The relationship of spinal muscular atrophy to motor neuron disease: Investigation of SMN and NAIP gene deletions in sporadic and familial ALS
Introduction
The terms ‘motor neuron disease’ (MND) and ‘amyotrophic lateral sclerosis’ (ALS) have been used interchangeably, to describe a progressive neurodegenerative disorder affecting both upper and lower motor neurons to variable degrees. The clinical criteria for a diagnosis of ‘definite’ ALS require the demonstration of both upper and lower motor neuron signs (Brooks, 1994). The classification also recognises incomplete clinical manifestations, with consequent reduced certainty of ALS, including presentation with lower motor neuron signs only (sometimes referred to as ‘progressive muscular atrophy’ (PMA)). This may cause diagnostic difficulties since exclusively lower motor neuron signs occur in other ‘motor neuron diseases’, including spinal muscular atrophy (SMA).
Spinal muscular atrophy (SMA) of childhood may be categorised as severe (Werdnig-Hoffman disease), intermediate, and mild (Kugelberg-Welander disease). Most cases appear to be inherited as recessive conditions, with phenotypic variation within families suggesting different non-allelic mutations, or different mutations within the same gene. All three types have been mapped to the same region of chromosome 5 (5q11.2–13.3), which has been further refined to the region 5q12.2–13, with continued mapping identifying gene deletions. Mutations in two different genes have now been identified; there are the survival motor neuron gene (SMN) (Lefebvre et al., 1995), and the neuronal apoptosis inhibitory protein gene (NAIP) (Roy et al., 1995). Recent studies have also demonstrated these mutations in adult SMA with limb-girdle phenotype (Brahe et al., 1995; Clermont et al., 1995). In 5q-linked SMA patients, more extensive features such as tongue fasciculation, also found in MND with bulbar involvement, are common findings, especially in early-onset cases (Munsat et al., 1990).
In investigating the genetics of familial ALS (FALS), we have ascertained families on the basis of a dignosis of amyotrophic lateral sclerosis in at least one affected member (DeBelleroche et al., 1995), but within individual families, we found that some members had a predominantly or exclusively lower motor neuron syndrome. Such patients had sometimes been given the diagnosis of ‘chronic spinal muscular atrophy’ by their attending physicians.
Shaw et al. (1991) reported PMA in two brothers, one with multiple colonic adenomata, and the other with invasive colonic carcinoma. Both brothers presented with similar clinical syndromes at 53 and 44 years, with asymmetrical, predominantly upper limb and neck muscle weakness, which progressed to involve the lower limbs and bulbar function, leading to death after 15 months. No upper motor neurons signs were present on examination, and the pyramidal tracts appeared normal at all levels on histopathological examination in the second patient (no post mortem examination was performed on the first). Four male siblings had all died within the first few weeks of life, but no precise cause was established. Familial adenomatous polyposis accounts for about 1% of colorectal cancer; the gene was mapped by linkage analysis to chromosome 5q (region of 5q21–22), and subsequently the gene was identified and characterised. Shaw et al. (1992) also reported a family in which a 67-year-old grandfather had an asymmetrical onset of arm weakness, progressing to involve both arms, legs, and bulbar function. He died after 2 years from pneumonia. The clinical and pathological features were of PMA, and again no upper motor neuron features were present. He had five grandchildren, four of whom died by the age of 9 months with the progressive lower motor neuron syndrome of Werdnig-Hoffman disease (SMA Type I).
Given these instances of a familial association of adult motor neuron disease and spinal muscular atrophy syndromes, the similar process of lower motor neuron loss in ALS and SMA, and the possibility of autosomal recessive inheritance in both sporadic and single generation familial ALS, we investigated patients with sporadic and familial ALS (including patients with PMA phenotype) for the mutations of the SMN and NAIP genes recently described in SMA.
Section snippets
Methods
54 adult patients with sporadic ALS, and a single affected representative of 10 families with a family history of ALS in one generation only (and no SOD-1 mutation), were studied. The inheritance in these individuals and families was consistent with possible autosomal recessive inheritance. The assessment of the clinical condition of the patient and of affected relatives was performed directly where possible, or by access to local assessments and records where available. The extent of the upper
Results
A total of 65 patients were studied (48 male, 17 female). 54 patients were sporadic (mean age 53.1 ± 11.4 (SD) years), 53 having features of ALS including upper motor neuron signs, and one with only lower motor neuron signs and a clinical diagnosis of PMA. This patient had an asymmetrical onset in the upper limbs, and died at age 62 years, with a disease duration of 5 years, and no upper motor neuron features on repeated examination. 10 patients from different unigeneration families with ALS
Discussion
SMN and NAIP mutations were not found in sporadic ALS patients or in families with pedigrees consistent with autosomal recessive inheritance of ALS, including 2 individuals with clinical diagnoses of PMA or SMA. Deletions of exons 7 and 8 of the telomeric copy of the SMN gene were originally identified in of patients with childhood SMA, with another lacking the telomeric copy of exon 7 alone, and having intragenic or splice junction mutations (Lefebvre et al., 1995). 45% of
Conclusion
In the patients we investigated it appeared that sporadic and familial ALS, including asymmetrical PMA syndromes, were not associated with the SMN or NAIP mutations recently described in patients with childhood onset or adult limb-girdle pattern SMA, and a refinement of the nosology may eventually be possible if the chronic asymmetrical spinal muscular atrophies of the adult prove not to have the same genetic basis as the chromosome 5q forms. In the interim, it would seem more appropriate to
Acknowledgements
We thank all the patients and families who have helped in this study and all their neurologists, general practitioners and clinical geneticists. We thank Juliet Greenwood for her work as genetic research nurse in support of this project. The work has been supported and funded by the Motor Neurone Disease Association and the Special Trustees of Charing Cross and Westminster Hospitals. We acknowledge the help and use of the resources of the MRC Human Genome Mapping Project.
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