Peripheral neuropathy and altered cobalamin metabolism in Parkinson's disease and other movement disorders
Author: Andréasson, Mattias
Date: 2022-05-13
Location: C1.87, Karolinska University Hospital, Huddinge
Time: 09.00
Department: Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience
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Thesis (12.81Mb)
Abstract
Peripheral neuropathy is a disorder of the peripheral nervous system (PNS) that may carry different underlying aetiologies. Studies have suggested PNS involvement may be prevalent in neurological diseases that traditionally have been regarded primarily as disorders of the central nervous system (CNS), including the neurodegenerative disorder Parkinson’s disease (PD). In PD, an increased prevalence of large and/or small fiber neuropathy has been reported. Underlying associations with biochemical signs of disturbed vitamin B12 (cobalamin) metabolism have been suggested, and proposed to be driven by chronic exposure to treatment with levodopa. However, peripheral neuropathy as an intrinsic disease feature has also been suggested, possibly driven by peripheral neurodegeneration associated with PD.
We investigated the prevalence of clinical signs of peripheral neuropathy in a levodopa treated population followed at Karolinska University Hospital. Assessments included biochemical, genetic, and clinical evaluations. We observed a significantly higher prevalence of clinical signs indicative of a peripheral neuropathy, as assessed by the Utah Early Neuropathy Scale (UENS), in PD patients relative to controls. Furthermore, an association between UENS scores and plasma levels of homocysteine, an amino acid involved in the cobalamin dependent methionine cycle, was demonstrated.(Study I) In Study II we explored if Restless legs syndrome (RLS) may constitute a clinical expression of peripheral neuropathy in patients with PD and co-existent RLS. PNS assessments included both functional and structural evaluations of large and small fibers. More specifically, we employed the UENS, nerve conduction studies, quantitative sensory testing, and a novel method visualising the small fibers of the corneal subbasal nerve plexus, in vivo corneal confocal microscopy. An association between PNS assessments and the clinical expression of RLS, in the setting of PD, could not be demonstrated. This finding argues against a peripheral degenerative aetiology of RLS in this context. However, associations between PNS assessments and direct or indirect measures of disease burden in PD were demonstrated. This may possibly support the notion that PNS pathology, to some extent, could reflect ongoing CNS pathology in PD.
Previous studies have highlighted a possible role of altered cobalamin metabolism also in the setting of CNS manifestations in PD. In Study IV we characterized an adult patient with PD demonstrating a rare biochemical alteration, related to the cobalamin dependent metabolic pathway that takes place in the mitochondrial compartment. We present the underlying genetic variants, including a novel variant, presumed to drive this alteration, and discuss possible clinical implications. Gaucher disease (GD) is a hereditary lysosomal storage disorder that, to some extent, shares genetic background with PD. An increased prevalence of both small and large fiber neuropathy has been associated with GD. We examined patients with GD type 1 followed at Karolinska University Hospital and patients with the Norrbottnian GD type 3 followed at Sunderby Region Hospital. We assessed symptoms and clinical signs compatible with a peripheral neuropathy, followed by electrodiagnostic testing in selected cases. Acknowledging small sample size, we believe our study may support the notion that small fiber neuropathy could represent an inherent disease feature in GD type 1, but argues against this being a prevalent finding in Norrbottnian GD type 3. We suggest that the recognition of an ongoing small fiber neuropathy in this disease may harbour treatment implications with regard to pain management.(Study III) Hereditary spastic paraparesis (HSP) constitutes a group of genetic movement disorders with vast phenotypic and genotypic hetereogeneity. We characterized the clinical phenotype, PNS involvement, and cerebrospinal fluid findings in two families with HSP-KIF5A. We confirm previous reports of inter- and intrafamilial variability of the clinical phenotype. Furthermore, we argue that elevated cerebrospinal fluid neurofilament light chain is not a mandatory finding in this upper motor neuron disease.(Study V)
In conclusion, I suggest monitoring and treatment of biochemical signs of altered cobalamin metabolism in PD may serve a protective role with regard to the PNS. I speculate that PNS pathology in PD may reflect both levodopa mediated effects and manifestations inherent to the disease itself, possibly with a predilection for large and small fibers respectively. Thus, I believe future studies addressing the potential biomarker role of PNS assessments, as a surrogate marker of general disease progression in PD, are warranted. Such studies must account for the possibility of clouding effects related to altered cobalamin metabolism mediated by levodopa.
We investigated the prevalence of clinical signs of peripheral neuropathy in a levodopa treated population followed at Karolinska University Hospital. Assessments included biochemical, genetic, and clinical evaluations. We observed a significantly higher prevalence of clinical signs indicative of a peripheral neuropathy, as assessed by the Utah Early Neuropathy Scale (UENS), in PD patients relative to controls. Furthermore, an association between UENS scores and plasma levels of homocysteine, an amino acid involved in the cobalamin dependent methionine cycle, was demonstrated.(Study I) In Study II we explored if Restless legs syndrome (RLS) may constitute a clinical expression of peripheral neuropathy in patients with PD and co-existent RLS. PNS assessments included both functional and structural evaluations of large and small fibers. More specifically, we employed the UENS, nerve conduction studies, quantitative sensory testing, and a novel method visualising the small fibers of the corneal subbasal nerve plexus, in vivo corneal confocal microscopy. An association between PNS assessments and the clinical expression of RLS, in the setting of PD, could not be demonstrated. This finding argues against a peripheral degenerative aetiology of RLS in this context. However, associations between PNS assessments and direct or indirect measures of disease burden in PD were demonstrated. This may possibly support the notion that PNS pathology, to some extent, could reflect ongoing CNS pathology in PD.
Previous studies have highlighted a possible role of altered cobalamin metabolism also in the setting of CNS manifestations in PD. In Study IV we characterized an adult patient with PD demonstrating a rare biochemical alteration, related to the cobalamin dependent metabolic pathway that takes place in the mitochondrial compartment. We present the underlying genetic variants, including a novel variant, presumed to drive this alteration, and discuss possible clinical implications. Gaucher disease (GD) is a hereditary lysosomal storage disorder that, to some extent, shares genetic background with PD. An increased prevalence of both small and large fiber neuropathy has been associated with GD. We examined patients with GD type 1 followed at Karolinska University Hospital and patients with the Norrbottnian GD type 3 followed at Sunderby Region Hospital. We assessed symptoms and clinical signs compatible with a peripheral neuropathy, followed by electrodiagnostic testing in selected cases. Acknowledging small sample size, we believe our study may support the notion that small fiber neuropathy could represent an inherent disease feature in GD type 1, but argues against this being a prevalent finding in Norrbottnian GD type 3. We suggest that the recognition of an ongoing small fiber neuropathy in this disease may harbour treatment implications with regard to pain management.(Study III) Hereditary spastic paraparesis (HSP) constitutes a group of genetic movement disorders with vast phenotypic and genotypic hetereogeneity. We characterized the clinical phenotype, PNS involvement, and cerebrospinal fluid findings in two families with HSP-KIF5A. We confirm previous reports of inter- and intrafamilial variability of the clinical phenotype. Furthermore, we argue that elevated cerebrospinal fluid neurofilament light chain is not a mandatory finding in this upper motor neuron disease.(Study V)
In conclusion, I suggest monitoring and treatment of biochemical signs of altered cobalamin metabolism in PD may serve a protective role with regard to the PNS. I speculate that PNS pathology in PD may reflect both levodopa mediated effects and manifestations inherent to the disease itself, possibly with a predilection for large and small fibers respectively. Thus, I believe future studies addressing the potential biomarker role of PNS assessments, as a surrogate marker of general disease progression in PD, are warranted. Such studies must account for the possibility of clouding effects related to altered cobalamin metabolism mediated by levodopa.
List of papers:
I. Andréasson M, Brodin L, Laffita-Mesa JM, Svenningsson P. Correlations between methionine cycle metabolism, COMT genotype, and polyneuropathy in L-dopa treated Parkinson’s disease: a preliminary cross-sectional study. J Parkinsons Dis. 2017:7(4):619-628.
Fulltext (DOI)
Pubmed
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II. Andréasson M, Lagali N, Badian RA, Utheim TP, Scarpa F, Colonna A, Allgeier S, Bartschat A, Köhler B, Mikut R, Reichert KM, Solders G, Samuelsson K, Zetterberg H, Blennow K, Svenningsson P. Parkinson’s disease with restless legs syndrome – an in vivo corneal confocal microscopy study. NPJ Parkinsons Dis. 2021:7(1):4.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Andréasson M, Solders G, Björkvall CK, Machaczka M, Svenningsson P. Polyneuropathy in Gaucher disease type 1 and 3 – a descriptive case series. Sci Rep. 2019:9(1):15358.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Andréasson M, Zetterström RH, von Döbeln U, Wedell A, Svenningsson P. MCEE mutations in an adult patient with Parkinson’s disease, dementia, stroke and elevated levels of methylmalonic acid. Int J Mol Sci. 2019:20(11):2631.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Andréasson M, Lagerstedt-Robinson K, Samuelsson K, Solders G, Blennow K, Paucar M, Svenningsson P. Altered CSF levels of monoamines in hereditary spastic paraparesis 10: A case series. Neurol Genet. 2019:5(4):e344.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Andréasson M, Brodin L, Laffita-Mesa JM, Svenningsson P. Correlations between methionine cycle metabolism, COMT genotype, and polyneuropathy in L-dopa treated Parkinson’s disease: a preliminary cross-sectional study. J Parkinsons Dis. 2017:7(4):619-628.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Andréasson M, Lagali N, Badian RA, Utheim TP, Scarpa F, Colonna A, Allgeier S, Bartschat A, Köhler B, Mikut R, Reichert KM, Solders G, Samuelsson K, Zetterberg H, Blennow K, Svenningsson P. Parkinson’s disease with restless legs syndrome – an in vivo corneal confocal microscopy study. NPJ Parkinsons Dis. 2021:7(1):4.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Andréasson M, Solders G, Björkvall CK, Machaczka M, Svenningsson P. Polyneuropathy in Gaucher disease type 1 and 3 – a descriptive case series. Sci Rep. 2019:9(1):15358.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Andréasson M, Zetterström RH, von Döbeln U, Wedell A, Svenningsson P. MCEE mutations in an adult patient with Parkinson’s disease, dementia, stroke and elevated levels of methylmalonic acid. Int J Mol Sci. 2019:20(11):2631.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Andréasson M, Lagerstedt-Robinson K, Samuelsson K, Solders G, Blennow K, Paucar M, Svenningsson P. Altered CSF levels of monoamines in hereditary spastic paraparesis 10: A case series. Neurol Genet. 2019:5(4):e344.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Svenningsson, Per
Co-supervisor: Samuelsson, Kristin; Paucar-Arce, Martin; Machaczka, Maciej
Issue date: 2022-04-20
Rights:
Publication year: 2022
ISBN: 978-91-8016-522-8
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