Pathology-supported genetic testing presents opportunities for improved disability outcomes in multiple sclerosis.

Background: Lipid metabolism may impact disability in people with multiple sclerosis (pwMS). Methods: Fifty-one pwMS entered an ultrasound and MRI study, of whom 19 had followed a pathology-supported genetic testing program for more than 10 years (pwMS-ON). Genetic variation, blood biochemistry, vascular blood flow velocities, diet and exercise were investigated. Results: pwMS-ON had significantly lower (p < 0.01) disability (Expanded Disability Status Scale) than pwMS not on the program (1.91 ± 0.75 vs 3.87 ± 2.32). A genetic variant in the lipid transporter FABP2 gene (rs1799883; 2445G>A, A54T) was significantly associated (p < 0.01) with disability in pwMS not on the program, but not in pwMS-ON (p = 0.88). Vascular blood flow velocities were lower in the presence of the A-allele. Conclusion: Pathology-supported genetic testing may provide guidance for lifestyle interventions with a significant impact on improved disability in pwMS.

This study investigated the role of a genetic variant that increases saturated fat absorption and may make people with multiple sclerosis (MS) more susceptible to disability progression. Of 51 people with MS, 19 had followed a program which includes normalization of blood test results and daily intake of unsaturated fatty acids for more than 10 years, while the others had not. The latter group had significantly greater disability than the people who had followed the program, suggesting that the unsaturated fatty acids modulated the effect of the genetic variant. Six MS cases are presented as examples, including a marathon athlete (Case 1) and a patient who showed a dramatic decrease in disability from being wheelchair-bound for 15 years to walking freely (Case 2).

Disability in multiple sclerosis is associated with vascular factors: An ultrasound study.

BACKGROUND: Although multiple sclerosis (MS) is an immune-related disorder, pharmaceutical interventions targeting the immune system do not stop or reverse disability progression; the major challenge for this condition. Studies show that disability progression in MS is associated with vascular comorbidity and brain volume loss, indicating that a multi-targeted approach is required to prevent debilitation. The aim of the present study was to examine the associations between vascular ultrasound, disability, biochemistry and lifestyle data in people with MS (pwMS). METHODS: Extracranial vascular ultrasound was performed on 51 pwMS and 25 age-matched controls. Sonographic interrogation determined carotid intima-media thickness (cIMT) and abnormal blood flow patterns. Disability was assessed using the Expanded Disability Status Scale (EDSS). Biochemical and lifestyle data were obtained for all participants. RESULTS: The EDSS had a highly significant positive association with the cIMT of the right (r = 0.63; p = 0.001) and left (r = 0.49; p = 0.001) common carotid arteries and negative associations with the peak systolic blood flow velocity of the right vertebral artery (r = -0.42; p = 0.01) as well as end-diastolic velocity of the left internal carotid artery (r = -0.47; p = 0.01). These associations were significantly influenced by biochemical and lifestyle factors. Both cIMT and age showed significant associations with the EDSS. When cIMT was adjusted for age in a regression analysis, the association between the EDSS and the cIMT remained significant (p < 0.01), while the age association was reduced to being significant only at 10% (p = 0.06). There was no association between the use of MS medication and the EDSS (p = 0.56). CONCLUSION: PwMS who had increased cIMT, a surrogate marker for atherosclerosis, and reduced carotid artery blood flow velocities were at risk for greater disability over and above the effect of aging. These findings provide important information for disease management and disability prevention in pwMS. Modification of diet and lifestyle may promote the unhindered flow of essential nutritional factors into the brain in pwMS.

Pathology-supported genetic testing as a method for disability prevention in multiple sclerosis (MS). Part I. Targeting a metabolic model rather than autoimmunity.

In this Review (Part I), we investigate the scientific evidence that multiple sclerosis (MS) is caused by the death of oligodendrocytes, the cells that synthesize myelin, due to a lack of biochemical and nutritional factors involved in mitochondrial energy production in these cells. In MS, damage to the myelin sheaths surrounding nerve axons causes disruption of signal transmission from the brain to peripheral organs, which may lead to disability. However, the extent of disability is not deterred by the use of MS medication, which is based on the autoimmune hypothesis of MS. Rather, disability is associated with the loss of brain volume, which is related to the loss of grey and white matter. A pathology-supported genetic testing (PSGT) method, developed for personalized assessment and treatment to prevent brain volume loss and disability progression in MS is discussed. This involves identification of MS-related pathogenic pathways underpinned by genetic variation and lifestyle risk factors that may converge into biochemical abnormalities associated with adverse expanded disability status scale (EDSS) outcomes and magnetic resonance imaging (MRI) findings during patient follow-up. A Metabolic Model is presented which hypothesizes that disability may be prevented or reversed when oligodendrocytes are protected by nutritional reserve. Evidence for the validity of the Metabolic Model may be evaluated in consecutive test cases following the PSGT method. In Part II of this Review, two cases are presented that describe the PSGT procedures and the clinical outcomes of these individuals diagnosed with MS.

Pathology-supported genetic testing as a method for disability prevention in multiple sclerosis (MS). Part II. Insights from two MS cases.

In Part I of this Review we evaluated the scientific evidence for a Metabolic Model of multiple sclerosis (MS). Part II outlines the implementation of an adaptive pathology-supported genetic testing (PSGT) algorithm aimed at preventing/reversing disability in two illustrative MS cases, starting with a questionnaire-based risk assessment, including family history and lifestyle factors. Measurement of iron, vitamin B12, vitamin D, cholesterol and homocysteine levels identified biochemical deficits in both cases. Case 1, after following the PSGT program for 15 years, had an expanded disability status scale (EDSS) of 2.0 (no neurological sequelae) together with preserved brain volume on magnetic resonance imaging (MRI). A novel form of iron deficiency was identified in Case 1, as biochemical testing at each hospital submission due to MS symptoms showed low serum iron, ferritin and transferrin saturation, while hematological status and erythrocyte sedimentation rate measurement of systemic inflammation remained normal. Case 2 was unable to walk unaided until her EDSS improved from 6.5 to 4.0 over 12 months after implementation of the PSGT program, with amelioration of her suboptimal biochemical markers and changes to her diet and lifestyle, allowing her to regain independence. Genotype-phenotype correlation using a pathway panel of functional single nucleotide variants (SNVs) to facilitate clinical interpretation of whole exome sequencing (WES), elucidated the underlying metabolic pathways related to the biochemical deficits. A cure for MS will remain an elusive goal if separated from nutritional support required for production and maintenance of myelin, which can only be achieved by a lifelong investment in wellness.