Tuesday, August 2, 2016

Untreatable genetic dsorders: to test or not to test

Some neurologists argue that having made a clinical diagnosis of an untreatable genetic condition, there is no need to undertake genetic testing to identify the precise genetic diagnosis. This nihilistic attitude is not uncommon in the increasingly financially challenging health service environment.

In this issue, Ingram et al eloquently report the process of identifying a rare mutation in the SLC5A7 gene as a cause of distal hereditary motor neuropathy with vocal cord paresis. Their paper provides an ideal opportunity to review the arguments for doing molecular testing for untreatable genetic conditions.

The most compelling reason to do molecular genetic testing is that patients want an accurate diagnosis. It is important not to underestimate the benefit for patients of receiving an accurate diagnosis, especially in terms of them coming to terms with their disease. A precise genetic diagnosis also allows a much more accurate prognosis and can have implications for medical management, for example a child with a slowly progressive axonal neuropathy that clinically resembles Charcot Marie Tooth disease type 2 (CMT2) whose genetic testing reveals the cause as a mutation in Gigaxonin, which causes Giant Axonal Neuropathy. This condition progressively involves the central nervous system and carries a much worse prognosis than most forms of CMT2. The use of next-generation sequencing techniques in routine diagnostic practice has highlighted several complex disorders such as giant axonal neuropathy that can initially present just as a neuropathy. Genetic diagnoses can also influence medical management, for example when a mitochondrial mutation is found to be the cause of a myopathy, this will mean more detailed clinical surveillance is needed especially of the heart. Another example is identifying one of the two genes (DNMT1 and PRP) that cause dementia with sensory neuropathy in patients who were thought to have an uncomplicated form of hereditary sensory neuropathy.

An accurate genetic diagnosis can avoid unnecessary tests and treatments. In Ingram et al's article, the proband had both multiple tests and an operation (thymectomy) in an attempt to diagnose and treat her hoarseness. Now that a diagnosis has been made, other family members can avoid further detailed tests. In assessing peripheral neuropathies, it can be difficult to interpret nerve conduction studies when differentiating CMT from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Nerve conduction study findings consistent with CIDP most commonly occur in CMTX1 from mutations in GJB1 and in four other rare types of CMT (MPZ, SH3TC2, SPTLC1 and FIG4).  A potential diagnosis of CIDP may involve invasive tests including cerebrospinal fluid and a nerve biopsy (especially in atypical cases) and trials of treatment with potentially serious side effects (intravenous immunoglobulin, plasma exchange, corticosteroids and other immunosuppressive drugs). The costs to the patient and the financial costs to health services far outweigh the costs of current genetic testing.

The major implication of an accurate genetic diagnosis for current practice is that it allows the inheritance pattern to be determined, enabling accurate genetic counselling for the patient and further genetic screening in the family (predictive, diagnostic and antenatal). For parents of affected children, a genetic diagnosis allows the calculation of risk of recurrence in future children. Identifying a causative mutation gives a patient the options of prenatal or preimplantation genetic diagnoses, something increasingly requested even for conditions that clinicians may consider to  be mild. It is important for clinicians to realise that their opinion regarding a patient's disability and quality of life may be quite different from the patient's own view. Although clinicians often regard the common form of CMT, CMT1A, as a mild condition, patients with CMT1A have similar emotional stress levels to patients with stroke, and over half the patients in one study reported that the disease interfered with their professional life.

A common argument used against genetic testing for many conditions is that they are untreatable; however, treatments are increasingly being developed and trialled for these conditions, for example, antisense oligonucleotide treatment for Duchenne' muscular dystrophy.  Having an accurate genetic diagnosis is a prerequisite for patients being eligible for trials of genetic therapies. A frequently encountered barrier to trial design in these conditions is the lack of natural history data. Patients with a genetic diagnosis are often keen to be involved in natural history studies to allow better prognostication for future patients and to help develop outcome measures for future trials.

Finally, a significant reason for many patients not being offered accurate genetic testing is a financial one. Genetic testing is often regarded as a non-essential expense in a system with finite funds. This argument is rapidly losing ground as the price of genetic testing (with next-generation sequencing) is falling rapidly, making the cost of comprehensive genetic testing (disease specific panels or whole exomes) comparable with routine MRI scanning and similarly priced tests. For the individual patient, a genetic diagnosis prevents other often more costly tests, avoids unnecessary onward referrals for diagnostic opinions and sometimes avoids expensive trials of potentially harmful treatments. The financial argument no longer holds up.

Like all patients, those with inherited conditions deserve the best opinion we can give and this includes an accurate genetic diagnosis.

Mary M Reilly.  Pract Neurol. 2016;16(3):174-175.


Ingram G, Barwick KES, Hartley L, et al. Distal hereditary motor neuropathy with vocal cord paresis: from difficulty in choral singing to a molecular genetic diagnosis. Pract Neurol 2016;16:247–51.

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