Intrafamilial heterogeneity in hereditary motor neuron disease

Appelbaum, James S.; Roos, Raymond P.; Salazar-Grueso, Edgar F.; Buchman, Aron S.; Iannaccone, Susan T.; Glantz, R.; Siddique, Teepu; Maselli, R.

doi:10.1212/wnl.42.8.1488

Cited by 45 publications

(11 citation statements)

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“…There are many case studies reporting the co-occurrence of SMA and ALS within a family (Appelbaum et al, 1992 ; Camu and Billiard, 1993 ; Orrell et al, 1997 ; Corcia et al, 2002a ) which suggests that SMN1 deficiency may lead to ALS in addition to SMA. SMN1 deletions, however, have not been observed in either familial or sporadic ALS patients (Orrell et al, 1997 ; Corcia et al, 2002a ).…”

Section: Smn1 and Smn2 Cnvs In Alsmentioning

confidence: 99%

Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases

Butchbach

2016

Front. Mol. Biosci.

134

122

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Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1) on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7) and produce a protein that is both unstable and less than fully functional. Although only 10–20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs) in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases.

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Section: Smn1 and Smn2 Cnvs In Alsmentioning

confidence: 99%

Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases

Butchbach

2016

Front. Mol. Biosci.

134

122

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“…In familial ALS related to superoxide dismutase 1 (SOD1) gene mutations, the same mutation can produce the phenotypes of PLS and ALS in affected family members, suggesting that PLS is a form of ALS. 12,13 Nonetheless, the isolated UMN variety of atypical ALS is more benign (than typical ALS) in its clinical course. 14 Gradually progressive spastic paraparesis is the major clinical feature in PLS, with evolution to quadriparesis in some patients late in the disease course.…”

Section: Primary Lateral Sclerosis (Pls)mentioning

confidence: 99%

“…In addition, in some families, the same SOD1 mutation can cause the phenotypes of PMA or ALS in affected families. 12,13 This suggests that PMA represents a form of ALS. Nevertheless, PMA often occurs in younger males, and it follows a more benign clinical course.…”

Section: Progressive Muscular Atrophy (Pma)mentioning

confidence: 99%

Atypical Motor Neuron Disease and Related Motor Syndromes

Verma¹,

Bradley²

2001

Semin Neurol

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There is an imperative need for the early diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) in the current era of emerging treatments. When evaluating the patient with ALS/MND, the neurologist must consider a number of other motor neuron disorders and related motor syndromes that may have clinical features resembling ALS/MND. The revised Airlie House-El Escorial diagnostic criteria have been established through the consensus of experts meeting at workshops. However, by definition, using these criteria a patient is likely to have fairly advanced disease at the time of a definitive ALS/MND diagnosis. The reasons for the difficulty in making an early ALS/MND diagnosis are several. No surrogate diagnostic marker currently exists for ALS/MND. ALS/MND at its onset is heterogeneous in clinical presentation, its clinical course is variable, and several clinical variants are recognized. In addition, certain motor syndromes, such as monomelic amyotrophy, postpolio muscular atrophy, and multifocal motor neuropathy, can clinically mimic ALS/MND. Therefore, not only may the diagnosis of ALS/MND be clinically missed in the early stages, but worse, the patient may be wrongly labeled as having ALS/MND. The diagnosis of ALS/MND requires a combination of upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Motor syndromes in which the deficit is restricted to the UMN or LMN through the entire course of the disease are described as atypical MND in this review. Approximately 5% of patients with ALS/MND have overt dementia with a characteristic frontal affect. ALS/MND with parkinsonism and dementia is rare outside the western Pacific region. The clinical course of motor disorder in these overlap syndromes does not differ from that in typical ALS/MND.

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“…Reports of the coexistence of SMA and ALS within families suggest the possibility of a common genetic basis. 12,13 Therefore, we elected to explore a possible role for the NAIP and SMN genes in the pathogenesis of FALS and SALS. Genomic DNA specimens from 69 patients with non-SOD1-mutated FALS and 194 patients with SALS were analyzed for the absence of exon 6 in the NAIP gene and for deletions or aberrant single strand conformational polymorphism bands in exons 7 and 8 of the SMN gene.…”

mentioning

confidence: 99%