Clinical, ocular motor, and imaging profile of Niemann-Pick type C heterozygosity

Bremova-Ertl, Tatiana; Sztatecsny, Clara; Brendel, Matthias; Moser, Matthias; Möller, Bettina; Clevert, D.‐A.; Beck-Wödl, Stefanie; Kun‐Rodrigues, Célia; Brás, José; Rominger, Axel; Ninov, Dimitar; Strupp, Michael; Schneider, Susanne A.

doi:10.1212/wnl.0000000000009290

Cited by 18 publications

(14 citation statements)

References 46 publications

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“…Recently, various subclinical abnormalities in asymptomatic heterozygote NPC1-mutation carriers have been described including hepatosplenomegaly, increased cholestantriol, and plasma chitotriosidase and features of early neurodegenerative disease, e.g., impaired cognitive function, hyposmia, features suggestive of REM sleep behavior disorder, and decreased glucose metabolic rates on PET imaging [26]. We found no retinal neuronal and axonal degeneration in our NPC1-MC, but we did observe a nonsignificant trend towards lower mRNFL as seen in NPC1-P.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, NPC1-P were assessed by the Spinocerebellar Ataxia Functional Index (SCAFI), comprising the 8-m-Walking-Test (8MW), performed by having patients walking twice as quickly as possible from one line to another excluding turning, 9-Hole-Peg-Test (9HPT), and the number of "PATA" repetitions over 10 s (PATA) [25]. NPC1-MC were clinically assessed by an experienced neurologist in the field of movement disorders (SAS) with a particular focus on signs and symptoms of NPC disease: 1 point each was given for presence of a reduced arm swing, intention tremor, increased muscle tone, ankle clonus, and/or gait abnormalities resulting in a final motor score [26]. Scores ≥ 1 were considered pathological.…”

Section: Clinical Assessmentmentioning

confidence: 99%

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Retinal axonal degeneration in Niemann–Pick type C disease

et al. 2020

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Objective Niemann-Pick disease type C1 (NPC1) is a rare autosomal-recessive lysosomal storage disorder presenting with a broad clinical spectrum ranging from a severe infantile-onset neurovisceral disorder to late-onset neurodegenerative disease. Optical coherence tomography (OCT) is established to detect retinal degeneration in vivo. We examined NPC1-patients (NPC1-P), clinically asymptomatic NPC1-mutation carriers (NPC1-MC), and healthy controls (HC) to (1) identify retinal degeneration in NPC1-disease and (2) to investigate possible subclinical retinal degeneration in NPC1-MC. Methods Fourteen NPC1-P, 17 NPC1-MC, and 31 age-matched HC were examined using spectral-domain OCT. Neurological examinations, clinical scales [modified Disability Rating Scale (mDRS); Scale for the Rating and Assessment of Ataxia (SARA); Spinocerebellar Ataxia Functional Index (SCAFI)], and video-oculography (VOG) were correlated with OCT data. Results Macular retinal nerve fiber layer and volumes of combined ganglion cell and inner plexiform layer were significantly lower in NPC1-P compared to HC [mRNFL (µm):0.13 ± 0.01 vs. 0.14 ± 0.02; p = 0.01; GCIPL (mm 3):0.60 ± 0.05 vs. 0.62 ± 0.04; p = 0.04]. No significant differences were found in NPC1-MC in comparison to HC. In NPC1-P, the amplitude of upward vertical saccades showed positive associations with peripapillary RNFL (ρ = 0.645; p < 0.05), and thinned GCIP (ρ = 0.609; p < 0.05), but not in NPC1-MC. In NPC1-P correlations between combined outer plexiform layer and outer nuclear layer (OPONL) with mDRS (r = − 0.617; p < 0.05) and GCIP with SARA (r = − 0.622; p < 0.05) were observed. Furthermore, in NPC1-MC, motor scores were negatively associated with pRNFL (ρ = − 0.677; p < 0.01). Conclusions Using OCT, we showed retinal degeneration in NPC1-P and significant correlation between retinal neuroaxonal degeneration with clinical measurements. We observed a non-significant trend of retinal degeneration in NPC1-MC correlating with subclinical motor abnormalities. Based on these preliminary data, OCT may be an important marker of neurodegeneration in NPC1-disease after onset of clinical symptoms.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Assessmentmentioning

confidence: 99%

Retinal axonal degeneration in Niemann–Pick type C disease

et al. 2020

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“…Gaucher disease Dementia, 1 visuospatial deficits 2 Psychotic symptoms: paranoia, somatic delusions, hallucinations and recurrent impulsive and compulsive rituals, 3,4 depression, [5][6][7] generalized anxiety disorder 8 RBD 6,7,9 Constipation, 6,10 dysphagia 11 Olfactory loss 12,13 GM2-gangliosidosis: Sandhoff disease…”

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confidence: 99%

The Lysosome and Nonmotor Symptoms: Linking Parkinson's Disease and Lysosomal Storage Disorders

et al. 2020

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Homozygous mutations in GBA1 cause the most common lysosomal storage disease (LSD), namely, Gaucher disease (GD). Mutations (homozygous or heterozygous) in GBA1 are also the highest genetic risk factor for Parkinson's disease (PD), 1 although the mechanistic basis for this relationship is not known. We now suggest, based on well-documented data in some cases and on more anecdotal data in others, that there is a resemblance in some nonmotor symptoms (NMSs) between PD and LSDs. This may indicate that brain regions associated with NMSs are more vulnerable to changes in lysosomal activity and α-synuclein deposition as a result of lysosomal dysfunction. NMSs in PD patients with an LSD mutation have been mainly examined clinically in individuals heterozygous for GBA1 mutations rather than in mutations for other genes that cause an LSD, as the latter have only been recently identified as risk factors for PD. 2 It is important to distinguish between LSD carriers and patients in terms of PD-related NMSs because LSD carriers do not display overt LSD symptoms, although LSD carriers do affect susceptibility toward the development of neurological diseases such as PD. 1 Indeed, a recent study on Niemann-Pick (NPC1) carriers suggested heterozygosity is a high risk factor for late-onset neurodegeneration. 3 The significant overlap in NMSs between PD and LSDs (documented with appropriate references in Table 1) suggests that NMSs may be the cause of at least 1 common trait between these apparently disparate diseases. LSDs are rare, and patients often succumb at a young age. Nevertheless, reports of NMSs in late-onset or chronic forms of LSDs suggest a similarity between the presentation of NMSs in LSDs and PD. For the purpose of this literature review, we chose the most prominent NMSs, namely, olfactory disorders, sleep disorders, mood disorders, psychosis, dysautonomia, and cognitive impairment. We excluded cognitive impairment and mental retardation in LSDs, as these are not symptoms in PD patients. We performed a literature search using the National Library of Medicine database (PubMed). However, it should be noted that the terminology used to describe NMSs in LSDs is often rather vague; thus, direct comparison with NMSs in PD is difficult and requires careful analysis of the described symptoms. Moreover, because LSDs are rare, large clinical studies for many of them are not available or are limited to a small number of patients. The presence of NMSs such as olfactory or autonomic dysfunction may be overlooked because they are usually not the main symptom. Thus, for LSD patients, we focus mainly, but not exclusively, on GD and GM2 gangliosidosis, as these 2 are the best studied with regard to NMSs.

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“…The number of saccadic steps varied from two to 10. These highly hypometric saccades are common for atypical Parkinson syndromes, such as PSP, the main differential Bremova-Ertl et. al, 2020 diagnosis for the adult form of NPC.…”

Section: Discussionmentioning

confidence: 99%

“…This reiterates the progressive frontal impairment in patients with NPC. Considering disease progression and later involvement of smooth pursuit, with vertical being more affected than horizontal, ocular motor brainstem and cerebral regions are affected earlier in the course of disease, followed by the cerebellar ocular motor abnormalities (even though saccadic Bremova-Ertl et. al, 2020 gain is also highly dependent on the cerebellum).…”

Section: Discussionmentioning

confidence: 99%

Ocular motor biomarkers in Niemann-Pick disease type C: A prospective cross-sectional multicontinental study in 72 patients

Bremova-Ertl

Abel

Walterfang

et al. 2020

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Niemann-Pick type C (NPC) is a rare lysosomal storage disorder with ocular motor involvement. In a multi-continental cross-sectional study we characterized ocular motor function in 72 patients from twelve countries by means of video-oculography. We also searched for ocular motor biomarkers interlinking with disease severity. Study protocol comprised reflexive and self-paced saccades, smooth pursuit, and gaze-holding in both planes. 158 healthy controls acted as data comparison. The Modified Disability Rating Scale, Scale for Assessment and Rating of Ataxia, Spinocerebellar Ataxia Functional Index, and Montreal Cognitive Assessment were also performed. In contrast to previous publications and the common belief that the downward saccadic system degenerates to greater extent than the upward one, our measurements of vertical saccades demonstrated that the involvement in both directions was similar. Mean saccadic peak velocity to 20 deg stimulus was 63.5 deg/s (SD, 95% CIs of the mean: 59.5, [47.9-79.2]) in NPC patients and 403.1 deg/s (69.0, [392.0-414.2 deg/s]) in healthy subjects (p<0.001). Downward saccades yielded 51 deg/s (68.9, [32.7-69.3]), whilst upward 78.8 deg/s (65.9, [60.8-96.8]) (p<0.001). Vertical position smooth pursuit gain was 0.649 (0.33, [0.554-0.744]) in NPC and 0.935 (0.149 [0.91-0.959]) in HC (p<0.001). The number of patient-specific saccadic patterns, incl. slow-pursuit like, hypometric and staircase-pattern saccades suggest varying involvement of the saccadic system with fragmentation of the velocity profile as a sign of omnipause neuron dysfunction. Observed compensating strategies, such as blinks to elicit saccades, head and upper body movements to overcome the gaze palsy, should be used clinically to establish a diagnosis. Vertical reflexive saccades were more impaired and slower than self-paced ones. Ocular motor performance depended on age of onset and disease duration. We found that peak velocity and latency of horizontal saccades, vertical saccadic duration and amplitude, and horizontal position smooth pursuit can be used as surrogate parameters for clinical trials, as they showed the strongest correlation to disease severity. By comparing saccadic with pursuit movements, we showed that 98.2% of patients generated vertical saccades (both up and down) that were below the 95% confidence intervals of the controls peak velocity. Only 46.9% of patients had smooth pursuit gain lower than that of 95% of healthy controls. Vertical supranuclear saccade palsy and not vertical supranuclear gaze palsy is the hallmark of NPC disease. The distinction between saccadic and gaze palsy is also important in other neurodegenerative diseases and inborn errors of metabolism with ocular motor involvement, such as progressive supranuclear palsy or Gaucher disease type 3.

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Clinical, ocular motor, and imaging profile of Niemann-Pick type C heterozygosity

Cited by 18 publications

References 46 publications

Retinal axonal degeneration in Niemann–Pick type C disease

Retinal axonal degeneration in Niemann–Pick type C disease

The Lysosome and Nonmotor Symptoms: Linking Parkinson's Disease and Lysosomal Storage Disorders

Ocular motor biomarkers in Niemann-Pick disease type C: A prospective cross-sectional multicontinental study in 72 patients

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