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    UK genetic testing policy

    At a recent MND MDT clinic appointment with a Consultant Neurologist, I asked about genetic testing...

    35 years ago, my father (30 years older than me) had EMG / NC studies at the same hospital. Although no formal diagnosis of a specific illness (MS and Parkinsons were initial concern), he was told he had mylelin sheath degradation and some motor nerve function impairment. Due to other acute matters shortly after (mainly stroke), there wasn't much more work done on neuromuscular aspects.
    By his 70s he had trouble doing much with his arms above chest height and had a lot of arm weakness and nerve pain issues and atrophy in upper arms.

    He had knee replacement surgery last year, the Orthopaedic Hospital are now suggesting his lack of expected recovery would seem to be due to wider neuromuscular weakness aspects and nothing wrong with the new knee implant. He has significant foot drop now too and leg muscle atrophy.

    I noticed last week he has first dorsal interossi wasting and fasciculations in one hand, the same as how visible symptoms started with my confirmed limb onset ALS.

    Apart from him having leg muscle atrophy, his other symptoms are the same as my own.
    Apparently the question of genetic testing was answered:-

    "Unfortunately you are 54, the NHS doesn't have a policy of testing over 50, it's not made of money..."

    (I'm aware that some senior Professors of neurology are 'uncomfortable' with arbitrary age cut offs for testing around the world).

    We often see standard deviation curves of MND onset being diagnosed around age 55 - therefore an age 50 cut-off seems perverse.
    I'm also aware that in some hereditary conditions, an offspring could present and be diagnosed years before a parent.
    It feels like a gap here, both personally and generally.

    Does the MNDA have an opinion and guidance on this?
    (I'm familiar with genetic counselling ethics and considerations).
    Last edited by Arcadian; 14 March 2023, 16:31. Reason: spelling
    2020: odd symptoms. Nov 2021: Hand atrophy.. Mar 2022: Second arm atrophy - Confirmed Apr 2022: MND.
    Also Crohn's Disease from 2005ish. (Hi, I'm Dan in Cheshire)...

    #2
    Sorry to comment before MND Connect have answered.

    There at least three possible genetic causes of myelin sheath degradation due to restricted supply of different nutrients - serine through SERPINA1 gene mutation, magnesium through TRPM7 gene mutation, lipids through PMM2 gene mutation.

    Finding a possible genetic cause might be a cheaper option for the NHS than drugs, regardless of age, but I don't know what NHS policy is on this.

    Comment


      #3
      Cheers PaulaF - just frustrating with my Dad and myself both having neuromuscular problems and significant symptoms overlap, but both being over 50 no tests (despite my diagnosis being confirmed).
      Also, depending on which consultation I count from, probably too long after my diagnosis for participation in medication trials.

      Academic paper on age cut off for genetic testing:-

      Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome. In up to 20% of cases, a family history is observed. Although Mendelian disease gene variants are found in apparently sporadic ALS, genetic testing is usually restricted to those with a family history or younger patie …
      2020: odd symptoms. Nov 2021: Hand atrophy.. Mar 2022: Second arm atrophy - Confirmed Apr 2022: MND.
      Also Crohn's Disease from 2005ish. (Hi, I'm Dan in Cheshire)...

      Comment


        #4
        Hello Arcadian

        I am so sorry that you feel let down by the answer to your question about genetic testing and people over 50 not being tested.

        Unfortunately we are unable to give our opinion on what you were told, as this relates to specific NHS guidelines on the testing they carry out .

        I would suggest that you might want to raise this issue with the NHS and you could contact the parliamentary and health service ombudsman to discuss this https://www.ombudsman.org.uk/about-us/contact-us or call 0345 015 4033


        MND Connect Adviser

        MND Connect
        Contact us on 0808 802 6262 or at [email protected]

        Comment


          #5
          Various NHS links on genetic testing policy.
          (405 page .pdf download at section R58 covers genetic testing age policy cut off for MND and ALS).

          As the testing age policy cut off is less than typically reported peak onset age (standard distribution curves), I feel (supported by several peer reviewed studies), that opportunity and awareness is missed and this may have implications for understanding hereditary influences for Motor Neurone Diseases.

          https://www.england.nhs.uk/publicati...t-directories/ Screenshot_20230323_140044_Google PDF Viewer.jpg
          2020: odd symptoms. Nov 2021: Hand atrophy.. Mar 2022: Second arm atrophy - Confirmed Apr 2022: MND.
          Also Crohn's Disease from 2005ish. (Hi, I'm Dan in Cheshire)...

          Comment


            #6
            Originally posted by Arcadian View Post
            Various NHS links on genetic testing policy.
            (405 page .pdf download at section R58 covers genetic testing age policy cut off for MND and ALS).

            As the testing age policy cut off is less than typically reported peak onset age (standard distribution curves), I feel (supported by several peer reviewed studies), that opportunity and awareness is missed and this may have implications for understanding hereditary influences for Motor Neurone Diseases.

            https://www.england.nhs.uk/publicati...t-directories/ Screenshot_20230323_140044_Google PDF Viewer.jpg
            This whole policy is absurd and inhumane:
            1. It used to be people under 51 who could have a test, now they have saved a few quid by excluding it from people aged 50 as well.
            2. You have to have both UMN and LMN signs or you can't have it, despite evidence that some genetic conditions only cause either UMN or LMN symptoms.
            3. In order to get the test, the commissioning consultant has to determine that the MND is 'likely' to be caused by a single gene, even though there is no way of knowing that until the test is done and the course of MND is likely to be influenced by more than one gene.
            4. They run a test of the whole genome, but only provide results from the limited number of genes on their panel.

            In my case, the test was carried out more than 10 months ago, with no sign of any results forthcoming. They say this is fine, because people used to be told the results would take 10 weeks, but now they are admitting it will take up to 10 months. Of little use if people have a fast progression.

            Private test companies in America are happy to read anyone's whole genome 30 times and report back on the entire thing within 3 months and at a cost of a couple of hundred pounds. Why is it the NHS can't or won't do it?




            Comment


              #7
              As someone from a non-medical, but test, measurement and test-methodology background - I have concerns about the robustness, representation and reliability of how 'heritable risk' of MND is calculated / reported if you exclude the population demographic most commonly presenting.
              One NHS website states:-

              "Motor neurone disease is an uncommon condition that mainly affects people in their 60s and 70s, but it can affect adults of all ages."

              With the NHS Genomics guidance:-

              "3. Amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia
              a. Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic or
              neuropathologic examination, AND
              b. Evidence of upper motor neuron (UMN) degeneration by clinical examination, AND
              c. Progressive course, AND
              d. Age of onset <50 years or family history of ALS or frontotemporal dementia, AND
              e. No evidence of other aetiology
              Referrals for testing will be triaged by the Genomic Laboratory; testing should be targeted at those where a
              genetic or genomic diagnosis will guide management for the proband or family.
              Where in Pathway
              At presentation following assessment by a Neurologist
              Requesting Specialties
              • Clinical Genetics
              • Neurology
              • Psychiatry
              Specialist Service Group
              • Neurology
              Associated Tests
              Please note that initially only WGS testing will be undertaken for R58 Clinical Indication requests, unless clinical
              presentation and/or initial results indicate all tests are necessary. Whilst this includes testing of all STRs in the gene
              panel, analysis is currently not optimal and therefore if a specific STR is suspected this should be stated at referral to
              prompt additional testing where necessary..."


              If most MND 'information literature' states:-

              "Inherited MND affects up to 1 in 10 people with MND and means they probably have a family history of the disease. Where this is the case, it is impossible to predict when or if a family history means MND will happen."

              If 'over 50s' are excluded from testing, then a proportion of people, relative to hereditary risk factor (or the wider population prevalence of genes associated with risk) are excluded.

              I'm going to try and get a couple of medical professional and statistical friends to go over my ideas and see if a change to the <50 age cut off being challenged can demonstrate some benefits for better understanding for researchers, potential access to a wider population to trial treatments, as well as any better guidance to families (subject to appropriate genetic counselling).​​​​​​
              Last edited by Arcadian; 25 March 2023, 10:30. Reason: exclusion paragraph added
              2020: odd symptoms. Nov 2021: Hand atrophy.. Mar 2022: Second arm atrophy - Confirmed Apr 2022: MND.
              Also Crohn's Disease from 2005ish. (Hi, I'm Dan in Cheshire)...

              Comment


                #8
                Originally posted by Arcadian View Post
                As someone from a non-medical, but test, measurement and test-methodology background - I have concerns about the robustness, representation and reliability of how 'heritable risk' of MND is calculated / reported if you exclude the population demographic most commonly presenting.
                One NHS website states:-

                "Motor neurone disease is an uncommon condition that mainly affects people in their 60s and 70s, but it can affect adults of all ages."

                With the NHS Genomics guidance:-

                "3. Amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia
                a. Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic or
                neuropathologic examination, AND
                b. Evidence of upper motor neuron (UMN) degeneration by clinical examination, AND
                c. Progressive course, AND
                d. Age of onset <50 years or family history of ALS or frontotemporal dementia, AND
                e. No evidence of other aetiology
                Referrals for testing will be triaged by the Genomic Laboratory; testing should be targeted at those where a
                genetic or genomic diagnosis will guide management for the proband or family.
                Where in Pathway
                At presentation following assessment by a Neurologist
                Requesting Specialties
                • Clinical Genetics
                • Neurology
                • Psychiatry
                Specialist Service Group
                • Neurology
                Associated Tests
                Please note that initially only WGS testing will be undertaken for R58 Clinical Indication requests, unless clinical
                presentation and/or initial results indicate all tests are necessary. Whilst this includes testing of all STRs in the gene
                panel, analysis is currently not optimal and therefore if a specific STR is suspected this should be stated at referral to
                prompt additional testing where necessary..."


                If most MND 'information literature' states:-

                "Inherited MND affects up to 1 in 10 people with MND and means they probably have a family history of the disease. Where this is the case, it is impossible to predict when or if a family history means MND will happen."

                If 'over 50s' are excluded from testing, then a proportion of people, relative to hereditary risk factor (or the wider population prevalence of genes associated with risk) are excluded.

                I'm going to try and get a couple of medical professional and statistical friends to go over my ideas and see if a change to the <50 age cut off being challenged can demonstrate some benefits for better understanding for researchers, potential access to a wider population to trial treatments, as well as any better guidance to families (subject to appropriate genetic counselling).​​​​​​
                Per Van Damme's paper in 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204935/, "estimated heritability in sporadic ALS is about 60%" (over and above familial ALS).

                Per M Ryan's study in 2019 https://www.ncbi.nlm.nih.gov › articles › PMC6646974, estimated heritability was "between 40% and 60%".

                Al Chalabi's (King's College) study in 2010 https://jnnp.bmj.com/content/81/12/1324 found heritability of 76% for familial ALS and 61% for sporadic ALS.

                In my view, even these are underestimates, as the health of motor neurons can be adversely affected by a combination of minor genetic dysfunctions that these studies might not pick up.

                Until we can identify which genetic causes are likely to be contributing to each individual's motor neuron loss, we cannot tell which type of motor neuron disease they have and so whether there there are any specific treatments which could potentially alleviate their condition.

                You can get a private test done, but in my experience the NHS consultants don't want to even look at the results and will only consider NHS tests (which you either cannot get, or for which the results take a year or more to arrive). It is all very frustrating.





                Comment


                  #9
                  PaulaF I can empathise with what I'd politely describe as 'ego barriers' I worked at a high level of laboratory accreditation and testing (testing & validating test and analysis laboratories to national and international standards).

                  I arranged an independent accredited Lyme Disease test as I'm higher than average risk and some symptoms ovelap with MND.
                  I had dismissive patronising dismissal of my risk as I live in the north-west - until a reasonable Neurologist looking at my additional ambiguous signs understundersdo a lot of voluntary conservation work in meadows and woodlands in Oxfordshire and Wiltshire and had a tick bite the previous year.

                  The barriers to rational testing policy for lots of illnesses in The UK are appalling, with dismissive reactions to a patient's risk dynamics.

                  I'm going to read through the links you shared - I had an intereting response on Twitter when questioning policy a few weeks ago:-



                  I'm going to try over the next month or so to put a robust document together that challenges the genetic testing status quo.

                  MNDA response further up diplomatically mentions NHS Ombudsman amd MP involvement - I'm on the All Party MND Select Committee output mailing list, so will also try to make a case via my MP to raise a question around policy.
                  It would be helpful if MNDA and other interested parties are able to reinterpretate the situation and make an input regarding review of this policy...

                  2020: odd symptoms. Nov 2021: Hand atrophy.. Mar 2022: Second arm atrophy - Confirmed Apr 2022: MND.
                  Also Crohn's Disease from 2005ish. (Hi, I'm Dan in Cheshire)...

                  Comment


                    #10
                    Notwithstanding what it says in the National Genomic Test Directory - I have seen c9orf72 testing done as a matter of routine in an NHS clinic for someone well over 50 - without a need to make a special request.

                    Comment


                      #11
                      fjay cheers, the Neurologist treating me completely refused to test, despite a direct relative having a confirmed neurodegenerative condition.

                      I might consider splashing out on an accredited test myself
                      2020: odd symptoms. Nov 2021: Hand atrophy.. Mar 2022: Second arm atrophy - Confirmed Apr 2022: MND.
                      Also Crohn's Disease from 2005ish. (Hi, I'm Dan in Cheshire)...

                      Comment


                        #12
                        Originally posted by Arcadian View Post
                        fjay cheers, the Neurologist treating me completely refused to test, despite a direct relative having a confirmed neurodegenerative condition.

                        I might consider splashing out on an accredited test myself
                        I would caution that the standard NHS panel test R58 is devised by people similar to those trying to restrict testing to people aged under 50. It is a fairly limited test of only the main variants categorically proven to be associated with neurodegenerative conditions, many of which we might be able to do little about.

                        The more interesting genetic variants to me are the fringe ones that might combine to trigger or aggravate motor neuron damage and that might be treatable in some way. For instance, none of the variants in the 3 genes I mentioned above (SERPINA1, TRPM7, PMM2) are included in the NHS panel test, despite them all playing a role in the synthesis of material that forms the protective sheath around neurons. Another example of an untested gene is TAF1D, variants in which are known to sometimes contribute to neurological problems. There are substitutes available that could potentially be counteracting damage that these dysfunctional proteins might be causing, so it might be helpful if people had a wider picture of their genetic profile.

                        Comment


                          #13
                          The MNDA Research Twitter feed and web pages have mentioned a recent policy change on ALS / MND genetic testing with age <50 now removed:-

                          Screenshot 2023-04-26 19.11.50.png

                          Here you can find the most up to date research news. Stay tuned to find out about clinical trial outcomes, breakthroughs in the lab, interesting research papers and more. Genetic testing guidelines for MND in the UK changed 26 April 2023 The UK guidelines (UK National Genomic Test Directory criteria) have been updated to state... Read more »


                          Page 312 of policy:-
                          Last edited by Arcadian; 26 April 2023, 18:17. Reason: .pdf policy link
                          2020: odd symptoms. Nov 2021: Hand atrophy.. Mar 2022: Second arm atrophy - Confirmed Apr 2022: MND.
                          Also Crohn's Disease from 2005ish. (Hi, I'm Dan in Cheshire)...

                          Comment


                            #14
                            Arcadian During my 2nd opinion at The National Hospital for Neurology and Neurosurgery (NHNN), Queen Square, it was agreed they would test me for heredity mnd in December 22 . I was 53 at the time. My nan and aunt had dementia, my birth mother has Dementia now. I haven't received any results yet.

                            Comment


                              #15
                              Future Health is worth considering
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