Pathology — comparison across MSA subtypes
| MSA-P (SND) | MSA-C (OPCA) | MSA-PC? | ||
|---|---|---|---|---|
| Brain anatomy schematic: Healthy brain | MSA-P (SND) | MSA-C (OPCA) | Degeneration of autonomic brainstem nuclei. Labelled structures — striatum, substantia nigra pars compacta, pons, inferior olive, cerebellum, SCN, PVN, Raphe, LC, IML, VML, DMV, NA, LDT, PPT, PAG. | VML, ventrolateral medulla; DMV, dorsal motor nucleus of the vagus; NA, nucleus ambiguus; IML, intermediolateral column of the thoracic spinal cord; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; PAG, periaqueductal gray. (Jellinger, 2018 #2132) more detailed pathology picture | |||
| Prevalence | Pathology | (2020 Jellinger) 22/42 | 20/42 (but none displayed "pure" OPCA pathology or more severe OPCA pathology than SND (i.e., OPCA III+SND I/II) | |
| clinical | (Watanabe, 2002 #1418) 75/230 | (Watanabe, 2002 #1418) 155/230 | ||
| HORC-MSA | 29.9% | 58.2% | ||
| Clinical (Kim, 2011 #1391) | 55% | 17% | 28% | |
| - Age at onset was significantly older in MSA-P patients tan in the other types: 62.3 ± 8.5 years for MSA-P, 58.2 ± 8.8 years for MSA-C, and 56.0 ± 7.3 years for MSA-PC. | ||||
| progression | - Similar time from disease onset to motor + autonomic manifestations - Similar time to survival (Watanabe, 2002 #1418) | |||
| Shorter time to disability (1. Aid-requiring walking, 2. Wheelchair-bound state, 3. Bedridden state) (Watanabe, 2002 #1418) | ||||
| MRI | hyperintense rim at the lateral edge of the dorsolateral putamen | 16.9-23.1% | 56.8%-64.7% | |
| Hot cross bun in the pointe basis | 37.8-35.3% | 76.9-81.4% | ||
| (Kim, 2019 #1436) illustrated in Fig. 1. At <3 years of disease duration, 83 (44.6%) of 186 MSA-C patients demonstrated HCB (hot cross bun) signs and 66 (35.5%) showed MH; At 3-7 years of disease duration, 29 (72.5%) MSA-C patients showed HCB signs; MH (midline hyperintensities) was observed in 11 (27.5%) patients including 3 (7.5%) patients who had initially shown MH within 3 years of disese uration. 75.0% MSA-C patients exhibited MCP (middle cerebellar peduncle) hyperintensities at 3-7 years of disease duration; Putaminal rim signs and putaminal hypointensities were observed in overall 7 (3.8%) and 12 (6.5%) patients with MSA-C, respectively | ||||
| DATScan | (김한준) faster progression than PD | (김한준) barely changes | ||
| L-dopa response | (Stankovic, 2019 #1649) response in 42-57% | (Stankovic, 2019 #1649) response in 13-25% | ||
TM in MSA
| MSA-P | MSA-C | MSA-PC? | |
|---|---|---|---|
| Behavior | Which are endpoints/BMs that are sensitive to change/Tx? 찾자. | Cbll 이 중요. 동물에서 cbll 평가 model/method available? Digital? Mouse model of cbll dysfunction 찾자! | 얼마나 의미있게 category가 의미 있나? |
| aSyn | (simoa-based) Antibody to MSA-specific aggregated aSyn (Juntendo univ: currently serum |
No genetics, oligodendrocyte가 SIGNAture? Additional questions: how to Dx? 저혈압 common? Response to levodopa? Type별 prevalence? The most trouble some symptom? What is the trigger? Mt (like in PD)? mt BMs? And related patients stratification strategy. PD: Campain 존재? 104 patients performed the second-year evaluation, 71 performed the third-year evaluation, 41 performed the fourth-year evaluation and 17 performed the fifth-year evaluation.
Mucolipidosis (ML)
| Type I | Type II | Type III | Type IV ((Jezela-Stanek, 2020 #1719) good review | |
|---|---|---|---|---|
| SYNONYM | Sialidosis, glycoproteinosis.[2] | I-Cell Disease | Pseudo-Hurler polydystrophy | gangliosidosis.[3] Ganglioside sialidase deficiency, Sialolipidosis Berman syndrome; Ganglioside neuraminidase deficiency |
| OMIM | 252650 | |||
| cause | mutations in the MCOLN1 gene, here are at least 29 known mutations in MCOLN1, located throughout the gene.[5] Many of the known mutations result in no expression of mucolipin1. | |||
| Onset | typically manifest early in life (within the first year). After disease onset there occurs a period of stability, typically lasting two to three decades during which very little disease progression occurs.[4] | |||
| Life span | People with the severe form of this disorder usually survive to adulthood; however, they may have a shortened lifespan (detail not known). (Boudewyn, 2019 #1720) many patients in the second to third decade of life suffer kidney disease and kidney failure, which as a major cause of morbidity in MLIV | |||
| Inheritance | Autosomal recessive | |||
| Systemic Sx | achlorhydria. → iron deficiency. hypergastrinemia are hallmark findings of MLIV [12,18]. All MLIV patients have been documented to suffer from achlorhydria associated with secondary increases in blood gastrin at 1507 pg/mL (range 400 to 4100 pg/mL; normal 0 to 200 pg/mL) [33] (Table 1). Achlorydia and frequent malabsorption of iron from food results in iron deficiency & anemia They do not have enlarged livers or spleens, skeletal involvement, or mucopolysaccharides in the urine. js: this disease is primarily neurologic condition as systemic Sx is not common and severe. | |||
| Neurologic Sx | Very good resource: https://rarediseases.info.nih.gov/diseases/94/mucolipidosis-type-4 delayed psychomotor development and various ocular aberrations (corneal opacity, retinal degeneration and other ophthalmological abnormalities. Motor skills include sitting, standing, walking, grasping objects, and writing. Psychomotor delay is moderate to severe and usually becomes apparent during the first year of life. Affected individuals have intellectual disability, limited or absent speech, difficulty chewing and swallowing, weak muscle tone (hypotonia) that gradually turns into abnormal muscle stiffness (spasticity), and problems controlling hand movements. Most people with typical mucolipidosis type IV are unable to walk independently. In about 15 percent of affected individuals, the psychomotor problems worsen over time. | |||
| Prevalence | 1 in 40,000 people. About 70 percent of affected individuals have Ashkenazi Jewish ancestry. | |||
| Imaging | agenesis of the corpus callosum (Schiffmann, 2014 #1717) (5 patients,) Over a period of up to 3 years, MLIV patients remained neurologically stable. There was a trend for increased cortical and subcortical gray matter volumes, and increased ventricular size, while white matter and cerebellar volumes decreased. Mean diffusivity (MD) was increased and fractional anisotropy (FA) values were below normal in all analyzed brain regions. There was a positive correlation between motor scores of the Vineland scale and the FA values in the corticospinal tract (corr coef 0.39) and a negative correlation with the MD values (corr coef. -0.50) in the same brain region. We conclude from these initial findings that deficiency in mucolipin-1 affects the entire brain but that there might be a selective regional cerebral neurodegenerative process in MLIV. In addition, these data suggest that diffusion-weighted imaging might be a good biomarker for following patients with MLIV. | |||
| MOA | Mucolipin1 is thought to be localized in endosomes. An important property of mucolipin1 is that decreasing pH (acidification) results in deactivation of the protein, likely through an assembly defect. LOF mutation → lysosomal accumulation of lipids & ↑ lysosomal pH | |||
| correction | Negative: {Cao, 2015 #1726} in vitro: in ML1-/- human fibroblasts ('ML4), OVERexpression of TRPML1 → failed to rescue Ca increase (fig 3f,g) or lipofuscin accumulation (fig4K,l) | |||
| Pathology | Accumulation of certain lipids (cholesterol & gangliosides) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body. Those appear as large vacuoles and fluorescent vesicles in patient cells (fibroblast) (characteristic of mucolipidoses and mucopolysaccharidoses.). | |||
| Neuropathology | {Misko, 2021 #1721} very good review! hypomyelinating leukodystrophy Fig. 1 — MLIV disease progression curve (Higher Function vs. Increasing Age). Stage I (Development), Stage II (Plateau), Stage III (Decline). Bullet annotations: - Initial Presentation - Stage I (Development): Slow developmental gains; Mild hypertonicity; Mild visual impairment - Stage II (Plateau): Plateau in development equivalent to the 18-20-month level; Worsening hypertonicity (spasticity and rigidity); Moderate to severe visual impairment - Stage III (Decline): Precipitous decline in neurological function around puberty; Severe hypertonicity; Loss of meaningful vision; Aspiration develops - Curve labels: Typical neurological function (dashed); MLIV neurological function (solid). - X-axis bracket markers: -0 to -6 years; -6 to 16 years; "Legally blind" terminus. - Y-axis: Higher Function. Bottom-row label: Visual Function. Fig. 1. Qualitative representation of disease progression and stages in MLIV. Patients typically present with psychomotor delay in the first year of life and continue to make slow developmental gains through -6 years of age (Stage I). A plateau in development is reached between -6-16 years of age during which time muscular hypertonicity and visual impairment continue to worsen (Stage II). In early adolescence around the time of puberty, patients begin to exhibit a precipitous decline in motor function that eventually leads to loss of all meaningful movement and the need for gastric and tracheostomy tube placement to sustain survival. - brain iron accumulation in BG [Misko] - js) from Sx (spasticity, rigidity), imaging (DTI on CST), cerebellar pathology may not be prominent. | |||
| Symptomatic | js) genetic testing and Gastrin blood test to check for low iron no specific treatment to this disorder. However, several symptoms may be alleviated. For instance, anemia is treated by iron supplements | |||
| Subtype | (continues on 20240722_184247) | |||
| TM in MSA | (continues on 20240722_184247) | |||
| Animal model | Elevated gastrin and cellular vacuolization have been confirmed in the McoIn1-/- mice [13], | |||
| Biomarker-established | Gastrin? (js: there is no clear statement that gastrin is a BM in this condition) Lysosomal pH & vacuoles (fibroblast)? | |||
| BM-new | (Vardi, 2021 #1718) (n=1) (patient postmortem brain & csf, mouse model brain & CSF) ↑ calbindin2 in patient & mouse CSF (no description from brain tissue though), ↑ CTSA/B,D/H (in human cerebrum, cbll, CSF, note that these are proteins not activity) |
Uncertain Spans
- “62.3 ± 8.5” / “58.2 ± 8.8” / “56.0 ± 7.3” — original photo prints “6” between integer and decimal where ± would be expected; OCR reproduces “6”, but the typographic intent appears to be ”±” (mean ± SD).
- “TRPML1” / “ML1-/-” / “ML4” — small text in the {Cao, 2015 #1726} bullet uses both
ML1-/-and('ML4)for the same construct; transcribed as printed. - “Subtype” / “TM in MSA” rows of the Mucolipidosis table appear at the very bottom of the page beneath the Stage progression figure, but their cell content is cropped off the photo; marked as continues on 20240722_184247.
- “I-Cell Disease” — Type II SYNONYM cell layout reads as “I-Cell Disease” on two lines; preserved as a single phrase in transcription.