Brain, Vol. 122, No. 10, 1805-1806,
October 1999
© 1999 Oxford University Press
Editorial |
Genetic testing – to screen or not to screen?
Neurosciences Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
In this issue of Brain, the paper by Mallucci and colleagues details the clinical features and molecular characterization of the prion protein gene, PNRP, in a large English/Irish family with an autosomal dominant syndrome of presenile dementia with ataxia and other neuropsychiatric features (Mallucci et al., 1999
). The phenotype of the affected individuals in this pedigree varies widely, ranging from dementia at a young age to a cerebellar syndrome, and from marked early extrapyramidal features to pyramidal signs, myoclonus, emotional lability and a pseudobulbar syndrome. Over the years many different diagnoses had been attributed to the affected individuals, including multiple sclerosis, dementia, cortico-basal degeneration, Creutzfeldt–Jakob disease (CJD), new variant CJD and Gerstmann–Sträussler–Scheinker syndrome. Molecular studies, however, reveal that all the affected individuals within the pedigree share a common mutation in the prion protein gene, PNRP, namely the substitution of a valine residue for an alanine at codon 117. The authors conclude that the variability in phenotypic expression of this single prion protein mutation `emphasizes the logic of molecular classification of the inherited prion diseases', rather than classification by phenotypic and/or pathological criteria.
There are several other examples in neurological disease where a particular genetic mutation gives rise to a widely varying phenotype. In type I hereditary motor and sensory neuropathy (HMSN), more than 80% of cases have a chromosome 17p11.2 duplication, encompassing the peripheral myelin protein-22 (PMP-22) gene. Individuals affected with the disorder show a great range in severity of muscle weakness, wasting and other features, both amongst and between families, and indeed it is not uncommon to find identical mutant chromosome 17p genotypes in unaffected siblings of such patients (see Thomas et al., 1997). It is also recognized that point mutations in the PMP-22 gene can cause an HMSN type I phenotype, as can point mutations in the Po gene encoded on chromosome 1 (Harding, 1995).
A further example of molecular classification superseding that based on clinical phenomenology alone is seen with the inherited adult onset spinocerebellar ataxias, which were originally subdivided into types I, II and III depending on whether the disorder was one of a pure cerebellar syndrome (type III), a cerebellar syndrome plus pigmentary retinal degeneration (type II) or a cerebellar syndrome plus other features such as extrapyramidal symptoms, nuclear and internuclear eye movement disorders, dementia, and muscle wasting (type I). Molecular genetic advances now allow the classification of these disorders on the basis of the underlying genetic mutation with, in the main, expansions in the SCA1, 2 and 3 genes causing type I disease, expansions in SCA7 giving rise to type II disease and mutations in possibly SCA5 and also SCA6 occurring in type III disease. As with HMSN, however, there is great phenotypic variability within the genetically defined subtypes of these disorders (see Schöls et al., 1997).
Various theories are proposed to account for the variation in phenotype given identical genotype, including the influence of diverse environmental factors and the effect of so-called modifying genes on the disease process. An example of such a modifying gene is the presence of the ApoEe4 genotype in familial Alzheimer's disease, contributing to the timing and rate of progression of the dementia (Saunders et al., 1993). A further example of the influence of a modifying locus is seen in autosomal recessive spinal muscular atrophy. Mutations in the telomeric copy of a duplicated gene, the survival motor neuron gene, SMN, on chromosome 5q13 have been shown to underlie the disease (Lefebvre et al., 1995). Families have been well described with segregation of both severe type I disease, with death in infancy, and milder type II or III disease, associated with a normal lifespan. In such cases some, but not all, of the variation in disease severity relates to the number of SMN-like copy genes, SMNc, upstream from the telomeric gene, expression from which can partially compensate for mutations in SMNt (Burghes, 1997).
Clearly the availability of a screening test in a family such as that described herein by Mallucci and colleagues is of value in establishing a firm diagnosis where diagnosis has proved difficult. But in itself, this is of limited value in determining the likely clinical course and features, other than allowing the diagnosis of a fatal condition. What else can one do on a practical clinical level with this genetic information? Is it appropriate to offer presymptomatic screening to those unaffected individuals in the pedigree? It is perhaps telling that only a single unaffected individual in the large pedigree described opted for such screening. Parallels with presymptomatic screening for Huntington disease (HD) can be drawn. A recent paper by Almqvist and colleagues concludes that the likelihood of suicide, attempted suicide or psychiatric hospitalization after predictive testing for HD is no higher in those receiving a positive result than that of the general symptomatic HD population (Almqvist et al., 1999). Of course, as discussed in the accompanying editorial to this HD study (Bird, 1999), suicide, attempted suicide and psychiatric hospitalization are only a small fraction of the potential adverse results of genetic testing for HD, the full psychological impact of such testing being unquantifiable.
The issue of prenatal diagnosis also rears its head. Arguments for such testing are most compelling when the disorder is of early onset, and is fatal or results in significant morbidity. Whilst the latter are undoubtedly true in inherited prion disease, the disorder has a relatively late onset, as evidenced by the family in the paper under discussion.
What of screening of the PRNP gene in the wider population of individuals with `atypical presenile dementia or ataxia, particularly if seen in association with neuropsychiatric features' as suggested by Malluci and colleagues? With regard to testing cases within pedigrees with a history of an autosomal disorder with features suggestive of a an inherited PRNP disease mutation, the screening may indeed yield a definitive molecular diagnosis, with the consequent advice on prognosis and so-forth. But this may then lead to the consideration once again of screening of presymptomatic cases and of prenatal screening, issues for which there is no clear right way to proceed. And should isolated cases with similar clinical symptoms be screened? It would seem reasonable, as these authors suggest, to analyse the PRNP in cases where a diagnosis of new variant CJD is being considered. But is there really enough evidence to throw the screening net so wide as to include all isolated cases of atypical dementia with neuropsychiatric features? In motor neurone disease/amyotrophic lateral sclerosis, mutations in the Cu/Zn superoxide dismutase gene, SOD-1, are found in a small percentage of seemingly sporadic cases and in some 20% of autosomal dominant cases (Siddique and Deng, 1996). Screening of SOD-1 is just now beginning to be offered to asymptomatic relatives of ALS individuals in which SOD-1 mutations have been found. There is as yet no screening of SOD-1 in sporadic ALS cases in routine clinical practice.
`To screen or not to screen' isolated cases for genetic disorders of later onset for which there is no cure, no disease modifying treatment and no effective symptomatic intervention remains a question to which there is no easy answer.
References
Almqvist EW, Bloch M, Brinkman R, Craufurd D, Hayden MR. On behalf of an international Huntington disease collaborative group. A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease. Am J Hum Genet 1999; 64: 1293–304.[Web of Science][Medline]
Bird TD. Outrageous fortune: the risk of suicide in genetic testing for Huntington disease. [Review]. Am J Hum Genet 1999; 64: 1289–92.[Web of Science][Medline]
Burghes AHM. When is a deletion not a deletion? When it is converted. [Editorial]. Am J Hum Genet 1997; 61: 9–15.[Web of Science][Medline]
Harding AE. From the syndrome of Charcot, Marie and Tooth to disorders of peripheral myelin proteins. [Review]. Brain 1995; 118: 809–18.
Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80: 155–65.[Web of Science][Medline]
Mallucci GR, Campbell TA, Dickinson A, Beck F, Holt M, Plant G et al. Inherited prion disease with an alanine to valine mutation at codon 117 in the prion protein gene. Brain 1999; 1823–37.
Saunders AM, Strittmatter WJ, Schmechel D, St George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993; 43: 1467–72.
Schöls L, Amoiridis G, Büttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 1997; 42: 924–32.[Web of Science][Medline]
Siddique T, Deng H-X. Genetics of amyotrophic lateral sclerosis. [Review]. Hum Mol Genet 1996; 5 Spec No: 1465–70.[Abstract]
Thomas PK, Marques W Jr, Davis MB, Sweeney MG, King RHM, Bradley JL, et al. The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 1997; 120: 465–78.
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