Objective
Despite the need for diagnostics and research, data on fluid biomarkers in hereditary spastic paraplegia (HSP) are scarce. We, therefore, explore Neurofilament light chain (NfL) levels in ...cerebrospinal fluid (CSF) of patients with hereditary spastic paraplegia and provide information on the influence of demographic factors.
Methods
The study recruited 59 HSP cases (33 genetically confirmed) and 59 controls matched in age and sex. Neurofilament light chain levels were assessed by enzyme‐linked immunosorbent assay. The statistical analysis included the effects of age, sex, and genetic status (confirmed vs. not confirmed).
Results
Levels of CSF NfL were significantly increased in patients with hereditary spastic paraplegia compared to controls (median 741 pg/mL vs. 387 pg/mL, p < 0.001). Age (1.4% annual increase) and male sex (81% increase) impacted CSF NfL levels in patients. The age‐dependent increase of CSF NfL levels was steeper in controls (2.6% annual increase). Thus, the CSF NfL ratio of patients and matched controls—expressing patients’ fold increases in CSF NfL—declined considerably with age.
Interpretation
CSF NfL is a reliable cross‐sectional biomarker in hereditary spastic paraplegia. Sex is a relevant factor to consider, as male patients have remarkably higher CSF NfL levels. While levels also increase with age, the gap between patients and controls is narrowing in older subjects. This indicates distinct temporal dynamics of CSF NfL in patients with hereditary spastic paraplegia, with a rise around phenotypic conversion and comparatively static levels afterward.
OBJECTIVE:Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias.
METHOD:Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families ...detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes.
RESULTS:Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling.
CONCLUSION:UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families.
Blood biomarkers are still largely missing in hereditary spastic paraplegias (HSPs). We here explored Neurofilament light chain (NfL) as a biomarker in HSP. Serum NfL was assessed in 96 HSP (63 ...genetically confirmed), 96 healthy control, and 33 ALS subjects by single molecule array (Simoa). Compared to controls, NfL was increased in HSP (P < 0.001), correlating with cross‐sectional disease progression (ρ = 0.28). Levels were lower than in ALS (P < 0.001), allowing to differentiate HSP from ALS (AUC = 0.91). Serum NfL might serve as a biomarker in HSP indicating neuronal damage and, if confirmed longitudinally, disease progression. It might also support differentiating HSP from ALS.
Objective
While the anticipated rise of disease‐modifying therapies calls for reliable trial outcome parameters, fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent ...form of hereditary spastic paraplegia. We therefore investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4.
Methods: We assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. The longitudinal study of sNfL levels in SPG4 patients covered a baseline, 1‐year follow‐up and 2‐year follow‐up visit.
Results
Levels of sNfL were significantly increased in patients with genetically confirmed SPG4 compared to healthy controls matched in age and sex (p = 0.013, r = 0.2). Our cross‐sectional analysis revealed a greater difference in sNfL levels between patients and controls in younger ages with decreasing fold change of patient sNfL elevation at older ages. Over our observational period of 2 years, sNfL levels remained stable in SPG4 patients. Disease severity and progression did not correlate with sNfL levels.
Interpretation: Our longitudinal data indicate a stable turnover of sNfL in manifest SPG4; therefore, sNfL levels are not suitable to monitor disease progression in SPG4. However, sNfL may be valuable as a therapy response biomarker, since its turnover could be modified by interventions. As the course of sNfL levels appears to be most dynamic around the onset of SPG4, the ability to detect a therapy response appears to be especially promising in younger patients, matching the need to initiate treatment in early disease stages.
Skin fibroblasts were obtained from a 47-year-old hereditary spastic paraplegia patient carrying a homozygous mutation Y275X in CYP7B1 (Cytochrome P450, Family 7, Subfamily B, Polypeptide 1), ...responsible for causing hereditary spastic paraplegia type 5 (SPG5). Induced pluripotent stem cells (iPSCs) were generated by transfection with episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC and hLIN28. The generated line iPS-SPG5-Y275X was transgene-free, retained the specific mutation with no additional genomic aberrations, expressed pluripotency markers and was able to differentiate into cells of all germ layers in vitro. The generated iPS-SPG5-Y275X line may be a useful resource for disease modelling of SPG5.
Background
The genetic causes of many rare inherited motoneuron diseases and ataxias (MND and ATX) remain largely unresolved, especially for sporadic patients, despite tremendous advances in gene ...discovery. Whole exome data is often available for patients, but it is rarely evaluated for unusual inheritance patterns, such as uniparental disomy (UPD). UPD is the inheritance of two copies of a chromosomal region from one parent, which may generate homozygosity for a deleterious recessive variant from only one carrier‐parent. Detection of UPD‐caused homozygous disease‐causing variants is detrimental to accurate genetic counseling. Whole‐exome sequencing can allow for the detection of such events.
Methods
We systematically studied the exomes of a phenotypically heterogeneous cohort of unresolved cases (n = 96 families) to reveal UPD events hindering a diagnosis and to evaluate the prevalence of UPD in recessive MND and ATX.
Results
One hereditary spastic paraplegia case harbored homozygous regions spanning 80% of chromosome 16. A homozygous disease‐causing mutation in the SPG35 disease gene was then identified within this region.
Conclusion
This study demonstrates the ability to detect UPD in exome data of index patients. Our results suggest that UPD is a rare mechanism for recessive MND and ATX.
Uniparental disomy, the inheritance of two copies of a chromosomal region from one parent, may generate homozygosity for a deleterious recessive variant when the chromosomal region is from the same parental allele (isodisomy). In this study, we identified chromosomal uniparental isodisomy from one proband's whole‐exome sequencing (WES) while screening 96 simplex, non‐consanguineous families of patients affected by hereditary ataxia and a spectrum of motoneuron diseases including ALS, ALS‐FTD and Hereditary Spastic Paraplegia (HSP).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
38.
Freezing of Swallowing Maetzler, Walter; Rattay, Tim W.; Hobert, Markus A. ...
Movement disorders clinical practice,
September/October 2016, Letnik:
3, Številka:
5
Journal Article
Recenzirano
Odprti dostop
View Supplementary Video 1
Background
Swallowing deficits and freezing phenomena represent severe parkinsonian features. Freezing as a symptom occurring during swallowing has not been reported on ...yet.
Methods
We report on 3 patients with probable PSP‐parkinsonism (PSP‐P) who manifested freezing of swallowing (FOS).
Results
All 3 patients experienced severe weight loss in recent months. At examination, 1 patient had freezing of gait. Video fluoroscopy showed nonfunctional trembling movements of the tongue and palate during chewing and volitional swallowing, with a 6‐ to 8‐Hz frequency that is typical for freezing episodes during walking and finger tapping. These freezing episodes were accompanied by impaired oral bolus transportation. The pharyngeal phase was not relevantly affected.
Conclusions
FOS represents a novel disease feature of PSP‐P. The feature may have fundamental, but potentially treatable, consequences for patients' health and quality of life and may be considered in patients with degenerative parkinsonism who experience severe and unexplained weight loss.
View Supplementary Video 1
Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessively inherited movement disorder characterized by progressive spastic gait disturbance and afferent ataxia. SPG5 is caused by ...bi-allelic loss of function mutations in CYP7B1 resulting in accumulation of the oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol in serum and cerebrospinal fluid of SPG5 patients. An effect of 27- hydroxycholesterol via the estrogen and liver X receptors was previously shown on bone homeostasis. This study analyzed bone homeostasis and osteopenia in 14 SPG5 patients as a non-motor feature leading to a potential increased risk for bone fractures. T-Scores in CT bone density measurements were reduced, indicating osteopenia in SPG5 patients. Further, we analyzed various metabolites of bone homeostasis by ELISA in serum samples of these patients. We identified a lack of vitamin D
metabolites (Calcidiol and Calcitriol), an increase in Sclerostin as a bone formation/mineralization inhibiting factor, and a decrease in cross-linked N-telopeptide of type I collagen (NTX), a marker indicating reduced bone resorption. As statin treatment has been found to lower oxysterol levels, we evaluated its effect in samples of the STOP-SPG5 trial and found atorvastatin to normalize the increased sclerostin levels. In summary, our study identified osteopenia as a non-motor feature in SPG5 and suggests the need for vitamin D
substitution in SPG5 patients. Sclerostin may be considered a therapeutic target and biomarker in upcoming therapeutical trials in SPG5.
Purpose: To quantify white matter anisotropy of the human cervical spinal cord is still a challenge. The purpose of this work is to develop a standardized evaluation method for a robust FA estimation ...of the pyramidal tracts (PT), dorsal columns (DC) and anterior horns (AH) in normal ageing and pathologic conditions. Methods: A monopolar EPI sequence with double spin-echo diffusion preparation optimized for both a high SNR and a high axial in-plane resolution of 0.8 mm.sup.2 was used. Impairment of the upper spinal cord was assessed in cross sectional images of 77 healthy subjects and 30 patients with hereditary spastic paraplegia (HSP) at 3T. To allow a semi-automated, bilateral ROI evaluation of the PT, DC and AH an ellipsoid was adjusted onto the individual FA image of each subject's spinal cord (Fig. 1). Results: Fig. 2 shows stable FA values from 18 years to the age of 65 for the PT (0.56, SD 0.03), DC (0.57, SD 0.03) and AH (0.38, SD 0.04). No decline of FA values can be demonstrated in normal ageing, at least until the age of 65. Fig. 3 shows a significant (p < .001) reduction in mean FA values of the pyramidal tracts of spastic paraplegia patients compared to controls. As HSP is the prototype disease of the degenerating first motor neuron, the measured decline in FA reflects well this pathologic condition. Conclusion: Spinal DTI of the upper cervical cord is clinically feasible at 3T, enabling robust FA measurements of PT, DC and AH in normal ageing and pathologic conditions.
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