GlcSph (continued) / GD: Dx, Epidemiology, Mutations Summary, mutation distribution
- Sema4’s kit for plasma GlcSph
- https://sema4.com/products/test-catalog/plasma-lyso-gl1-analysis/
- Lyso-GL1 is extracted from plasma, fully separated from its isomer galactosylsphingosine, and analyzed by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.
- Turnaround time: 5 days
Role of GlcSph
- I can’t find a reference
LacCer (Lactosylceramide)
- sequential precursors of all more complex GSLs
GD
Dx of GD
- See the section GBA activity (‘BGL test’)
Epidemiology of GD (prevalence)
- The annual incidence of GD in the general population is about 1/60,000
- The prevalence is approximately 1/100,000 (10/1 million). (이러면 미국 2억 인구중 2천명이 GD, 이중 100명이 type 3 (=0.5/1 million = 0.00125/2500) 3억 인구중 150명이 GD 3)
https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=355,
- Ngd: 5% of GD, 1 in 2,000,000 (1 in 2 million) this is ultra-rare because 1 in 50,000 is the definition of ultra-rare
- In Asian countries, nGD comprises approximately 60% of GD cases. The difference in nGD prevalence between Asia and Western countries is believed to result from a dissimilar GBA1 mutation distribution.
Mutations Summary
| ERAD | Ambroxol effect | GBA Protein Brain | GBA Activity Brain | GlcCer Brain | GlcSph brain | neuropathology | GD phenotype | OR for PD (2015 Gan-Or) | In PD, Sx 발현 | In PD, Acceleration | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Hetero | ↓ (80% of control, Kurzawa 2012, N370S와 L444P 비슷하게 감소) | ↓ (75% of control, Kurzawa 2012, N370S와 L444P 차이는 불확실) | No change (2015 Gegg) | No change | 3.2 | 그냥 PD 보다 심함 (L444P가 N370S보다 약간 심한 경향) (2018 Thaler) | 그냥 PD acceleration UPDRS III 시킴 (2015 Brockmann, ) | ||||
| N370S Homo | Yes (2010 Wei) | Yes (2011 Bendikov-Bar) | 별다른 감소 없는 듯 언급?(2011 chol) | ↓↓ (둘이 비슷하게) | ↑ (1985 Nilsson) | 거의 안 증가 (1985 Nilsson) | Astrogliosis without prominent neuronal loss | 그냥GD | 2.2 | 위보다도 더 심함 (2017Thaler) | 정보 없음. |
| L444 Homo | Yes (2011 Bendikov-Bar) | Yes (2011 Bendikov-Bar), No (Maegawa, J Biol Chem. 284 (2009) 23502-23516) | Greatly diminished (2011 choi) | ↓↓ (둘이 비슷하게 크게 감소, 4% of control, 2011choi) | ↑↑ (1985 Nilsson) | ↑↑ (2002 Orvisky) | Neuronal loss (type 2에서 심하고, type3에서는 일부환자), astrogliosis | nGD | 10.3 | 환자 없음 (2017 Thaler, 2018 Thaler) | |
| (2003 Schueler) GlcSph is neurotoxic |
- 즉 N370S Homo 가 L444P hetero보다 심함.
- N370S Homo 와 L444P Homo가 GBA activity감소 정도까지는 비슷한데, L444P Homo가 GlcCer를 더 올리고, GlcSph 는 더더욱 올리면서 neurologic manifestation 쪽으로 확 빠짐
| GBA activity | Correlation of GBA activity with disease severity | Onset | Phenotype | |||||
|---|---|---|---|---|---|---|---|---|
| The two most common among 300 different mutations | N370S (c.1226A > G) | ~24% of GD | non-neuronopathic | No | 23 y (Dx) |
Very varied, Milder
| 2008 Fairley Journal of Inherited Metabolic Disease December 2008, 31:738 | |
| L444P (c.1448T > C) | Neuronopathic → protein misfolding, not impairing the catalytic site, thus can be potentially rescued by small molecule chaperones | 1-13% (fibroblast) | No | 15 month |
Very varied, GBA activity: 1-13.3% of control (in fibroblast and/or EBV-transformed lymphoblast cell pellets)
| 2008 Goker-Alpan J Med Genet 2005;42:e37 (http://www.jmedgenet.com/cgi/content/full/42/6/e37). doi:10.1136/jmg.2004.028019 | ||
| N370S/L444P | Ultra-rare | Low normal | 16.9 y |
Mild
| http://www.ashg.org/2008meeting/abstracts/fulltext/f21919.htm | |||
| c.1093G > A (E326K) | homozygous E326K does not cause GD. glucosylceramide is unlikely to accumulate since residual activity is still much greater than other GBA mutations | |||||||
| c.1223C > T (T369M) | homozygous T369M does not cause GD. | |||||||
| D409H |
homozygotes (designated here as 9H) manifest early onset of variable visceral and the CNS involvement9. 9H patients also uniquely manifest calcific aortic root and valvular disease10. Mutation at this position (D409V, D409H) leads to an unstable enzymes that predisposed them to protease degradation compared to WT. |
GBA mutation distribution figure (figure labels)
Gene-diagram pointers (5’ → 3’ along exons 1-11):
- 84GG, K(-27)R, R120W, D140H, G195E, H255Q, E326K, R257Q, R359X, P266L, T369M, G377S, N370S, E388K, D409H, L444P, L444R, A456P, N462K, R463C, R463P
Pie-chart slices:
- Non-carriers 89.7% (N = 1,723)
- Carriers 10.3% (N = 198)
- E326K (79)
- T369M (46)
- N370S (28)
- E388K (2)
- Complex alleles (14)
- L444P (12)
- R463C (2)
- 84dupG (1)
- R120W (1)
- G195E (1)
- H255Q (1)
- R257Q (1)
- P266L (1)
- R359X (1)
- G377S (1)
- D409H (1)
- L444R (1)
- A456P (1)
- N462K (1)
- K(-27)R (2)
- R463P (1)
Figure caption:
FIGURE 1: Distribution of mutations in the Gaucher’s disease gene GBA among study patients with Parkinson’s disease. Over-0.3% of the 1,921 patients with Parkinson’s analyzed using sequencing were carriers of a GBA mutation. The location of mutations identified in this study is shown in (A) (RefSeq NM_001005741.2). Mutations reported in neuropathic GD type 3 are shown in magenta font. Mutations associated with mild, non-neuropathic GD type 1 (eg N370S) are shown in brown Risk variants are shown in green, and those variants, whose clinical phenotype is not established, in black font. The distri-of mutations is shown in the pie chart to the right of (B) with the number of carriers observed in parenthesis. Gaucher’s disease.
The Gaucher Registry: Demographics and Disease Characteristics of 1698 Patients With Gaucher Disease Arch Intern Med. 2000;160(18):2835-2843. doi:10.1001/archinte.160.18.2835
Prevalence of GBA mutation in GD
Pathophysiology In GD
↓ GBA → ↑ glucosylceramide accumulation in lysosome → ↑ glucosylceramide is deacylated by acid ceramidase to form glucosylsphingosine → glucosyls…
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Mutations Summary / N370S Homo / GBA Protein Brain | 별다른 감소 없는 듯 언급?(2011 chol) | reads as written; chol may be intended Choi. |
| Phenotype table / N370S / Phenotype | Eye problem (HSNP, saccadic eye movement): | trailing : is left without a value in the source. |
| Phenotype table / N370S / Eye problem | HSNP | reads as written; OCR alternates with HNSP. |