studies in neuronopathic Gaucher mouse models defined the anatomical course of the disease, the selective neuronal vulnerability, the mechanism of inflammation and neuronal cell death, the degree to which the neurological disease is reversible, and candidate disease modifying genes. 50., 53., 59., 60., 61.

What is the condition of a collodion baby?

Congenital Gaucher disease leading to a form of “collodion baby” is associated with the virtual absence of residual GBA activity, an association that was first reported in 1988. 19., 22. These newborns are dead at parturition or die within the first few days of life, at least partly due to the excessive water evaporation caused by the abnormal lipid composition of the epidermis. 23 There have been several reports of this variant in the literature, many associated with hydrops foetalis. 19 The phenotype appears to be analogous to that of the null-allele mouse, which was created by the targeted disruption of the GBA1 gene. 24

What is Gaucher disease?

Gaucher disease is one of the most prevalent hereditary lipid storage disorders in humans. Patients are classified into three phenotypes depending on whether the central nervous system (CNS) is involved and on the age of onset of clinical manifestations. This autosomal recessive disorder is caused by mutations in the GBA1 gene leading to insufficient activity of the hydrolase glucocerebrosidase. This results in the accumulation of glucocerebroside in macrophages, and in some cases, in cells of the CNS. The systemic manifestations of the disease are hepatosplenomegaly, anemia, thrombocytopenia, and destructive skeletal disease. The neurological manifestations consist of supranuclear gaze palsy, variable cognitive dysfunction, movement disorders, and sometimes a progressive myoclonic encephalopathy. Glucocerebrosidase activity in peripheral blood white cells and the identification of biallelic GBA1 mutations confirm the diagnosis. Current research is focused on correcting the primary metabolic defect in the CNS and understanding the pathogenesis of the disease. The latter will likely lead to therapeutic approaches designed to counteract the downstream effects of glucocerebrosidase deficiency.